PROGNOSTIC SIGNIFICANCE of CD68 EXPRESSION for Korean PATIENTS with HODGKIN'S LYMPHOMA

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3888-3888
Author(s):  
Dok Hyun Yoon ◽  
Young Wha Koh ◽  
Shin Kim ◽  
Chan-Sik Park ◽  
Dae Ho Lee ◽  
...  

Abstract Abstract 3888 Background: A lower incidence of Hodgkin's lymphoma (HL) in Asians has been recognized and the incidence of HL in Korea was reported to be 5.3%. This low incidence of HL in Asian population has hindered the evaluation of pathogenesis and prognostic factors of the disease. Although international prognostic score (IPS) has been largely utilized as prognostic stratification tool, there has been unmet need to further clarify those with poor prognosis until an increased number of tumor-associated macrophages was identified as a predictor of poor clinical outcome. Hence, we evaluated the prognostic significance of CD68, a marker of macrophages, in Korean HL patients. Methods: We performed immunohistochemical analysis of CD68 in 144 classic HL patients treated with ABVD (n=113, 78.5%), MOPP (n=10, 6.9%), ABVD/MOPP hybrid (n=15, 10.4%) or BEACOPP (n=6, 4.2%) chemotherapy with or without radiotherapy between November 1990 and December 2009 in the Asan Medical Center. The relative percentage of CD68+ cells in relation to overall cellularity was calculated and the results were correlated with clinical outcome. Results: We examined various cutoff points of CD68 expression from 10 to 90 percentile with a rising gradient constructed using 5% steps (5%, 10%, 15%, 20%, 25%, 30%, 35% and 40%). The most significant statistical difference in disease-specific survival (DSS) was observed at a cutoff value of 20%, employing the log-rank test. The high (>=20%, n=78) CD68 group included more patients with older patients (Age 45 yr, 45.5% vs. 28.2%, p=0.032) and higher IPS (>=4, 37.9% vs. 21.8%, p=0.034) compared with the low (<20%, n=66) CD68 group. In total, 18 patients in the low CD68 group and 20 patients in the high CD68 group experienced relapse or progression. Nine patients in the low CD68 group (6 patients of progressive disease [PD], 1 of treatment-related infection during salvage treatment, 1 of moyamoya disease and 1 of unknown cause) and 15 patients in the high CD68 group (8 of PD, 5 of treatment-related infection, 1 of intraventricular hemorrhage during primary therapy, 1 of unknown cause) died by the time of data cutoff. Treatment-related mortality (TRM) was significantly higher in the high CD68 group (n=1 vs. n=6, p=0.048). The 5-year EFS rates were 74.7% and 49.5% in the low and high CD68 expression groups, respectively (P=0.009) with a median follow-up period of 5.4 years (range, 0.6–19.0 years) in surviving patients. The 5-year DSS rates were 95.7% in the low CD68 expression group and 76.5% in the high CD68 expression group (P=0.011). In the multivariate analysis with clinical variables significantly correlating with EFS/DSS in univariate analyses including IPS (>=4), age (>=45 years) and presence of B symptoms, CD68 expression was found to be an independent prognostic factor for EFS (Hazard ratio [HR] =1.846; 95% confidence interval [CI] 1.106–3.354; P=0.044) and DSS (HR = 2.955; 95% CI, 1.148–7.607; p=0.025). However, the prognostic significance of CD68 seems to be more prominent in patients with localized disease (n=48) in a subgroup analysis. While 5-year EFS (85.8% vs. 25.7%, p=0.001) and DSS (95.7% vs. 78.8%, p=0.007) for patients with localized disease were significantly higher in the low CD68 group, both EFS (66.5% vs. 56.5%, p=0.144) and DSS (92.7% vs. 75.7%, p=0.144) were not significantly different between the high and low CD68 groups. Conclusion: The number of CD68+ macrophages is a significant prognostic factor in Korean HL patients. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4629-4629
Author(s):  
Neta Goldschmidt ◽  
Omer Or ◽  
Martine Klein ◽  
Bella Savitsky ◽  
Ora B. Paltiel

