Prognostic Factor In Hodgkin Lymphoma Research Articles

Plateletcrit as a prognostic marker in Hodgkin lymphoma: A pilot study

Background/Aim: Hodgkin lymphoma (HL) is a lymphoproliferative malignancy associated with inflammation. Plateletcrit (PCT) is a mean platelet volume (MPV) and platelet count-derived marker that is useful for evaluating malignancies and inflammatory diseases. International Prognostic Score (IPS-7) and more recently, IPS-3, are two indices indicating the prognosis of patients; however, widespread and easy to interpret prognostic markers are still needed for HL evaluation. Very few studies evaluating the prognostic significance of platelet indices in HL have been published, so we aimed to show the relationship between PCT and other adverse prognostic factors in HL and evaluate whether PCT can be used as a prognostic marker in HL. Methods: After excluding patients with insufficient data, 75 patients diagnosed with HL and 150 healthy controls were retrospectively analyzed in this case-control study. Evaluation of relationship of PCT and adverse HL prognostic factors, such as age, gender, hemoglobin, leukocytes, lymphocytes (absolute value and percentage), albumin, Ann Arbor stage and B symptoms, IPS-3 and-7 prognostic scores and post-treatment relapse, and progression-free survival of the patients were studied. Results: Mean MPV values were significantly lower, mean platelet values were significantly higher inpatient group (all P<0.001). Patients with high sedimentation had significantly higher mean PCT than those without (P=0.031) and a moderately positive correlation between PCT and sedimentation were found (r=0.33, P<0.01). Mean PCT values after treatment significantly decreased compared to baseline levels (P<0.001). Conclusion: PCT may be useful as a prognostic marker in HL. Further studies were needed to evaluate the relationship between PCT and other prognostic factors, such as IPS-3 and -7.

Prognostic and Therapeutic Role of CD15 and CD15s in Cancer.

Simple SummaryCD15 (Lewis X) is a typical myeloid antigen presented in myeloid and monocytic lineages of cells. This molecule interacts with E-, L- and P-selectins, which allows for adhesion with endothelial cells. CD15 is found on various cancer cells, including renal cancer, prostate and bladder cancers, acute leukaemias, hepatocellular carcinoma, breast cancer and melanoma cells. Its high expression can serve as a prognostic marker for patients and is a potentially valuable target for immunotherapy against cancer. Blockage of the antigen’s function results in reduced metastatic potential and it may be an immunotherapeutic target. CD15s is a sialyl derivative of CD15; however, unlike the high expression of CD15, which is a prognostic factor in Hodgkin lymphoma, CD15s relates to poor prognosis for patients. CD15 is considered a marker of cancer stem cells. This review presents a comprehensive description of the prognostic role of CD15 and CD15s and their use in anticancer therapy.CD15 (Lewis X/Lex) is a fucosyl (3-fucosly-N-acetyl-lactosamine) moiety found on membrane proteins of various cancer cells. These cancers include renal cancer, prostate and bladder cancers, acute leukaemias, hepatocellular carcinoma, breast cancer and melanoma. The biological role of CD15 is interaction with E-, L- and P-selectins (adhesion molecules), allowing for adhesion with endothelial cells. In this way, cancer cells start to interact with the endothelia of blood vessels and consequently move out from the blood flow to the surrounding tissues. Blockage of the antigen’s function results in reduced metastatic potential. Moreover, the molecule may be a therapeutic target against cancer in monoclonal antibody-based therapies. CD15 may serve as a prognostic marker for patients and there are high hopes for its use in the immunotherapeutic treatment of tumours. CD15s is a sialyl derivative of CD15 that possesses its own unique characteristics. Its soluble form may act as a competitive inhibitor of the interaction of cancer cells with epithelial cells and thus disallow migration through the vessels. However, the prognostic relevance of CD15 and CD15s expression is very complex. This review presents a comprehensive description of the role of CD15 and CD15s in cancer development and metastasis and overviews its significance for clinical applications.

Expression of the novel tumour suppressor sterile alpha motif and HD domain‐containing protein 1 is an independent adverse prognostic factor in classical Hodgkin lymphoma

The expression patterns and prognostic significance of sterile alpha motif and HD domain-containing protein 1 (SAMHD1) protein in the neoplastic Hodgkin and Reed Sternberg (HRS) cells of Hodgkin lymphoma (HL) were investigated in a cohort of 154 patients with HL treated with standard regimens. SAMHD1 expression was assessed by immunohistochemistry using diagnostic lymph node biopsies obtained prior to treatment. Using an arbitrary 20% cut-off, SAMHD1 was positive in HRS cells of 48/154 (31·2%) patients. SAMHD1 expression was not associated with clinicopathologic parameters, such as age, gender, stage or histologic subtype. In 125 patients with a median follow-up of 90months (7-401months), SAMHD1 expression in HRS cells significantly correlated with inferior freedom from progression (FFP) (P=0·025), disease-specific survival (DSS) (P=0·013) and overall survival (OS) (P=0·01). Importantly, in multivariate models together with disease stage, histology subtype and type of treatment as covariates, SAMHD1 expression retained an independent significant association with unfavourable FFP (P=0·005) as well as DSS (P=0·022) and OS (P=0·018). These findings uncover the significance of a novel, adverse prognostic factor in HL that may have therapeutic implications since SAMHD1 inhibitors are now available for clinical use.

