Zeitschriftenartikel: „HL-1 buňky“

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Pophali, Priyanka A., Lisa A. Rybicki, Kathleen B. Fenner, Deepa Jagadeesh, Robert M. Dean, Brad Pohlman, Mitchell R. Smith und Brian T. Hill. „Bulky Disease Does Not Adversely Affect Overall Survival in Early Stage Hodgkin Lymphoma: Role of Interim PET and Possible Omission of Radiotherapy in Select Patients“. Blood 124, Nr. 21 (06.12.2014): 4428. http://dx.doi.org/10.1182/blood.v124.21.4428.4428.

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Abstract Background: Bulky disease is considered a major driver of unfavorable prognosis in early stage Hodgkin Lymphoma (HL). Treatment guidelines for bulky early stage HL call for more aggressive initial therapy compared to non-bulky disease. There are limited data on outcomes in bulky disease, particularly in patients treated with chemotherapy alone, or on the utility of interim PET scans. We retrospectively analyzed data on patients with early stage HL to assess the impact of disease bulk, interim PET and treatment modality on outcomes. Methods: We reviewed charts of 151 consecutive patients diagnosed with previously untreated early stage (I & II) HL at the Cleveland Clinic from 1995-2011. Bulky disease was defined as a mediastinal mass >1/3 intra-thoracic diameter on PA chest x-ray or any mass ≥ 10 cm on CT scan at diagnosis. Patients were grouped by intent to treat strategy as chemotherapy alone (C) or combined modality treatment (CMT) with chemo-radiation. Baseline characteristics were compared: categorical variables by the Chi-square or Fisher's exact test; continuous variables by the Wilcoxon rank sum test. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazards analysis was used to test univariable prognostic factors for OS and PFS. Results: 121 patients (mean age 40±16) with early stage HL had adequate clinical data for inclusion. At the time of review, 106 (87.6%) patients were alive with median follow-up of 47.4 (0-328) months. Characteristics at diagnosis were: 54% female; 80% Caucasian; 77% nodular sclerosis HL; 78% stage II; 31% with B-symptoms; 12% with extranodal disease; 30% (N =36) with bulky disease of whom 89% had bulky mediastinal disease. 96% patients received standard ABVD chemotherapy. The only significant differences in the baseline characteristics of patients with bulky vs. non-bulky disease were age (mean 35 vs. 42 years, P=0.03), hemoglobin (mean 12.4 vs. 13.4 g/dL, P=0.01) and absolute lymphocyte count (mean 1.29 vs. 1.71 k/µL, P=0.02). Although there was no statistically significant difference in the initial treatment strategy chosen, patients with bulky disease tended to receive CMT more often than patients with non-bulky disease (66% vs. 51%, P=0.16). More females were treated with C compared to CMT (70% vs. 43%, P=0.004). Patients with bulky disease received a greater number of chemotherapy cycles (mean 5.6 vs. 4.6, P=0.01). Five years after diagnosis, patients with non-bulky HL had Kaplan-Meier estimates of 83% OS and 69% PFS while patients with bulky HL had 88% OS and 81% PFS. There was no statistical difference in OS [Figure 1] or PFS based on disease bulk. Analysis of the available PET status (65 interim scans) revealed that both the bulky and non-bulky patients had comparable responses on interim PET (negative 82.6% vs. 95.2%, P=0.17). Interim PET scan was highly prognostic for all early stage HL patients for both OS (P < 0.01) and PFS (P < 0.001) as well as specifically for patients with bulky disease (negative vs. positive PET: 5 year OS 90% vs. 75%, P=0.012; 5 year PFS 95% vs. 25%, P<0.01 [Figure 2]). Among the 23 patients with bulky disease managed with initial CMT, 4 required 2nd line treatment including 3 who underwent autologous stem cell transplant (Auto-SCT). Among the 12 patients managed initially with C, 5 required 2nd line treatment and all 5 underwent Auto-SCT. In total, among those with bulky disease, the OS and PFS were similar irrespective of initial treatment strategy chosen. In univariate analysis, extra-nodal disease was the only baseline variable that impacted PFS (HR=2.7, CI 1.01-7.20, P=0.048) but did not affect OS (HR=2.46, CI 0.66-9.19, P=0.18). Conclusions: Patients with bulky early stage HL have comparable survival to patients with non-bulky disease. Among patients with bulky disease, treatment with initial C or CMT resulted in comparable OS and PFS, although a higher proportion of patients treated with C alone required 2nd line treatment. These data support the observation that radiation therapy is not essential to achieve cure in bulky HL. Specifically, omitting radiation in female patients who achieve a negative interim PET scan is a viable treatment strategy which may mitigate the long-term risks of radiation. Figure 1: OS in Early Stage HL Based on Disease Bulk Figure 1:. OS in Early Stage HL Based on Disease Bulk Figure 2: PFS in Bulky Early Stage HL Based on Interim PET Figure 2:. PFS in Bulky Early Stage HL Based on Interim PET Disclosures No relevant conflicts of interest to declare.

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Ngeow, J. Y., R. Quek, M. Tao, H. C. Tan, L. Lim, I. Tan, R. Kaneswaran und S. T. Lim. „Analysis of long-term treatment outcomes and toxicty of HL“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): e19536-e19536. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e19536.