Abstract Abstract 4629 Introduction Up to 30% of patients with Hodgkin's lymphoma (HL) and 60% of patients with aggressive Non-Hodgkin's lymphoma (A-NHL) will relapse after first remission. Early detection of relapse, associated with a low tumor burden, may improve survival. The optimal follow up method - clinical versus imaging - for the detection of relapse has not been clarified. Methods We retrospectively reviewed the files of 125 patients with HL and A-NHL diagnosed between 1.1993 - 1.2009 who relapsed at least one month after the end of initial therapy. We assessed whether relapse was detected by clinical symptoms or by imaging and specifically queried whether recent imaging techniques i.e. [18F] fluorodeoxyglucose positron emission tomography (FDG-PET), have changed the pattern and outcomes of relapsed disease. Results Forty two (34%) patients had HL and 83 (66%) had A-NHL. Of the 125 patients, age was <30 years in 50% of HL and >60 years in 47% of A-NHL patients; 75 (60%) had advanced disease and 50 (40%) had early disease at diagnosis. Seventy patients (56%) relapsed in the first year following treatment, 20 (16%) in the second year and the rest (33, 26%) relapsed thereafter. In 75 (60%) patients, relapse was detected based on patient's symptoms or an abnormal physical finding (clinical detection of relapse, CDR) and in 50 (40%) patients relapse was detected by routine imaging (image detection of relapse, IDR). A significantly higher proportion of A-NHL patients had CDR as opposed to IDR (67% versus 33%), whereas in HL the opposite was found (45% CDR and 55% IDR) (p=0.022). In the years 2001-2009, when FDG-PET was available at our institution, 28% of HL patients had CDR and 72% were diagnosed by IDR (p=0.065). Multiple regression analysis confirmed the independent effect of histology (OR 2.6, 95% CI 1.19-5.69 for HL versus NHL) and period of relapse (OR 2.4, 95% CI 1.1-5.4 for ≥2001 versus '2000) on the probability of IDR. Characteristics at relapse including time to relapse, stage, presence of B symptoms, prognostic score, site of relapse, extranodal involvement and period of relapse did not influence the mode of diagnosing relapse. The overall survival after relapse of all 125 patients did not differ significantly whether they had CDR or IDR. However, in patients with HL (but not in patients with A-NHL), IDR was associated with improved survival (albeit non-significant) (Fig 1). The risk of death was more than twice for HL patients with CDR versus IDR (Hazard ratio (HR) 2.4, 95% CI 0.73-7.63) whereas in A-NHL patients the mode of detection of relapse was not associated with survival (HR 0.91, 95% CI 0.5-1.66). Conclusions These preliminary results show that the major mode of detecting relapses in lymphoma remains the clinical exam and not imaging. However, routine surveillance by imaging may be important in HL as opposed to A-NHL and the use of contemporary imaging modalities, i.e. FDG-PET, may be more sensitive for relapse detection. Although non significant, our findings suggest that image detection of relapse in patients with HL may be associated with improved survival. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3881-3881
Author(s):  
Deau Benedicte ◽  
Bachy Emmanuel ◽  
Ribrag Vincent ◽  
Delarue Richard ◽  
Rubio Marie-Therese ◽  
...  