Prognostic Role of the Red Blood Cell Distribution Width (RDW) in Hodgkin Lymphoma

Simple SummaryThe red blood cell distribution width (RDW) increases in inflammatory conditions and is described as having a prognostic role in different types of cancer. As Hodgkin lymphoma (HL) has a proinflammatory background, we aim to study the prognostic role of RDW in HL. We report in a large retrospective series of homogenously treated HL, for the first time, that RDW is a simple, cheap, and easily available prognostic factor in HL, that identifies a group with worse EFS, OS, and a higher potential incidence of secondary malignancies. RDW seems to be related to most adverse prognostic factors in HL and this may make RDW a good candidate to be included in current or new prognostic scores for HL.The red blood cell distribution width (RDW) is a parameter available from an automated blood count, which measures the degree of heterogeneity of erythrocyte volume and increases in inflammatory conditions. The prognostic role of RDW has been described in different types of cancers. Hodgkin lymphoma (HL) is a hematological malignancy, known to have a proinflammatory background. We aim to study the prognostic role of RDW in HL. We retrospectively analyzed 264 patients with HL from two hospitals in the Balearic Islands between 1990 and 2018. Higher levels of RDW were independently related to anemia, B-symptoms, and low albumin. In age ≥45 years, the presence of lymphopenia and higher RDW were independently associated with worse event-free survival (EFS) and overall survival (OS). Long-term incidence of secondary malignancies was significantly higher in patients with higher RDW, particularly lung cancer. In conclusion, we report for the first time that RDW is a simple, cheap, and easily available prognostic factor in HL that identifies a group with worse EFS, OS, and a higher potential incidence of secondary malignancies. RDW seems to be related to most adverse prognostic factors in HL, making RDW an excellent candidate to be included in prognostic scores for HL.

Prognostic Implication of the Absolute Lymphocyte to Absolute Monocyte Count Ratio in Patients With Classical Hodgkin Lymphoma Treated With Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine or Equivalent Regimens.

Low absolute lymphocyte count (ALC) to absolute monocyte count (AMC) ratio (ALC/AMC) is an independent prognostic factor in Hodgkin lymphoma (HL), but different cutoffs (1.1, 1.5, and 2.9) have been applied. We aimed to validate the prognostic significance of ALC/AMC in 537 homogenously treated (doxorubicin, bleomycin, vinblastine, and dacarbazine or equivalents ± radiotherapy) classical HL patients at various cutoffs. The median ALC/AMC was 2.24 (0.44-20.50). The median AMC was 0.653 × 10(9)/L (0.050-2.070). Lower ALC/AMC was associated with established markers of adverse prognosis. In total, 477 (89%), 418 (78%), and 189 (35%) patients had an ALC/AMC ratio of ≥1.1, ≥1.5, and ≥2.9; respectively; 20% had monocytosis (≥0.9 × 10(9)/L). Ten-year time to progression (TTP) was 77% versus 55% for patients with ALC/AMC ≥1.1 and <1.1 (p = .0002), 76% versus 68% for ALC/AMC ≥1.5 and <1.5 (p = .049), 77% versus 73% for ALC/AMC ≥2.9 and <2.9 (p = .35), and 79% versus 70% for ALC/AMC ≥2.24 and <2.24 (p = .08), respectively. In stages ΙΑ/ΙΙΑ and in patients ≥60 years old, ALC/AMC had no significant effect on TTP. In advanced stages, ALC/AMC was significant only at the cutoff of 1.1 (10-year TTP 67% vs. 48%; p = .016). In younger, advanced-stage patients, the differences were more pronounced. In multivariate analysis of TTP, ALC/AMC < 1.1 (p = .007) and stage IV (p < .001) were independent prognostic factors; ALC/AMC was independent of International Prognostic Score in another model. ALC/AMC was more predictive of overall survival than TTP. At the cutoff of 1.1, ALC/AMC had independent prognostic value in multivariate analysis. However, the prognostically inferior group comprised only 11% of patients. Further research is needed prior to the widespread use of this promising marker.