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e19536 Background: Prognosis of patients with Hodgkin lymphoma (HL) has substantially improved but therapy of HL can however contribute to delayed toxicity. Long term treatment outcomes of HL in our local population were evaluated. Methods: Clinical and treatment data was prospectively collected from all patients with a histological diagnosis of HL. Patients were all fully staged with CT scan and bone marrow biopsy. Results: On the basis of 217 patients seen at the National Cancer Centre Singapore between 1990–2008, we found that there was a peak in young adulthood with 103 patients who were diagnosed before the age of 30 (48%), median age of presentation 32 (range 17–84). Patients who were young (< 30 years) were more likely to present with nodular sclerosis HL (p=0.0001). Treatment outcomes were comparable to other published series, 85% of cases received ABVD based treatment. 5 year OS for early stage HL was 92% and 88% for advanced stage HL. Overall FFTF was 93% at 5 years. Of note, comparing patients with early stage (Stage I/ II) HL (n=114) who had ABVD 4 cycles followed by involved field radiotherapy (IFRT) with those who received 6–8 cycles of ABVD, there was no difference in OS, FFTF (p= 0.99, 0.48 respectively). Bulky early stage HL who received 6 cycles of ABVD and IFRT had better FFTF rates than those who had just 4 cycles of ABVD followed by IFRT (p=0.06). In contrast, patients patients with advanced HL (Stage III/ IV) (n=70) who completed 6–8 cycles of ABVD did not benefit from additional IFRT even in the presence of bulky disease (n=15). Acute toxicities included that of bleomycin induced pneumonitis (BIP) seen in 15% of cases. Neither the omission of bleomycin nor the presence BIP adversely affected treatment outcomes. Hematological malignancies were seen in 1% of survivors appearing after a median of 7.3 years. Hypothyroidism was noted in 3% of cases. Conclusions: 1) Epidemiology of HL in Singapore is increasingly similar to that of developed countries with a peak in young adults. 2)Young age was predictive of a nodular sclerosis subtype 3) Abbreviated chemotherapy using 4 cycles of ABVD followed by IFRT performed similarly to 6 cycles of ABVD in early stage HL, but in patients with bulky disease this may not be sufficient. 4) BIP occurred in 15% of cases. BIP and the omission of bleomycin did not adversely affect treatment outcomes. No significant financial relationships to disclose.

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Abd-Elrahman, Ihab, Vladimir Rapoport, Tzahi Neuman, Liat Appelbaum, Tamar Shiloach, Riki Perlman und Dina Ben-Yehuda. „Clinical and Molecular Significance of Tumor Necrosis In Newly Diagnosed Patients with Hodgkin's Lymphoma and Diffuse Large B Cell Lymphoma“. Blood 116, Nr. 21 (19.11.2010): 1995. http://dx.doi.org/10.1182/blood.v116.21.1995.1995.

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Abstract Abstract 1995 Lymphoma of various types in newly diagnosed patients may exhibit necrotic areas in the tumor mass on imaging. To date, little is known about the clinical significance of this finding and even less is known about the mechanism of cell death in the necrotic tissue - apoptosis, molecular necrosis or autophagy. The objective of this study was to investigate the prognostic significance of tumor necrosis in newly diagnosed Hodgkin's lymphoma (HL) and diffuse large B cell lymphoma (DLBCL) patients and to define the molecular mechanism of cell death responsible for the necrosis. Two hundred and four CT scan or CT-PET studies from newly diagnosed patients with DLBCL (131) and HL (73) were analyzed for the presence of tumor necrosis. Radiographic appearance of necrosis was present in 47% of all patients, 34% HL and 53% DLBCL. A statistically significant correlation was found between necrosis and bulky disease (tumor mass size≥10 cm) (p=0.0002×10-6) and also between necrosis and elevated LDH (p=0.00002) (see Table 1). Radiographic appearance of necrosis Bulky disease tumor mass size ≥10 cm Elevated LDH Yes 41.1% 60.2% No 5.5% 29.9% No statistically significant correlation was found between necrosis and age >60 or more advanced stage of disease. There was also no statistically significant difference in interim response to treatment, disease-free survival and overall survival between patients with necrosis and without it. Our results show that in contrast to solid tumors, tissue necrosis in lymphoma is not a predictor of worse prognosis: though more patients with radiographic appearance of necrosis had also the known bad prognostic signs- elevated LDH and/or bulky disease, this group did not have worse outcome. We suggest that necrosis can lead to a better response to treatment in lymphoma. Among 56 HL and DLBCL patients that underwent an open surgical biopsy of the tumor mass nineteen presented necrotic morphology in the biopsied tissues: 8 HL and 11 DLBCL. Biopsies without evidence of necrotic morphology (10 patients from the above 56) and reactive lymph nodes (4) were included as controls. All sections were stained for ki-67 (proliferation marker), activated caspase-3 (apoptosis marker) and HMGB-1 (necrotic cell death marker). DLBCL cells showed high proliferation rate, with ki-67 index ranging from 40 to 90% and in HL cells the ki-67 index ranged from 5 to 50%. All the samples positive for HMGB-1 were from patients with HL and 10/11 of activated caspase-3 positive samples were from DLBCL. These results show a differential molecular mechanism of cell death in the tumor mass of newly diagnosed HL and DLBCL patients. The constitutive activation of the survival factor Nuclear Factor-kB (NF-κB) was found in Hodgkin and non-Hodgkin lymphoma. We stained the same biopsies for p65/RelA and examined the nuclear localization of NF-κB as an indication for activation of the NF-κB pathway. Four DLBCL and 4 HL samples were positive for NF-κB activity. Nevertheless, we found that activation of caspase-3 and/or HMGB-1 induced cell death in these tissues. In summary, tumor necrosis in HL and DLBCL is correlated with bulky disease and high LDH, yet is not correlated with prognosis. The molecular mechanism of cell death differs between the two types of lymphoma. Disclosures: No relevant conflicts of interest to declare.

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Tartas, Norma, Marta Zerga, Graciela Alfonso, María P. Amoroso Copello, Isabel Santos, Jorge Korin, Elsa Nucifora et al. „More Than 4 Cycles of ABVD for the Treatment of Stage I–II Hodgkin’s Lymphoma?.“ Blood 106, Nr. 11 (16.11.2005): 4719. http://dx.doi.org/10.1182/blood.v106.11.4719.4719.