Abstract Abstract 3881 Classical Hodgkin's lymphoma is a highly curable lymphoma and about 80% of patients can be cured with modern treatment strategies. In spite of great clinical progress, a significant minority of classical Hodgkin's lymphoma experiences treatment failure after primary chemotherapy including a first line of anthracyclin-based regimen. Patients with refractory Hodgkin's lymphoma represent 5 to 10% of classical Hodgkin's Lymphoma. Many of these patients have a poor overall survival estimated at 25% at 5 years. A better biological characterization of such primary refractory patients might allow the use of early therapeutic intervention including targeted therapy. It remains, however, a challenge to identify patients whose disease will not be eradicated by standard therapy. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not yet been established to improve the International Prognostic Score. For these reasons, reliable biomarkers for predicting long term survival at diagnosis are needed for such patients. Steidl et al. (Nejm,2010) recently reported the prognostic value of tumor-associated macrophages in patients with classical Hodgkin's lymphoma, showing that higher infiltration is associated with a shortened survival. The value of tumor-associated macrophages in primary refractory Hodgkin's lymphomas has not been specifically assessed. In a retrospective study (Canioni et al., Plos one 2009), we previously evaluated 59 patients (18 with primary refractory or early relapse disease and 41 responders) collected from 1997 to 2004 in two hematology centres (Necker Hospital and Gustave Roussy Institute, Paris France) for c-kit expression by immunohistochemical analysis as a marker of mast cell infiltration and correlated the results with the response to treatment. All available poor prognosis patients were first identified (18 patients with primary refractory disease or early relapse (< 1year)) and the control group (47 responders) was randomly selected. Patients received conventional chemotherapy-based treatments [(MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), ABVD (doxorubicine, bleomycine, vinblastine, and dacarbazine) or the combination of both or BEACOPP (bleomycine, etoposide, doxorubicine, cyclophosphamide, vincristine, procarbazine, prednisone)] and radiotherapy in stages I and II. Most patients presented a nodular sclerosis subtype of Hodgkin's lymphoma regardless whether they were refractory (17/18cases, 94.5%) or responders (37/41cases, 90%). In this cohort, 44 (75%) patients had a localized stage, whereas 19 (25%) had a disseminated disease. The results showed that refractory Hodgkin's lymphoma were associated with an excess of mast cells infiltration in the tumor cells microenvironment. The number of mast cells stained was significantly higher in refractory Hodgkin's lymphoma (c-kit+ mast cells > 6 per field) than in responders (c-kit+ mast cells ≤ 6) (p=0.001 and 0.0194 in univariate and multivariate analysis, respectively). In this cohort of patients, using CD68 staining we also found a statistically significant higher proportion of tumor-associated macrophages in refractory Hodgkin's lymphoma as compared to responders in univariate and multivariate analyses (p=0.0048 and p=0.0041, respectively). Therefore, we confirmed a strong correlation between the number of CD68 positive macrophages in the tumor stroma and clinical outcome. The use of such markers (CD68 and c-kit) in combination with well-established clinical risk factors could improve on the predictive value of a single biomarker used alone. Therefore, in addition to mast cells, macrophages are also important players in refractory Hodgkin's lymphoma that may confer drug resistance to Hodgkin Reed Sternberg cells. Taken together, these data strongly suggest that microenvironment should be targeted in Hodgkin's lymphomas. In this regard, the use of kinase inhibitors that target both c-kit and M-CSF receptors could restore chemotherapy sensitivity in refractory Hodgkin's lymphoma and should be evaluated in clinical trials. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1818-1818
Author(s):  
Luis P Monteiro ◽  
Catia L Gaspar ◽  
Margarida Fevereiro ◽  
Ana L Tome ◽  
Nuno Almeida ◽  
...  

Abstract Introduction: the shortage of some anticancer drugs has forced their substitution in established combination chemotherapy regimens, but the replacement may have critical effects on the results of treatment and need careful evaluation. Since 1996 we treat Hodgkin's lymphoma (HL) with the Stanford V (SV) regimen, which achieves the same results as the more widely employed ABVD regimen with the benefits of a shorter duration (12 weeks) and lower cumulative doses of bleomycin and doxorubicin. When mechlorethamine became unavailable in 2008, we substituted cyclophosphamide at a dose of 650 mg/m2 for mechlorethamine 6 mg/m2. In 2012 the Pediatric Hodgkin Lymphoma Consortium, which had adopted the same policy, suggested in a retrospective analysis that the modification could lead to an inferior event-free survival (EFS). To assess the impact of the substitution, we retrospectively compared our results with the original SV (SVo) and the modified SV (SVm). Methods: we evaluated the 265 patients consecutively treated in our center with SV between Nov/96 and Dec/14. We compared the pre-treatment characteristics, the complete remission (CR) rate, EFS and overall survival (OS) of the 184 patients who received SVo to those of the 81 patients treated with SVm. Radiotherapy indications and supportive measures were unchanged between the 2 periods. Results: median age of the 2 groups was identical: 31 (16-69) for SVo and 31 (15-72) for SVm. No differences were found in histologic subtypes (nodular sclerosis 76/74%), frequency of B symptoms (36/47%, p=0.09), proportion of advanced stages (32/33%) or International Prognostic Score (≥3 in 20/13%, p=0.22). The CR rate was 89% for SVo and 86% for SVm. With a median follow up of 9 years for the SVo group and 4.6 years for the SVm group, there were no significant differences in EFS (76/73%, p=0.66) and OS (89%/85%, p=0.63) at 5 years. Conclusion: the impact of forced substitutions in components of combination chemotherapy regimens due to drug shortage must be carefully scrutinized, notably in first line protocols for curable diseases. In the case of HL treated with the SV regimen, the present study is the first, to our knowledge, to evaluate the impact of replacing mechlorethamine by cyclophosphamide in adults. We found no difference in OS nor, unlike the pediatric study, in EFS. The substitution can be considered safe, since the modified version of SV achieves the same favorable results as the original SV. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5004-5004
Author(s):  
Ibraheem H Motabi ◽  
Syed Ziauddin A. Zaidi ◽  
Shahid Iqbal ◽  
Atta Munawar Gill ◽  
Imran Khan Tailor ◽  
...  