Neutrophil - Lymphocyte Ratio (NLR) at Diagnosis Is an Independent Prognostic Factor in Patients with Nodular Sclerosis Hodgkin Lymphoma: Results of a Large Multicenter Study Involving 990 Patients

▪BackgroundThere is an increasing amount of data showing that tumor microenvironment, host immunity and inflammatory responses play an important role in determining the clinical course and outcome in patients with malignant lymphoma. Several investigators have considered the absolute monocyte count (AMC) as a surrogate biomarker of tumor associated macrophages within the tumor microenvironment, the absolute lymphocyte count (ALC) as an important biomarker of tumor infiltrating lymphocytes, reflecting host immunity status, and the absolute neutrophil count (ANC) as indicative of the systemic inflammatory response to malignancy. All the above parameters have been suggested as significant prognostic factors in Hodgkin lymphoma (HL). The aim of the present retrospective study was to verify in whether neutrophil : lymphocyte ratio (NLR) can be utilized as an independent prognostic factor in a large cohort of patients with nodular sclerosis (NS) subtype HL.Patients and MethodsThis retrospective analysis included data from 1017 patients diagnosed with NS HL according to the WHO criteria. We reviewed the clinical and laboratory data of consecutive "therapy-naïve" patients, treated in different centers in Italy and in Israel between 1993-2012, after approval by local institutional review boards.Patients had received different combination chemotherapy regimens : doxorubicin, bleomycin, vinblastine and darcarbacine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), Vinblastine, bleomycin, and methotrexate (VBM), bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) and Stanford V.The cut-off for NLR was determined from the analysis of the log (HR) as a function of NLR, using Cox cubic spline regression. The importance of the covariate was examined using the bootstrap inclusion frequency (BIF) with log-likelihood ratio test, (cut-off of 0.05), over 1000 resample of hierarchical Cox PH model, where NLR was added to IPI.Progression free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier estimates and risk groups compared using the log-rank test .We also performed Cox proportional hazard analysis. The effect size of risk was reported as a hazard ratio (HR) with the associated 95% confidence interval (CI95).ResultsOf the 1017 patients, 990 (97%) had data on both IPS and NLR. Median age was 31 years (range 17-69) and 49% were males. The 5-yr PFS and OS after median follow-up of 85 months (range 1-244 months) were 81% (95CI 78-84) and 91% (95CI 89-93), respectively, for all patients. The log(HR) for PFS and OS varied linearly for the function of NLR and the cut-off was selected at 6 for both outcomes. Patients with NLR >6 had a worse PFS and OS compared to NLR ≤6 (84% vs 75% and 92% vs 88% at 5-years, respectively). Figure 1). For PFS the HR for patients with NLR>6 was 1.65 (CI95 1.25-2.18, p<0.001), while for OS the HR was 1.82 (CI95 1.25-2.65, p=0.002). When adjusted in Cox PH regression by IPS score, NLR >6 maintained it's prognostic value in both PFS (HR 1.49, CI95 1.12-1.98, p=0.006; with a BIF of 76%) and OS (HR 1.56, CI95 1.06-2.29, p=0.023; with a BIF of 64%). This was also evident in continuous form for NLR both s in PFS (HR adjusted by IPS 1.02, CI95 1.01-1.04, p=0.010) and OS (HR adjusted by IPS 1.02, CI95 1.01-1.05, p=0.039).Conclusion.Although the majority of patients with HL can be cured, about 1/3 of those with advanced stage disease relapse or progress after first line therapy. Several approaches have been employed to recognize high risk patients, including gene expression profiling and positron emission tomography. However these procedures are expensive and not always easy to perform and interpret. In conclusion, despite it is retrospective nature, our study shows that NLR can reliably identify high risk patients at the time of diagnosis. This easily obtainable simple prognostic parameter could well be utilized to improve the discriminating power of the IPS score in patients with NS HL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PRAME Expression and Its Clinical Relevance in Hodgkin's Lymphoma

Objectives: Although Hodgkin's lymphoma (HL) is one of the most curable cancers in adult patients, new targets have to be defined in cases resistant to traditional chemotherapy. The preferentially expressed antigen of melanoma (PRAME) is a cancer testis antigen and its expression is very scarce or absent in normal tissues. For this reason PRAME is a promising candidate for tumor immunotherapy. The aim of this study is to understand the correlation of PRAME expression with prognostic factors in HL, to determine the utility of PRAME as a targeted molecule for immunotherapy and to compare real-time polymerase chain reaction (real-time PCR) and immunohistochemistry (IHC) for the detection of PRAME. Methods: In 82 patients, PRAME was studied using real-time PCR and IHC. Data analyses were performed using statistical methods such as t test, Mann-Whitney U test, χ² test, Kaplan-Meier method, log-rank test and Cox regression analysis. Results: PRAME was detected in 15 (18.3%) patients using IHC and in 8 (9.8%) patients using real-time PCR. A correlation was found between PRAME positivity and higher International Prognostic Score (p = 0.039). PRAME positivity detected using real-time PCR was found to be correlated with shorter disease-free survival (DFS) and overall survival (OS, p = 0.0005). Discussion: The demonstration of PRAME especially in histiocytes and Reed-Sternberg cells may provide guidance for immunotherapy. Although PRAME positivity increases the risk for death (3.56), independent risk factors that affected DFS and OS occurred in advanced age and high-risk groups. Conclusion: Although real-time PCR is sensitive in the detection of PRAME, IHC can be another useful method. Despite the need for studies conducted on larger patient samples, PRAME expression is considered as a poor prognostic parameter in HL.