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Abstract Patients with stage I-II A non bulky Hodgkin’s lymphoma (HL) are successfully treated with 2–4 cycles of ABVD plus IF radiotherapy (RT). Although the negative impact in DFS and OS of B symptoms and bulky disease(X) is widely accepted, other risk factors such as number of lymph node regions involved or extensive spleen involvement have also been reported. What is the best treatment for such patients? Is radiotherapy necessary? We report here our experience with protocol HD 98 in 62 patients, with stage I–II HL. Since January 98 we have included 30 individuals without risk factors and 32 with one of the following risk factors: B symptoms (n:11), X (n:9), extensive spleen involvement (n:1) and involvement of more than two lymph node regions (n:11). Other patient characteristics were: age: x 31yrs (15–69), sex: females 31, males :31. Ann Arbor stage IA :11, IB :1, IIA: 36, IIB :14. Histologic subtypes were: LP: 4, NS: 42, MC: 15, lymphocyte rich :1. Patients with favourable features received 4 cycles of ABVD plus IFRT, those with unfavourable factors received 6–8 cycles of ABVD plus RT in areas of bulky or residual disease. Results: 59/61 evaluable patients obtained CR or CRu. Two patients were considered primary resistant. Three patients relapsed at 7, 13 and 30 months after completion of treatment. Autologus bone marrow transplant was performed in four patients. The two primary resistant patients relapsed after the transplant and died with proggressive disease. Those patients transplanted in a chemosensitive relapse are currently in CR. With a median follow up of 46m (13–84) 96.7% of the patients are alive, in CR. Conclusions: In our experience patients with unfavourable stages I–II HL are succesfully treated with 6–8 cycles of ABVD. In such patients RT might only be necessary in areas of bulky or residual disease.

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Canellos, George P. „Chemotherapy Alone for Localized Non-Bulky Hodgkin Lymphoma“. Blood 112, Nr. 11 (16.11.2008): 2591. http://dx.doi.org/10.1182/blood.v112.11.2591.2591.

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Abstract Combined modality therapy with radiation and chemotherapy has been the standard treatment for limited-stage HL. Long-term toxicities, including cardiac and disease and secondary cancers, s have been reported in multiple series with long follow-up. Lower doses and smaller fields may be less toxic, but mediastinal/cardiac radiation is unavoidable in most cases. The Dana-Farber Cancer Institute and Massachusetts General Hospital lymphoma teams have now treated 74 patients with localized, non-bulky classical HL with chemotherapy as the only therapy. The median age of the series was 29 years (17–42). The M/F ratio was 33/41. The clinical stages were IA (10), IIA (56), IIB (9). The treatment consisted of ABVD × 6 cycles (70 pts), ABVD × 4 cycles (3 pts), and variants of ABVD (2 pts). The median F/U is 48+ months (4+–174+). One patient had primary refractory disease. Seven patients (median age 30, range 20–38) have relapsed (6, 10, 10, 11, 14, 20 and 63 months) whose original stage was IA (1), IIA (3), IIB (3). The progression-free survival at 4 years is 91%. All patients are alive. Six of seven patients received salvage RT and autologous stem cell transplantation, and only one has relapsed to date. In retrospect, all seven patients who relapsed from CR or CRu were FDG-PET negative at mid-cycle. Thus far, there has been no long-term, chemotherapy-related toxicity in the patients who remain in remission. 94% (62/66) asymptomatic patients remain in remission compared to 6/9 (67%) IIB patients. Conclusion: In young adults with non-bulky, localized HL chemotherapy alone with ABVD can achieve excellent progression-free and overall survival, especially those asymptomatic at diagnosis. These data and previously published results indicate an equivalent long-term outcome when compared to combined modality trials but without the long-term risks of radiation therapy. Avoidance of radiation therapy may be even more important in the pediatric age group.

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Linardi, Camila C. G., Luis Fernando Pracchia, Rodrigo Dolphini Velasques, Claudia Bitti Barroso und Valeria Buccheri. „Hodgkin Lymphoma: 20 Years Experience From a Single Brazilian Institution“. Blood 118, Nr. 21 (18.11.2011): 3153. http://dx.doi.org/10.1182/blood.v118.21.3153.3153.

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Abstract Abstract 3153 Hodgkin Lymphoma (HL) is characterized by high cure rates. Approximately 90% early stage and 60–70% advanced stage patients have long term disease free survival. In Brazil it is observed that about 60% of patients present with advanced stage, while in developed countries about 40% belong to this group. The aim of this retrospective study was to analyze data of patients with HL from the Oncohematology Unit of University of São Paulo- Medical School and evaluate the event free survival (EFS) and the overall survival (OS) according to clinical stage. We included all consecutive patients diagnosed with HL between January 1991 and June 2010. The collection of data from medical records was done and the following variables at diagnosis were evaluated: age and sex, staging according to Cotswolds modified Ann-Arbor criteria (CS), histological subtype, presence of B symptoms and bulky disease, International Prognostic Index (IPI) according to International Prognostic Factors Project on Advanced Hodgkin's Disease, laboratorial data, and the protocol used in first line therapy. The complete remission (CR) rate, EFS and OS were analyzed in all patients. The survival analysis was estimated by the Kaplan-Meier method and the survival curves were compared by the log-rank test. Differences in CR rates among staging groups were compared using the chi squared test. Overall, 564 HL patients were identified; thirteen did not have adequate information about clinical staging and were excluded from the analysis. The median age, at diagnosis, of the remaining 551 patients was 28 (12–83) and 54.3% were male. Histological subtypes lymphocyte rich classical HL, nodular sclerosis, mixed cellularity and lymphocyte depletion were found in 3.6%, 51.4%, 24.2% and 5.6% cases, respectively, and 11.8% patients were diagnosed as HL classic not classifiable otherwise. Nodular lymphocyte predominance was observed in 3.3% cases. Stage I, II, III and IV were found in 42 (7.6%), 208 (37.7%), 145 (26.3%) e 156 (28.3%) patients, respectively. B symptoms and bulky disease were present in 65.5%and 58.8% patients, respectively. After staging the patients were divided in three groups: group 1 -CS I/II, without B symptoms nor bulky disease= 62 (11.25%) patients, group 2 -CS I/ II, with B symptoms and/or bulky disease=188 (34.12%) patients and group 3- CS III/ IV= 301 (54.62%) patients. IPI high risk score was recognized in 63.9% patients of group 3. Only 1.5% of patients were treated with exclusive radiotherapy. Of the patients that were treated with chemotherapy, 4.9% were treated with MOPP, 23.1% with MOPPABV, 70.5% with ABVD and 1.5% with other types of chemotherapy. The median follow-up of the entire cohort was 59.6 months (0–258.8 months) and 88.3% (CI 95%: 85.2%-91.1%) were in CR at the end of treatment (CS I: 100%, CS II: 90.6% CS III: 84.6% and CS IV: 85.3%; p=0.03) (group 1: 98.2%, group 2: 90.2% and group 3: 84.9%; p=0.012). The 5-year EFS rate was 69.2% (CS I: 84.8%; CS II: 77.8%; CS III: 64.5%, CS IV: 56%; p=0.0008) (group 1: 88%, group 2: 76% and group 3: 60.3%; p=0.0002) (Figures 1 and 2). The 5-year OS rate was 86.44% (CS I: 90.3%, CS II: 94.6%, CS III: 87.6%, CS IV: 71.4%; p<0.0001) (group 1: 98.3%, group 2: 92.6% and group 3: 79, 6%; p=0.0003).Figure 1Figure 1. Figure 2Figure 2. We found that there were more advanced stage patients (stage III/IV) in comparison to developed countries, however, patients classified as stage I/II without poor prognostic factors, like B symptoms and/or bulky disease, showed high rates of CR, EFS and OS. These data suggest that there is a need to enhance early diagnosis in Brazilian patients, in order to detect less advanced stage patients due to late diagnosis. Disclosures: No relevant conflicts of interest to declare.