Abstract The International Prognostic Score (IPS) is the standard stratification system for survival in patients with classical Hodgkin's lymphoma (cHL). However, the IPS only applies to patients with advanced stage disease and it does not offer risk stratification for classical Hodgkin's lymphoma patients diagnosed with limited disease [i.e., stages I and IIA, without constitutional symptoms and no bulky disease. Furthermore, early interim positron emission tomography (PET) has been shown to have a prognostic value superior to that of the IPS in patients with advanced-stage cHL in an analysis (Gallamini et al). Lymphopenia (<600/ul), monocytosis >750 per ul (Tadmore et al) and high tumor-associated macrophages (TAM) are reported to be negative prognostic factors for survival in classical Hodgkin's lymphoma (Koh et al). More recent studies suggested a prognostic role for the peripheral blood absolute lymphocyte count/absolute monocyte count (ALC/AMC) ratio at diagnosis in cHL patients treated with multitude of chemotherapies (Porrata et al, Tadmor et al). It is intriguing to investigate the significance of the ALC/AMC ratio in relation to PET negativity after treatment. Out of 164 cases of cHL treated at our center with ABVD +/- radiation therapy, we identified 70 patients who were evaluated by PET Scan. Median age was 26 years (range 14-80), 33 (47%) were stage IV, Median IPS was 3 (range1-6). We tested correlation of a high ALC/AMC ratio (>2.1) with achievement of a negative PET scan after ABVD chemotherapy. We arbitrarily chose cut-off value of >2.1 (Tadmore et al) from the multiple values reported recently, as this multicenter study had the largest number of patients. A total of 45 patients achieved a negative PET scan. Mean ALC/AMC ratio was 2.39 (range0.19-14.6). ALC/AMC ratio of >2.1 did show a trend for better OS in addition to a negative PET scan. A Spearman correlation test of a negative PET result showed a positive correlation with ALC/AMC ratio of >2.1 though it was weak. This study suggests that the ALC/AMC ratio may be a simple, inexpensive, and independent prognostic factor in cHL outcome and may have a role in the stratification of cHL patients in addition to the International Prognostic Score, TAM content and acheivement of a negative PET scan early post chemotherapy. However we plan to define our own best cut off value for ALC/AMC ratio by ROC and AUC analysis as ALC/AMC Ratio of ≥2.1 did not discriminate survival advantage very well and it may be a reason for weaker correlation with likelihood of a negative PET. Further larger studies are needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4529-4529
Author(s):  
Samer Nakkar ◽  
Toni Pacioles ◽  
Gabriela Ballester ◽  
Maria Tirona ◽  
Oscar F Ballester

Abstract Abstract 4529 Introduction Age older than 45 years is a recognized independent prognostic factor for patients with Hodgkin's Lymphoma (HL), and it is part of the International Prognostic Score (IPS) system. This score system was based on data derived from selected patients included in clinical trials. It is unclear from these studies if age affects primarily disease biology or the ability of older patients to tolerate therapy. Patients and Methods We retrospectively reviewed all consecutive patients with newly diagnosed HL at our institution. Data collected included their IPS and a co-morbidity score (CoM) which includes assessment of co-existing cardiac, hepatic, pulmonary, renal and other morbidities. Results Forty five patients were identified. Twenty nine patients (64%) were younger than 45 years and 16 (35%) were 45 years or older. Patients were treated wit ABVD (adriamycin, bleomycin, vinblastine and DTIC) chemotherapy, with or without radiotherapy, except for 4 patients who were accrued to clinical trials. An IPS of 2 or more was documented in 17% of younger patients as compared to 71% of those older. There was a significant association between age and IPS score (p= 0.001). Similarly, there was a significant association between age and CoM score (p= 0.01). A CoM score of 4 or higher was seen in only 7.6% of the younger population but in 46.6% of the older patients. With a median follow up of 62 months, overall survival is 86 % for the entire population. Overall survival for the younger patients is 93% and for the older 71% (p= 0.01). Five of the six documented deaths occurred in patients 45 years or older, and 4 of these 5 were seen in patients over 60 years of age. Crude death rates for patients <45 (n= 29), 45 to 59 (n= 9) and 60 or older (n= 7) are: 3.4%, 11% and 57% respectively. Conclusions Older patients are more likely to present with high IPS and CoM scores which explain at least in part their poor outcomes. A high mortality rate in patients >60 years underscores the need to explore new therapeutic approaches in the older population. Disclosures: No relevant conflicts of interest to declare.