Differential Impact of Relative Dose-Intensity Reductions (DIR) in Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP21 or R-CHOP14

Introduction:DLBCL is the more common non Hodgkin lymphoma. This is an aggressive lymphoma that is treated with a standard chemotherapy regimen: R-CHOP. In the last years attempts have been done to improve the outcome both increasing dose-density (CHOP14) or intensity (CHOEP, ACVBP, autologous stem cell transplantation) without obtaining benefit in terms of survival. This has allowed setting R-CHOP administered every 21 days (R-CHOP21) as the standard treatment for DLBCL patients.RDI is an important issue to consider when treating malignancies. Although this a well-known prognostic factor in Hodgkin lymphoma, scarce information has been published in DLBCL.Objective:The purpose of this study is further analyzing the prognostic impact of RDI in two cohorts of DLBCL patients treated with R-CHOP21 or R-CHOP14, to evaluate its differential impact when increasing dose density.Material and methods:All patients diagnosed of DLBCL from January-1999 to June-2013 at University Hospital Son Espases were retrospectively identified from Pathology Department registry to avoid selection bias. Only patients treated with R-CHOP21 or R-CHOP14 +/- radiotherapy were included (N=115). To increase the R-CHOP14 cohort we added also all patients treated with R-CHOP14 in the same time period in two additional hospitals (Hospital Son Llatzer of Palma and Hospital del Mar of Barcelona) identified from their Pharmacy registries to avoid selection bias (N=42). Other regimes, consolidations or maintenance were excluded. Table 1 shows main characteristics of the global series (N=157).RDI represents the ratio of the amount of a drug actually administered to the amount planned for a fixed time period. RDI was calculated as previously described. Briefly, RDI of each drug was obtained followed by an average of RDI in CHOP consisting in the sume of RDI of the 3 drugs divided by 3.Main prognostic factors at diagnosis in DLBCL were obtained, including international prognostic index (IPI) factors. Evaluations were carried out following standard guidelines.Results:Overall response and complete response rates were similar in both groups:86% and 76% for R-CHOP21 and 94% and 74% for R-CHOP14(p=0.17 and p=0.85, respectively). Median follow-up for alive patients was 68 months (4-156). There were no differences between the two cohorts in terms of either OS or PFS (Figure 1). In the R-CHOP21, both a reduction higher than 15% in RDI [RR 7.41 (2.51-21.83); (p<0.001)] and an unfavorable R-IPI [RR 2.99 (1.1-8.16); (p=0.032) were independently associated with a worse OS. For PFS only a reduction higher than 15% in RDI [RR 4.41 (1.77-10.99) (p=0.001) was independently associated to worse PFS. By contrast, in the R-CHOP14 group an unfavourable NCCN-IPI [RR 8.74 (2.23-34.25); (p=0.002)] and the presence of B-symptoms [RR 5.13 (1.98-13.3); p=0.001)] was independently associated to worse OS and having a AA stage III-IV [RR 5.09 (1.14-22.62); p=0.032)] and bulky disease [RR 3.95 (1.46-10.7); p=0.007)] were independently related to worse PFS. RDI reductions did not show any significant impact in OS or PFS in patients treated with R-CHOP14 (Figure 2).Conclusions:Overall in our series there were no differences in terms of response or survival between patients treated with R-CHOP21 or R-CHOP14. A higher rate of RDI reduction was observed in the R-CHOP14 group. However, the impact of RDI reductions on response and survival was only observed in the R-CHOP21 group but not in patients treated with R-CHOP14. We can conclude that R-CHOP21 and R-CHOP14 are equivalent regimens in terms of response and survival only if RDI reductions are avoided. For patients receiving R-CHOP21 we recommend using clinical and support measures in order to avoid RDI reductions.Table 1Main clinical characteristics of the patients.R-CHOP21 group(n=74)R-CHOP14 group(n=83)PAge (median & range)65 (25-88)55 (15-79)0.005Sex (M/F)34 (46%) / 40 (54%)51 (61%) / 32 (39%)0.056ECOG PS > 117 (23%)18 (22%)0.85Ann Arbor stage III-IV40 (54%)48 (58%)0.75B-symptoms25 (34%)26 (31%)0.86Elevated LDH33 (46%)40 (49%)0.75> 1 extranodal site8 (11%)19 (23%)0.057Bulky disease23 (31%)34 (41%)0.24R-IPI unfavorable24 (32%)26 (32%)1NCCN-IPI:- Low- Low-intermediate- High-intermediate- High9 (13%) 27 (39%) 26 (38%) 7 (10%)17 (21%) 35 (44%) 24 (30%) 4 (5%)0.31ElevatedBeta-2-microglobulin32 (49%)31 (39%)0.24Radiotherapy27 (36%)27 (32%)0.62 [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Baseline metabolic tumour volume is an independent prognostic factor in Hodgkin lymphoma.