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Park, Steven I., Kristy L. Richards, Oludamilola Olajide, Nishitha M. Reddy, Nilanjan Ghosh, Elizabeth E. Budde, Matthew C. Foster et al. „A Phase 2 Trial of Induction Chemotherapy with ABVD Followed By Brentuximab Vedotin Consolidation in Patients with Previously Untreated Non-Bulky Stage I or II Hodgkin Lymphoma“. Blood 124, Nr. 21 (06.12.2014): 4431. http://dx.doi.org/10.1182/blood.v124.21.4431.4431.

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Abstract Background: Treatment of Hodgkin lymphoma (HL) requires a careful balance between providing enough therapy to cure the disease and avoiding unnecessary treatment that could result in excessive long-term treatment-related complications. The preferred treatment option for limited stage non-bulky HL currently involves the use of combined chemotherapy and involved-field radiation therapy. Given the unclear overall survival advantage and the long-term side effects associated with consolidative radiation, the use of this modality remains one of the most controversial topics in the treatment of HL. Therefore, alternative consolidation approaches are worthy of exploration for treatment of limited stage non-bulky HL. Brentuximab vedotin has been associated with favorable response rates in patients with relapsed or refractory HL. We hypothesize that brentuximab vedotin may be safe and effective in eradicating residual disease after induction chemotherapy and may potentially replace radiation therapy for consolidation in patients with newly diagnosed limited stage non-bulky HL. Methods: In this phase 2 multicenter study, patients with non-bulky (< 7.5 cm) stage I or II HL are being enrolled to determine the efficacy and safety of brentuximab vedotin when administered for consolidation after a standard chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (ClinicalTrials.gov #NCT01578967). The primary objective of the study is to estimate the proportion of patients who achieve PET-negative disease (Deauville score of 2 or less) after induction chemotherapy followed by consolidation with brentuximab vedotin. Involved-field radiation is recommended only if the PET scan is positive at the completion of therapy with brentuximab vedotin. Patients received 2 to 6 cycles of ABVD based on their baseline risk factors and the interim PET scan result; patients with favorable disease with negative interim PET received 2 cycles, favorable disease with positive interim PET or unfavorable disease with negative interim PET received 4 cycles, and unfavorable disease with positive interim PET received 6 cycles of ABVD. Approximately 6 to 8 weeks after the induction chemotherapy, 1.8 mg/kg of brentuximab vedotin was given every 3 weeks for 6 cycles for consolidation. Results: Interim analysis was performed per protocol for futility and safety after 15 evaluable patients were enrolled since April 2012. Out of 15 evaluable patients, 8 patients have completed 6 cycles of brentuximab vedotin, and the remaining 7 patients are currently under active treatment. The median age was 28 years (range 19 – 58), and 7 patients (47%) presented with unfavorable disease defined by the presence of B symptoms, ESR > 50, or > 3 sites of disease. All patients had masses measuring less than 7.5 cm in diameter except one patient who requested an exception to the eligibility criteria for a conglomerate mediastinal mass measuring 10 cm. No grade 3 or above adverse events have been observed with brentuximab vedotin therapy. No grade 2 or above peripheral neuropathy or pulmonary toxicity has been reported. Ten out of 12 patients, who completed ABVD, achieved PET-negative disease after 2 cycles of ABVD, and all 7 patients who completed brentuximab vedotin achieved PET-negative disease and remain in remission with a median follow-up of 7.6 months (range 5.6 – 15). Thus far, none of the treated patients on this protocol required consolidative radiation therapy. Conclusion: In this interim analysis of 15 patients with newly diagnosed limited stage non-bulky HL, brentuximab vedotin as consolidation therapy demonstrates promising safety and clinical activity following ABVD. Enrollment is currently open with the target accrual of 40 patients to assess the feasibility of achieving PET-negative disease and thereby avoiding radiation therapy in at least 85% of patients who receive ABVD followed by brentuximab vedotin consolidation. Table: PET results in HL patients who received ABVD followed by BV Consolidation Interim-PET2 (n = 12) Post ABVD (n = 12) Post BV (n = 7) Deauville 1 0 1 4 Deauville 2 10 11 3 Deauville 3 2 0 0 Deauville ≥ 4 0 0 0 PET, positron emission tomography; HL, Hodgkin lymphoma; ABVD, doxorubicin, bleomycin, vinblastine, dacarbazine; BV, brentuximab vedotin; Interim-PET-2, PET scan after 2 cycles of ABVD; Post ABVD, PET scan after 2 to 6 cycles of ABVD; Post BV, PET scan after 6 cycles of brentuximab vedotin Disclosures Park: Seattle Genetics: Research Funding; Teva: Research Funding; Janssen: Travel, Travel Other. Off Label Use: Brentuximab vedotin in previously untreated Hodgkin lymphoma patients.