2005 ◽  
Vol 23 (16) ◽  
pp. 3773-3779 ◽  
Author(s):  
Stephen J. Sup ◽  
Carlos A. Alemañy ◽  
Brad Pohlman ◽  
Paul Elson ◽  
Serena Malhi ◽  
...  

Purpose Although most classical Hodgkin's lymphoma (CHL) patients are cured, a significant minority fails primary therapy and may die as a result of their disease. Age, stage, and other basic clinical and laboratory parameters, which comprise the International Prognostic Score (IPS), are used at diagnosis to predict outcome. To date, there is no consensus on biologic markers that add value to these parameters. Patients and Methods We evaluated 107 CHL patients for bcl-2, p53, and p21 expression by immunohistochemistry using tissue microarrays and correlated the results with outcome. The median follow-up of the 79 surviving patients was 6.8 years. Results Univariate analysis showed that age ≥ 45 years, stage III or IV, and IPS ≥ 3 were associated with a poor failure-free survival (FFS) and overall survival (OS). bcl-2 was expressed in 26% of patients and was associated with poor FFS and a trend for OS. p53 expression in combination with lack of p21 expression was not associated with outcome. Multivariate analysis showed that three factors were independently associated with both FFS and OS: age ≥ 45 years, stage III or IV, and bcl-2 expression. Using these three parameters, a scoring system was devised that stratified patients into three risk groups (with zero, one, or two to three of these risk factors) and a progressively worse FFS and OS (P < .001). Conclusion Expression of bcl-2 in CHL is a useful, independent prognostic marker and can be used in association with clinical parameters to identify newly diagnosed patients with a good, intermediate, or poor prognosis.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5001-5001
Author(s):  
Nidhi Bhatt ◽  
Gregory Brandt ◽  
Daniel Niebrugge ◽  
Aziz U. Khan

Abstract Background: There has been little investigation into the incidence or prognostic significance of a pleural effusion when present with the diagnosis of Hodgkin's Lymphoma. In our small clinical practice we had two patients with Hodgkin's lymphoma who presented with pleural effusion and subsequent poor outcomes, including relapse and eventual death. These events stemmed this retrospective study investigating the incidence of pleural effusion with the diagnosis of Hodgkin's disease and whether the presence of pleural effusion at the time of diagnosis would reveal any association with outcomes in a larger cohort of patients. Procedure: A single centered retrospective chart review of 134 patients' age 0-50 with confirmed Hodgkin's lymphoma was performed. Charts were evaluated for the presence of any radiographic evidence of pleural effusion at the time of diagnosis, along with the patient's eventual outcome. Result: 8/133 (6%) patients with Hodgkin's lymphoma had a pleural effusion at the time of diagnosis. Death is dependent on pleural effusion (p= 0.019) with 3 of 8 (37.5%) of patients that had pleural effusion who died.There is an 8.77 (CI 1.8 - 43.5) times greater odds of death for patients with pleural effusion versus those without pleural effusion. Recurrence is dependent on pleural effusion (p= 0.0061) with 5/8 (62.5%) of patients that had pleural effusion who experienced recurrence.There is an 8.75 (CI 1.9 - 39.6) times greater odds of recurrence for patients with pleural effusion versus those without pleural effusion. Of the 5 patients who had recurrence, as stated above 3 patients died, 1 patient was salvaged by stem cell transplant and another patient was recently diagnosed with relapse thus, clear outcome is yet to be determined Conclusion: The presence of a pleural effusion at the time of diagnosis of Hodgkin's lymphoma is a rare finding, yet when present, was associated with death and recurrence. This finding may suggest a more aggressive initial treatment be required given the association with poor outcomes. An evaluation of a larger cohort of patients, along with a determination of the diagnostic stage, will be required to confirm prognostic potential. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 265-272 ◽  
Author(s):  
O Hermine ◽  
C Haioun ◽  
E Lepage ◽  
MF d'Agay ◽  
J Briere ◽  
...  

Abstract Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T- cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.


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