The presence of a bulky tumour at staging in Hodgkin lymphoma (HL) is a predictor of a poor outcome. The total metabolic tumour volume at baseline (TMTV0) computed on PET may improve the evaluation of tumour burden. To explore the clinical usefulness of TMTV0, we compared the prognostic value of TMTV0, tumour bulk and interim PET response in a retrospective single-centre study. From 2007 to 2010, 59 consecutive patients with a first diagnosis of HL were treated in our institution. PET was done at baseline (PET0) and after two cycles of chemotherapy (PET2), and treatment was not modified according to the PET2 result. TMTV0 was measured with a semiautomatic method using a 41 % SUVmax threshold. SUVmax reduction between PET0 and PET2 (ΔSUVmaxPET0-2) was also computed. Based on ROC analysis, patients with a ΔSUVmaxPET0-2 >71 % were considered good responders and a TMTV0 >225 ml was considered to represent hypermetabolic bulky disease. Median TMTV0 was 117 ml and 17 patients (29 %) had a TMTV0 >225 ml. TMTV0 (>225 ml vs. ≤225 ml) and tumour bulk (<10 cm vs. ≥10 cm) were predictive of 4-year PFS: 42 % vs. 85 % (p = 0.001) and 44 % vs. 79 % (p < 0.03), respectively. In multivariate analysis, using ΔSUVmaxPET0-2, TMTV0 and bulky tumour as covariates, only ΔSUVmaxPET0-2 (p = 0.0005, RR 6.3) and TMTV0 (p < 0.006, RR 4.4) remained independent predictors of PFS. Three prognosis groups were thus identified: ΔSUVmaxPET0-2 >71 % and TMTV0 ≤225 ml (n = 37, 63 %), ΔSUVmaxPET0-2 = <71 % or TMTV0 >225 ml (n = 17, 29 %), and ΔSUVmaxPET0-2 = <71 % and TMTV0 >225 ml (n = 5, 8 %). In these three groups the 4-year PFS rates were 92 %, 49 %, and 20 % (p < 0.0001), respectively. TMTV0 is more relevant than tumour bulk for predicting the outcome in patients with HL, and adds a significant prognostic insight to interim PET response assessment. The combination of TMTV0 and ΔSUVmaxPET0-2 made it possible to identify three subsets of HL patients with different outcomes. This may guide clinicians in their choice of therapeutic strategy.

Positron Emission Tomography Combined with Computed Tomography (PET-CT) Should Substitute Classical CT in the Initial Staging of Hodgkin Lymphoma (HL).

AbstractAbstract 2632 Background.Disease stage remains the most powerful prognostic factor in HL and guides optimal therapy. Despite high (18)F-FDG avidity in HL, PET-CT is not mandatory in the initial staging of HL. To establish if PET-CT should substitute classical CT in the initial staging of HL we evaluate the influence (18)F-FDG PET-CT on HL stage migration and its impact on treatment selection. Materials and methods.96 HL patients (pts) underwent conventional CT and PET-CT staging with a median time 19 days between two tests; the stage of HL was defined separately based on CT or PET-CT results that were read afresh independently by the radiologist and the nuclear medicine specialist. The number of nodal areas and extranodal sites involved, detected by each imaging modality were scored and compared. In CT assessment, classical radiologic criteria were used. Lymph nodes >15mm in longest dimension were considered pathological. In PET-CT assessment sites of nonphysiological uptake above background were reported as pathologically involved. Focal uptake in the spleen, liver and bones/bone marrow (BM) was treated as indicative of HL involvement. Diffuse uptake in the spleen was also assumed to be indicative of HL involvement if the uptake was greater than the liver uptake. In contrast diffuse uptake in the BM even if higher than the liver was conservatively not treated as HL infiltration. Results.The number of patients in stage I, II, III, IV was 5, 49, 28, 14 using CT and 7, 37, 22, 30 using PET-CT. In 33 (34%) patients PET-CT changed HL stage, specifically 27 (28%) pts were upstaged whereas 6 (6,3%) pts were downstaged compared to CT results. As a consequence 20 (21%) patients required treatment modification: reduction in 4 pts and intensification in 16 pts. All 4 patients with treatment reduction had CT stage III, most (3 pts) were without B symptom. The stage was reduced due to lack of (18)F-FDG uptake in increased (>15mm) single nodes on the other site of diaphragm. All 16 pts with treatment intensification had CT stage II and two third suffered from B symptoms. The stage was upgraded mainly to the extranodal involvements (47 sites in 26 pts) detected by PET-CT that were not seen on conventional CT. Among them the most often was bone marrow (10 pts), following by spleen (5pts) and lung (2pts) involvement. In 9 pts two or more coexisting locations were detected. Extended nodal involvement seen in PET-CT compared to CT resulted in upstage only in one patient despite detection of more nodal areas compared to CT; Depending on location, 36–56% of these nodes were smaller than 15mm in greatest dimension. Moreover, PET-CT helped to define atypically located small nodes in 25 patients; in 7 of them radiotherapy was a part of radical treatment and the omission of PET-CT could have resulted in a geographical miss. BM biopsy was positive in 3 of 96 pts; in all cases PET-CT revealed diffuse BM uptake higher than the liver uptake.Table 1The reasons for upstaging. In brackets number of patients with B symptomslocationFinal (PET-CT) stageNo of ptsInitial (CT) stageIIIIIIBone marrowIV1003 (2)7 (7)SpleenIII505 (4)ndLungsIV201 (0)1 (0)Lymph nodesII11 (0)00More than 1 locationIII, IV905 (4)4 (4)Total27114 (10)12 (11) Conclusions.The addition of PET-CT in the initial staging of HL modifies the disease stage in a significant proportion of patients, leading to treatment modification in majority of them. The impact of PET-CT on staging is of special significance in patients with CT stage II especially with B symptoms. Disclosures:No relevant conflicts of interest to declare.