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Savage, Kerry J., Joseph M. Connors, Don Wilson, Richard Klasa, Tamara Shenkier, Paul Hoskins, Nicholas Voss und Laurie H. Sehn. „FDG-PET Guided Consolidative Radiotherapy in Patients with Advanced Stage Hodgkin Lymphoma with Residual Abnormalities on Post Chemotherapy CT Scan.“ Blood 110, Nr. 11 (16.11.2007): 213. http://dx.doi.org/10.1182/blood.v110.11.213.213.

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Abstract Consolidative radiotherapy (RT) is often administered following chemotherapy for advanced stage Hodgkin lymphoma (HL) with bulky disease at diagnosis or for residual abnormalities on post-chemotherapy CT imaging. It is unknown whether RT is necessary for such patients if the residual mass is FDG-PET-negative (PET-neg) following chemotherapy (CHT). Further, it has been previously shown that a post-therapy PET-positive (PET-pos) scan is highly predictive of future relapse; however, it is unclear whether consolidative RT can be used to salvage these cases. Methods Since July 2005, adult (> 16 y) patients in British Columbia (BC) with advanced stage HL (stage III /IV and/or the presence B symptoms and/or bulky disease (> 10cm)) have been treated with 6 cycles with ABVD followed by a PET scan for further treatment planning if residual abnormalities ≥2 cm were observed on CT imaging. Prior to this, post-treatment PET scans were obtained in some individuals by self-pay. If the PET scan was positive, RT was administered if feasible, otherwise, patients were observed. There were 68 eligible patients, including 7 self-pay patients, that were identified in the BC Lymphoid Cancer Database. 16 patients were excluded (PET not performed (5); palliative tx or refusal (3); composite lymphoma (1); progressive disease during CHT or at the time of PET scan (4); HIV + (1); PET mid-therapy (1); death due to unrelated cause prior to PET scan (n=1).), leaving a total of 52 patients who had a PET scan post-chemotherapy for a residual mass and who had adequate follow-up (median 19 m, 10–59 m). Patient characteristics include: M:F 1.1:1, Median age 29 (17–81); 55% stage II, 46% stage III/IV 44%; 49% bulky disease; 69% B symptoms; IPFP Prognostic score 0 8%; 1 39%; 2 26%; >3 26%. Results In total, 40/52 (77%) were PET-neg and 12/52 (23%) were PET-pos (SUV mean 4.4, 2.2–6.8). PET-pos patients had an inferior 2 y PFS compared to PET-neg patients (26% vs 91%, p=.001). In the PET-pos group, 10/12 received the planned RT and 5 have relapsed. In the PET-neg group, there was no difference in the 2 y PFS in patients with bulky (n=17) vs non-bulky disease (n=20) (86% vs 94%, p=.35). Conclusions Advanced stage HL patients who achieve a post-CHT PET-neg status are at a low risk of relapse and do not require additional consolidative RT thus avoiding potential long-term side effects. The majority of patients with bulky disease who have a PET-neg scan following CHT also remain in remission, however, longer follow-up is still needed. Although some patients with a positive PET-scan may be salvaged by consolidative RT, a high proportion ultimately relapse. Figure Figure Figure Figure

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Gallamini, Andrea, Andrea Bianchi, Anna Borra, Jan M. Zaucha, Bogdan Malkowski, Antoine Thyss, Nicolas Mounier et al. „Dual-point FDG-PET: A novel scanning technique in Hodgkin lymphoma with bulky disease.“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): 8077. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8077.

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8077 Background: Interim 18F-FDG-PET (iPET) is the most important prognosticator in advanced-stage ABVD-treated Hodgkin Lymphoma (HL), but in early stage w/ or w/o bulky lesion a low PPV of iPET was reported. Dual-point PET scan (2P-PET) has been used to discriminate unspecific inflammatory from neoplastic FDG uptake. At the Tx end, with a single FDG-avid mass (SFAM), the specificity of PET in Tx response evaluation was sub-optimal. We report here preliminary results from a cohort of HL patients (p) presenting with bulky lesions, scanned with 2P-PET with the aim to increase specificity and PPV. Methods: From 12.2008 till 01.2012 24 HL bulky p from Italian, French and Polish centers underwent 2P-PET at baseline (2P-PET-0), after 2 ABVD (2P-PET-2) and at Tx end (2P-PET-end). 2P-PET scanning technique consisted in 2 consecutive image acquisitions +60’ (EaS) and +120’(LaS) after single, standard-dose FDG injection. Tx was ABVD (x4 or x6) ± consolidation RxT. No Tx change was done based on iPET results. Scans were reviewed by 2 expert readers in a consensus session. Standardized-Uptake Value (SUV)MAX was calculated both in EaS and LaS using Volume of Interest Regions (VOIs) in sites of residual FDG uptake already recorded in PET-0. ΔSUVMAX and FDG retention index (RI) were calculated from SUVs in the same VOIs of both scans. Results: In 24 p (1 stage I,12 II, 4 III, 7 IV), 34 2P-PET were done.10 p underwent 2P-PET-0: in 10/10 SUVMAX increased from EaS to LaS (ΔSUVMAX 1-4.3). 15 p had a 2P-PET-2: 12 with a mean-follow-up of 18.36 months were evaluable, 3 too short ( +1, +5, +6 months). 7/12 p showed a RI reduction of 55% (200-14): all are in continuous CR (CCR). 5/12 p. showed a 20% (11-26) RI increase: all progressed +1 to +9 months after Tx end. Overall 3/12 cases (1 false +, 2 false- with a Deauville score 4 and 2,3 respectively) were correctly classified after 2P-PET. 9 p with a SFAM had a 2P-PET-end: in the 5/9 with an increased RI of 23% (9-43) a biopsy proved HL relapse. In 4/9 a reduced RI of -29% (9-45) was found: in 2 biopsy disclosed presence of residual thymic along with inflammatory tissue and 2 were in CCR +2 to+8 after Tx end. Conclusions: DSUV Max increased at baseline and in all relapsing patients, and decreased in patients in CCR. The PPV and a PNV of 2P-PET were 100%.