Expression of COX-2 on Reed-Sternberg cells is an independent unfavorable prognostic factor in Hodgkin lymphoma treated with ABVD

AbstractCyclooxygenase 2 (COX-2) is an inflammatory enzyme involved in the pathogenesis and prognosis of several malignancies. In the present study, we investigated the prognostic value of COX-2 expression in a large (N = 242), uniformly treated Hodgkin lymphoma (HL) population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analysis was done, including comparing the most recognized clinical variables: the early- and advanced-stage subgroups. COX-2 was expressed on Reed-Sternberg cells in 37% of patients. There were no differences in the distribution of clinical variables according to COX-2 expression. With a median follow-up time of 58 months, PFS at 5 years was 60% and 79% for COX-2+ and COX-2− patients, respectively (P = .003). The overall survival was 73% and 91%, respectively (P < .001). The major impact on prognosis was observed in the early AA stage (I-II) group. In fact, in these low-risk groups the expression of COX-2 defined a group with significantly worse progression-free and overall survival. In conclusion, COX-2 was expressed on Reed-Sternberg cells in one-third of HL patients and was a major independent, unfavorable prognostic factor in early-stage HL. We conclude that COX-2 may be a major prognostic variable in HL and a potential therapeutic target.

“Large Mediastinal Tumor Mass” is a Prognostic Factor in Hodgkin Lymphoma (HL): Is the Definition on the Basis of a Chest Radiograph in the Era of CT Obsolete?

“Large Mediastinal Tumor Mass” is a Prognostic Factor in Hodgkin Lymphoma (HL): Is the Definition on the Basis of a Chest Radiograph in the Era of CT Obsolete?

Hodgkin lymphoma of the elderly veterans: Veterans Affairs Cancer Registry analysis.

9138 Background: Hodgkin lymphoma (HL) is a very treatable disease that is known to have a bimodal age distribution. Unlike the younger patients,elderly patients with HL have a prognosis which is still unsatisfactory. Prospective studies selected for elderly patients are rare and randomized trials are missing. We studied the clinical and pathological characteristics, treatment received and survival outcomes of patients ≥60yrs and <60 yrs using the Veterans Affair Cancer Registry database. Methods: Retrospective analysis of 947 patients diagnosed with Hodgkin disease from 1995-2003 was obtained.Demographics, histology, tobacco use, agent orange exposure, stage at presentation, presence of B symptoms and type of treatment received data was extracted.Variables were analyzed with Kaplan-Meier and Cox models. Results: Of the 947 patients 38.8% were >60yrs and 61.2% were <60. Racial distribution among the elderly and the younger HL patients were similiar. In histological subtypes there was an increased prevelance of lymphocyte depleted and nodular lymphocyte predominant subtypes among older patients. Older patients also had higher incidence of stage IV disease compared to their younger counterparts. Overall survival was significantly higher in the <60 years age group (17.83 mos vs 3.23mos). Median survival was better in the <60 years age group when compared for stage at presentation, type of histology, treatment received and absence of B symptoms (P <0.0001) .Multivariate analysis revealed Stage 1(HR=0.68; 0.48-0.95; p=0.024), age <60 years (HR=0.31; 0.26-0.38; p<0.0001) was associated with improved outcomes whereas Lymphocyte depleted (HR=1.44; 1.07-1.93; p=0.015) subtype correlated with poor outcome. Conclusions: HL of the elderly has a dismal prognosis compared to the younger patients.Older age, lymphocyte depleted subtype and advanced stage at presentation are negative prognostic factors in HL patients.Co-morbid illnesses, delay in diagnosis,incomplete staging, inadequate adherence to treatment protocols and failure to maintain dose intensity are other potential factors which needs to be investigated in multi-centre randomized controlled trials.

Prognostic factors in Hodgkin lymphoma

Depending on stage and risk factor profile, up to 95% of patients with Hodgkin lymphoma at first presentation reach complete remission after the initial standard treatment including radiotherapy, combination chemotherapy or combined modality therapy. Patients who relapse after first complete remission can achieve a second complete remission and long-term disease-free survival with salvage treatment including radiotherapy for localized relapse in previously nonirradiated areas, conventional salvage chemotherapy, or high-dose chemotherapy with stem cell transplantation. In general, risk-adapted treatment strategies are used in the treatment of patients with Hodgkin lymphoma. Adequate staging of newly diagnosed patients enables optimal treatment planning, which is of particular importance for finding a balance between treatment efficacy and toxicity. In this review, an overview is given of the current knowledge of clinical and biological risk factors and the role of imaging modalities during and after treatment.