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Balhara, Kirti, Sarika Singh, Shyamlata Jain, M. K. Daga und Anubhav Vindal. „Epstein Barr Virus in Hodgkin’s Lymphoma a Path Less Treaded: An Observational Study“. Annals of Pathology and Laboratory Medicine 7, Nr. 6 (07.07.2020): A311–319. http://dx.doi.org/10.21276/apalm.2845.

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Background: Epstein-Barr virus (EBV) is a ubiquitous virus belonging to γ-Herpesvirus subfamily, infecting B cells, T cells, Natural killer (NK) cells & causes both benign and malignant diseases. It has been detected in large subset of Hodgkin lymphoma (HL) cases around the world, especially in countries with poor socioeconomic conditions and among younger age. Limited studies are available reflecting the Indian scenario of HL and EBV association. EBV positivity in Indian HL varies from 28-97% Majority of these studies employed Immunohistochemistry (IHC) for LMP1, a few performed In Situ Hybridisation (ISH) for EBER. Objective: To study the association of EBV in classical HL by immunohistochemical expression of latent membrane protein 1 (LMP1) antigen in North Indian population and to correlate it with different demographic variables & subtypes of HL. Materials and Methods: Observational study including 26 untreated HL cases diagnosed on lymph node excision biopsy. IHC was performed for EBV LMP1, CD15, CD30, CD45, CD3, CD20. Results: Patients ranged in age from 5-55years (median 18yrs), with M:F ratio of 3.3:1. Palpable lymphadenopathy was found in all cases followed by pallor (64%), B symptoms (50%), nodal pain (30.8%) & bulky disease (19.2%). Maximum number of patients were in Stage I (65.4%) followed by stage II&III (15.4% each) & stage IV (3.8%). Mixed cellularity HL comprised 77%, lymphocyte depleted 11.5%, nodular sclerosis 7.7% & lymphocyte rich 3.8%. IHC for EBV LMP1 was positive in 73.1% cases. Mixed cellularity HL showed an association in 70% cases. Conclusions: HL in India is a disease of young males, with mixed cellularity as the commonest subtype, highly associated with EBV and presentation at an early stage.

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Nguyen, Van T., Judy P. Tsai, John P. Greer, David S. Morgan und Nishitha M. Reddy. „Combined Modality Approach for Early Stage Unfavorable Hodgkin Lymphoma- Can We Avoid Radiation Therapy Based on Interim PET Imaging?“ Blood 124, Nr. 21 (06.12.2014): 5430. http://dx.doi.org/10.1182/blood.v124.21.5430.5430.

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Abstract Background: Prior studies have demonstrated the utility of involved field radiation therapy to reduce relapse rates and improve local control in Hodgkin Lymphoma (HL). The standard treatment for early stage unfavorable HL is combined modality approach with chemotherapy and radiation therapy (XRT). Despite reduction in the fields of XRT, long term adverse outcomes are associated with the combined modality approach. Recent clinical trials have focused on adapting therapy based on interim PET scans. There is, however, limited data evaluating patient outcomes with chemotherapy alone in unfavorable, bulky HL patients. Methods: Two hundred and fifteen patients diagnosed with HL at our institution were included in our retrospective analysis after obtaining IRB approval. Statistical analysis was performed by chi-square analysis, Wilcoxon signed rank sum test and Kaplan-Meier plots using SPSS.19 software. Results: Of the 215 patients, 48 had early stage unfavorable HL and were included in this analysis. Unfavorable HL was defined as bulky disease (>10cm or >1/3 thoracic diameter), ESR >50 or >3 extra nodal sites involvement at presentation. The median age at diagnosis was 31 years (range 17-58). Twenty-two patients (46%) were male. All patients had an Eastern Cooperative Oncology Group performance status of either 0 or 1. Nineteen patients (40%) presented with B symptoms. The majority (83%) of patients were treated with 4-6 cycles of ABVD as first line therapy, while the remainder were treated with COPP/ABV, Stanford V, ABV or MOPP/ABV. Approximately half of the patients received XRT (54%), which was determined by physician choice. Forty-six patients (96%) were alive at the time of analysis. Seven patients (15%) underwent autologous stem cell transplantation for either disease relapse or for an incomplete response. Interim PET data was missing in 8 patients, who were excluded from subsequent analysis. Interim PET was positive in 13 of the remaining 40 patients, 9 of whom received consolidative radiation therapy and 4 of whom received high dose therapy followed by autologous stem cell transplantation. Among the 27 patients with negative interim PET, 12 received XRT. The median overall survival (OS) of all patients was 38.8 months. In patients with negative interim PET scan, the PFS was 83% and 80% in patients who received chemotherapy with and without XRT, respectively. The OS was 83% and 100% in patients who received chemotherapy with and without XRT, respectively. The differences in PFS and OS were not statistically significant between the two groups. Two patients died in the group that received combined modality treatment after negative interim PET, one from pre-existing cardiomyopathy and one from progression of disease. No death was related to XRT. In a subgroup analysis, eleven of the 27 patients with negative interim PET had bulky disease, 8 of whom received XRT. The PFS in this subgroup was 75% and 100% in patients who received chemotherapy with and without XRT, respectively. The OS in this subgroup was 88% and 100% in patients who received chemotherapy with and without XRT, respectively. Conclusion: Our data suggests that radiation therapy can be avoided based on interim PET scan in early stage unfavorable HL without compromising OS. The high overall survival of these patients may be accounted for by the fact that many who fail initial treatment can be salvaged with high dose chemotherapy and autologous stem cell transplantation. Given the potential for reduction in radiation related adverse outcomes, we encourage participation in ongoing prospective, PET-adapted, clinical trials investigating the need for consolidative XRT following chemotherapy in patients with unfavorable, bulky disease. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Bhethanabhotla, Sainath, Sreenivas Vishnubhatla und Sameer Bakhshi. „Predictors of Poor Response to Salvage Chemotherapy in Relapsed/ Refractory Pediatric Hodgkin Lymphoma- A Retrospective Analysis from Tertiary Cancer Centre in India“. Annals of the National Academy of Medical Sciences (India) 54, Nr. 03 (Juli 2018): 160–70. http://dx.doi.org/10.1055/s-0040-1712842.

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ABSTRACT Background: Previous studies identified prognostic factors for survival in relapsed pediatric Hodgkin lymphoma (HL) who received salvage chemotherapy followed by autologous stem cell transplant (ASCT). However, data regarding predictors of poor response to salvage chemotherapy is limited. Methods: We conducted retrospective study in all relapsed HL treated from January 2003 to December 2013. Logistic regression analysis was done to identify predictors of response to salvage chemotherapy. Cox regression analysis was done to identify prognostic factors for Freedom from treatment failure (FFTF) and overall survival (OS). Results: Forty six patients had relapsed HL. Among 45 patients who received salvage chemotherapy only 34 (73.4%) underwent ASCT. Stage 4 disease (p=0.02) and bulky disease at relapse (p=0.03) were predictors of poor response to salvage chemotherapy. FFTF and OS at 5 yr for entire cohort were 50.1% and 63.3%, respectively, while the same for patients who underwent ASCT were 66.3% and 80.7%, respectively. Among ASCT patients, those who had primary refractory /early relapse [HR-4.7, (95% CI-1, 22); p=0.05] had significant impact on 5 yr FFTF whereas disease status at transplant (CR vs. No CR) had significant impact on 5 yr OS [HR-4.6, (95% CI-1.03, 20.5); p=0.04]. Conclusions: Identification of predictors of poor response to salvage chemotherapy is an unmet need in the management of pediatric HL since complete response (CR) before transplant is independent predictor of survival. Stage 4 and bulky disease at relapse are high risk factors to predict incomplete response. Future trials should explore newer agents for effective salvage for these patients to attain complete response before ASCT.

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Advani, Ranjana, Fangxin Hong, Leo I. Gordon, Randy D. Gascoyne, Henry Wagner, Richard T. Hoppe, Richard I. Fisher et al. „Patterns of Failure in Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma (HL) Treated with ABVD + Radiotherapy or the Stanford V Regimen in the Randomized Phase III North American Intergroup Trial: E2496“. Blood 118, Nr. 21 (18.11.2011): 1603. http://dx.doi.org/10.1182/blood.v118.21.1603.1603.

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Abstract Abstract 1603 Background: We have previously reported similar outcomes for patients with bulky stage I or II mediastinal HL treated with combined modality therapy either with ABVD + radiotherapy or the Stanford V regimen in the North American Intergroup trial E2496 (Advani et al, ASH 2010 abstract 416). In the current analysis, we compare the patterns of failure between the two groups. Methods: Patients with stage I/II bulky mediastinal HL (maximum mediastinal mass width > 1/3 of intrathoracic diameter) were randomized to receive chemotherapy (CT) on either Arm A (ABVD x 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V administered weekly). Two-3 weeks after completion of chemotherapy all patients received modified involved field radiotherapy (RT) (36 Gy) delivered to the mediastinum, hila, and supraclavicular regions. Patients on Stanford V arm also received involved field RT to any other sites ≥ 5 cm at diagnosis. Patients were assessed 3, 6 and 12 months after completing RT with computed tomography scanning and then every 6 months for 5 years. The primary end points were failure free survival (FFS) and overall survival (OS). Disease progression was defined as 'in-field', 'distant' or both relative to the radiation fields prescribed in the E2496 protocol. Distant sites of failure were further characterized as intra-thoracic, intra-abdominal or other (bone, bone marrow and axillae, if not previously irradiated). Results: Two hundred and sixty-seven patients were randomized: 136 on the ABVD arm and 131 on the Stanford V arm. Patient characteristics were well matched with no differences between two arms in overall response rates (ORR), FFS and OS. (Advani et al ASH 2010 abstract 416). At a median follow up of 5.5 years 40 patients have relapsed with no difference in ABVD (n=18, 13%) versus Stanford V (n=22, 17%) (p=0.49). Central review of RT fields available in 37/40 patients found major violations with under treatment of tumor noted in 7/37 (19%). Patterns of failure are shown in Table 1. There were no differences in patterns of relapse for the two study arms. In-field relapses occurred in <10% in both study arms. Conclusion: For patients with stage I/II bulky mediastinal HL, combined modality therapy with either ABVD +RT or the Stanford V regimen results in excellent disease control. In-field relapse was uncommon. These results set a benchmark for assessing ongoing trials omitting RT in patients with stage I/II bulky mediastinal HL. Future research efforts should focus on risk stratification to identify the small subset of patients who are likely to fail standard upfront therapy. US cooperative group efforts in this subset of patients are ongoing that use interim PET-CT imaging based risk-adapted strategies. Disclosures: Horning: Genentech: Employment, Equity Ownership.

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Gallamini, Andrea, Alessandro Rambaldi, Alberto Biggi, Silvia Tavera, Caterina Patti, Caterina Stelitano, Alessandro M. Gianni et al. „BEACOPP Chemotherapy Is Able to Induce Durable Complete Remission in Poor-Prognosis Hodgkin’s Lymphoma Patients with a Positive Interim PET after 2 ABVD Cycles“. Blood 112, Nr. 11 (16.11.2008): 2594. http://dx.doi.org/10.1182/blood.v112.11.2594.2594.