Expression of COX-2 Is An Independent Unfavourable Prognostic Factor in Hodgkin Lymphoma Treated with ABVD with or without Radiotherapy.

Abstract 1560Poster Board I-583 BackgroundHodgkin lymphoma is defined by Reed Stemberg (RS) tumor cells in a microenvironment composed of a deregulated cytokine network and diverse cell populations, associated with their respective extracellular matrix, defining an inflammatory microenvironment. COX-2 (cyclooxygenase 2) is an inflammatory induced enzyme involved in the pathogenesis and prognosis of several solid tumors (colorectal, breast, ovarian, lung, etc). Its role in hematological malignancies is being recognized and specifically its expression in Hodgkin lymphoma has been associated with higher proliferation and angiogenesis. AimTo investigate the prognostic value of COX-2 expression in a large uniformly treated population with Hodgkin lymphoma. MethodsWe examined tissue microarrays for COX-2 expression in 242 patients of the Hodgkin Lymphoma Spanish Network treated with ABVD with or without Radiotherapy (XRT) according to AA (Ann Arbor) staging. Tissue sections were stained with monoclonal antibodies to COX-2 and the expression was scored and validated by a pathology review. Cox-2 was dichotomized as either negative (no RS staining) or positive. Plots of Kaplan Meier were constructed for survival analysis and most recognized clinical variables (age, sex, presence of bulky disease, B symptoms, AA stage, International prognostic system for Hodgkin lymphoma (IPS), ECOG performance status (PS) were investigated for their prognostic importance along with COX-2 expression by univariate and multivariate analysis. ResultsMedian age was 33 (10 to 83). COX-2 was expressed in 89 pts (37%), 99 pts (41%) presented with AA stage III-IV, 98 pts presented B symptoms (40%) and 124 pts (51%) received XRT added to ABVD chemotherapy, 66% of patients with AA stage I-II and 30% of pts presenting with AA stage III-IV.There were no differences in the distribution of clinical variables according to the COX-2 expression, except for a trend to increased positivity in nodular sclerosis and lymphocyte-depleted subtypes and higher AA stage. With a median follow up for alive patients of 59 months, the PFS at 5 years were 61% and 79% for COX-2 + and negative respectively (p=0.004). OS were 73% and 91% respectively (p<0.001) (Figure). By univariate analysis age higher than 45 years, presence of B symptoms, AA stage III-IV, PS >=2, IPS>2, no XRT treatment and COX-2 expression were associated with an unfavourable PFS and OS. By multivariate analysis only the IPS (HR 3.72) and COX-2 (HR 1.72) expression were independently associated with the outcome. Interestingly the major impact in the prognosis was observed in the favourable AA stage (I-II) and IPS (0-2) groups. In fact in these low risk groups the expression of COX-2 define a group of significant worse prognosis. Accordingly, the 46 patients (32%) of the 143 patients presenting an AA stage of I-II had a PFS at 5 years of 73% versus 86% of those COX-2 negative (p=0.031). Similarly the OS at 5 years of both groups also differ with 82 and 94% for COX + and negative respectively (p=0.004). ConclusionCOX-2 is expressed in approximately a third of RS cells and is a major independent unfavourable prognostic factor. Of main relevance is the fact that in the favourable groups of the AA and IPS the expression of COX-2 identify a group of significant worse prognosis that need different approach. According to our data COX-2 can be a major prognostic variable in this disease and potentially could be a therapeutic target. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparative Assessment of Different Criteria for Interim-PET Interpretation in a Cohort of Hodgkin Lymphoma Patients Treated in a Single Center.

Abstract 3657Poster Board III-593 IntroductionInterim-PET scan performed early during treatment is the most important prognostic factor in Hodgkin lymphoma (HL). However, simple reproducible criteria for scan interpretation are lacking and still await standardization. Aim of the studyTo evaluate in a cohort of ABVD-treated HL patients in a single centre the overall accuracy of different criteria of interim PET interpretation in which interim scan was not decisional for treatment change. Patients and methodsFrom December 2003 till June 2008, 75 HL patients were consecutively admitted to hematology department of Santa Croce Hospital in Cuneo. Baseline and interim-PET (PET-2) scans were performed with a PET/CT equipment. Limited-stage patients (I-IIA) were treated with ABVD x 3-4 plus Involved-field radiotherapy; advanced-stage (IIB-IVB) patients with ABVD x 6 plus consolidation radiotherapy on bulky disease. The injected dose was 370 MBq/70 kg. 2D images were acquired a mean of 71 (47-122) minutes after Fluorodeoxyglucose (FDG) injection. Images were reconstructed with OSEM (3 iteration, 26 subsets). PET-2 was performed after a median of 11(8-13) days from 2nd ABVD end, and no treatment change was allowed based on PET-2 results. Two expert nuclear medicine physicians independently interpreted the PET-2 scans and jointly reviewed the discordant cases. Six interpretation criteria on the basis of literature reports were used: three qualitative, two quantitative, based on Standardized Uptake Value (SUV) assessment, and one with a qualitative/dimensional approach, with a dimensional cutoff value for FDG correction of 15 mm.: Juweid 2007 (Ju), Gallamini 2007 (Ga), Barrington 2008 (Ba) for qualitative, SUVmax determination, SUVmax variation (deltaSUV) for quantitative, and Barrington + dimensional (Ba/d) for a qualitative/dimensional approach. ResultsClinical characteristics of the patients were: mean age 33 (14 - 73), male sex 39/75, limited vs. advanced stage 37/38, International Prognostic Score (IPS), (in 69/75 patients) was 0 in 17,1 in 19, 2 in 19, 3 in 8, 4 in 5, 5-7 in 1 patients. After a mean follow-up of 937 days 67 patients are in CR, and 8 experienced treatment failure, three of them have died. In case of residual FDG uptake the mean diameter of the persisting lesion was 19.9 mm. Overall, 2/8 patients with treatment failure (True PET-2+) and all the 9 patients with false+ or false- PET-2 (whatever criteria) showed a persistent FDG uptake in a single lesion, with a median diameter of 14 millimetres. Sensitivity and specificity, were:100%,70%, for Ju; 63%, 87% for Ga; 63%, 91% for Ba; 75%, 93% for SUVmax; 50%, 94% for deltaSUV; 89%, 89% for Ba/d. Among the qualitative assays Ba and Ba/d showed the best results. The latter were equivalent to both quantitative assay. Using the Ba /d score 8 patients showed false-positive scans: 6/8 with stage IIA and 7/8 with bulky disease, and the 3-year failure-free survival for the entire cohort and for advanced-stage patients were 98%, 53% and 96% and 25% for PET-2 negative and positive patients, respectively. ConclusionsThis study suggest that (1) the criteria of the Harmonization Study for end-treatment evaluation of response should not be used for PET-2 interpretation (2) the lower performance of qualitative in respect to the quantitative criteria is offset by the adjunction of dimensional parameters; (3) due to the small size of the residual lesion with a persistent FDG avidity in PET-2, the contribute of the dimensional criteria could sensibly improve the performance of qualitative criteria, such as Ba, that are currently used for multicenter clinical trials. Disclosures:No relevant conflicts of interest to declare.

Biologic features of Hodgkin lymphoma and the development of biologic prognostic factors in Hodgkin lymphoma: Tumor and microenvironment

Classical Hodgkin lymphoma is now recognised as a B-cell lymphoma. Improved therapy has increased cure rates dramatically; however, relapse and death still occurs in a minority of patients. Much has been learned about the biology of Hodgkin and Reed Sternberg cells and their interactions with the microenvironment, which has informed studies exploring biologic markers that may improve upon clinical prognostic models. This manuscript reviews recent advances in our understanding of the pathobiology of cHL with an emphasis on biologic prognostic markers.

Tumor-infiltrating cells as a prognostic factor in Hodgkin's lymphoma: A quantitative tissue microarray study in a large retrospective cohort of 267 patients

The present study aimed to describe the general tissular composition of the immune infiltrate observed in Hodgkin's lymphoma (HL) and its possible relationship with clinical and survival prognostic factors. In this retrospective study of 267 HL patients, the relative proportions of infiltrating T lymphocytes (CD4 + , CD8 + ), natural killer cells (CD56 + , CD57 + ), cytotoxic cells (Granzyme B + , TIA-1 + ) and dendritic cells (CD21 + , S-100 + ) were quantified immunohistochemically with tissue microarray technology. Our results confirm the predominance of CD4 + T lymphocytes in the background of tumoral cells, in addition to a high number of cytotoxic lymphocytes (CD8, CD57 and TIA-1). Patients with low numbers of infiltrating CD8, CD56, CD57 + cells and high numbers of Granzyme B and TIA-1 + cells presented a significantly unfavourable clinical course (presence of leukocytosis, B symptoms, advanced clinical stage (III/IV), non-responding patients). A reduced infiltration of CD4 + T lymphocytes was related with the presence of Epstein – Barr virus. Significantly longer survival times were observed in patients with a high level of infiltrating CD57, as well as a low level of Granzyme B and TIA-1 + cells (log-rank test). When evaluated in a multivariate model, high levels of infiltrating TIA-1 and Granzyme B + cells were shown to be independent prognostic factors that negatively influenced overall survival. The presence of TIA-1 + cells was found to be the only unfavorable prognostic factor of event-free survival and disease-free survival. The overall detection of tumor-infiltrating cells in HL confirms the importance of cytotoxic T lymphocyte infiltration (Granzyme B and TIA-1 + cells) in these patients. Independently of the classical clinical and pathological features, these cells appear to be an unfavourable prognostic factor in HL and, more particularly, the presence of cytotoxic TIA-1 + cells.