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Abstract Background: Early interim-PET (PET-2) is the most powerful factor able to predict treatment outcome in advanced-stage Hodgkin Lymphoma (HL) patients treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). The 2-y PFS of PET-2 positive patients is only 12%, but the optimal treatment for this patient subset is still unknown. For this reason in January 2006 a treatment policy was designed by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) to early intensify chemotherapy with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for HL patients with a PET-2 positive after 2 ABVD cycles. Patients and methods: 136 HL patients with advanced-stage or intermediate-stage with adverse prognostic factors (more than 3 nodal sites, ESR > 50 mm, sub diaphragmatic presentation, bulky lesion), consecutively admitted to nine GITIL Italian centers were treated with two ABVD courses and re-evaluated with interim-PET. Twenty-one of these 136 patients proved to be PET-2 positive, and 19/21 are the object of this analysis. The mean age was 31.7 years (16–64), 10 patients were in stage II, 9 in stage III–IV. Bulky disease was present in 11, and B-symptoms in 16. Fourteen patients showed an IPS score 0–2, 5 patients a score 3–7. The median interval between the end of second ABVD course and PET-2 was 11 days (5–14). BEACOPP (4 escalated and 4 standard cycles) was followed by consolidation radiotherapy in 3 patients for bulky mediastinal tumor. PET scan were centrally reviewed by two well-experienced nuclear medicine experts, using the blood pool mediastinal structures (BPMS) as reference for the residual uptake, as elsewhere published (Gallamini, JCO 2007). Results. Upon central review, 2 interim-PET scan were classified as minimally positive in 2 patients, with a single MRU (Minimal Residual Uptake) lesion showing a SUV (Standardized Uptake Value) lower than BPMS, and therefore only 19 cases were suitable for the BEACOPP salvage treatment. After a mean follow-up of 14.3 months (7.0–30.2), 15 patients remain in continuous CR and 4 had a treatment failure because of disease relapse (1) or progression (3). For the responding patients the mean duration of CR was 13.0 months (6.5–30.2). The IPS score for progressing patients was 2, 3, and 4; for the relapsing-one, 0. At time of this analysis, l8 patients are still alive and 1 died during BEACOPP treatment for disease progression. The 1-year second treatment failure-free survival (1-y 2TFFS) was 94.7 % (95% C.I. 84.7–100). The 1 y OS survival was 93.3 (95%C.I. 80.7–100). In univariate analysis the only clinical factor related to treatment failure was the presence of extra-nodal disease. (Log-rank=6.8 p=0.009). Conclusions. BEACOPP-escalated regimen was able to induce durable CR in most (15/19) HL patients with a positive interim-PET. These results, although requiring a longer follow-up and a higher number of patients, seem to suggest that the very-poor prognosis of PET-2 positive, ABVD-treated HL patients can be substantially improved by early chemotherapy intensification; escalated-BEACOPP is likely to represent a good treatment choice for this very poor prognosis patient subset.

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O'Brien, Maureen M., Sarah S. Donaldson, Raymond R. Balise, Alice S. Whittemore und Michael P. Link. „Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy“. Journal of Clinical Oncology 28, Nr. 7 (01.03.2010): 1232–39. http://dx.doi.org/10.1200/jco.2009.24.8062.

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Purpose Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation. Patients and Methods Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires. Results One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (± SE) 5-year disease-free and overall survival were 76% ± 12% and 85% ± 10% with median follow-up 5 years from SMN diagnosis. Conclusion Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.

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Advani, Ranjana, Fangxin Hong, Richard I. Fisher, Nancy L. Bartlett, Sue Robinson, Randy D. Gascoyne, Henry Wagner et al. „Randomized Phase III Trial Comparing ABVD + Radiotherapy and the Stanford V Regimen In Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the US Intergroup Trial E2496“. Blood 116, Nr. 21 (19.11.2010): 416. http://dx.doi.org/10.1182/blood.v116.21.416.416.

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Abstract Abstract 416 Background: Standard therapy for locally extensive Hodgkin Lymphoma (HL) defined as stage I/II with bulky mediastinal disease [mediastinal mass ratio (MMR) > than 1/3 of the chest diameter on standing postero-anterior chest x-ray or 10 cm on computerized tomography] is combined modality therapy (CMT). E2496 was a North American intergroup, randomized phase III study comparing ABVD versus the Stanford V regimen for patients with locally extensive and advanced stage HL. In this subgroup analysis we compare two CMT approaches, ABVD + radiotherapy (RT) and the Stanford V regimen, in patients with stage I/II bulky mediastinal HL. Methods: Patients with stage I/II HL bulky mediastinal disease were randomized to receive chemotherapy (CT) on either Arm A (ABVD × 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V, administered weekly). Two-3 weeks after completion of chemotherapy, modified involved field RT was delivered at 36 Gy to the mediastinum to patients on ABVD as well as Stanford V. Patients on Stanford V also received involved field RT to any other sites >5 cm at diagnosis. The primary endpoint was failure free survival (FFS) defined as the time to either progression/relapse or death. The log-rank test was used to compare FFS and OS (overall survival) for all eligible patients. Results: Of the 812 eligible patients with advanced HL enrolled on the study 267 had locally advanced bulky mediastinal disease: 136 on ABVD and 131 on Stanford V. Patient characteristics between the two randomized groups were well matched with a median age of 30 years and 86% had stage II disease. On ABVD 61% of patients received 6 cycles, 29% 8 cycles of CT and 77% required some dose modification. In Stanford V 97% completed the assigned 12 weeks of CT and 76% required some dose modification. 82% received RT per protocol in ABVD versus 88% in Stanford V. The overall response (CR+PR) was 82% in ABVD and 86% in Stanford V. At a median follow-up of 5.47 years, there are 19 failures and 6 deaths in the ABVD group and 25 failures with 9 deaths in the Stanford V group. We failed to detect statistically significant differences between ABVD +RT and Stanford V for FFS (5y 85% versus 77% p=0.13, HR=1.56 95% CI (0.87, 2.88) and OS (5y 95% versus 92% p=0.31, HR=1.69 95% CI (0.60, 4.75). No difference in hematologic toxicity was observed between the two arms. Evaluation of pulmonary function and patterns of failure are pending. Conclusions: For stage I/II patients with bulky mediastinal disease, CMT with either ABVD +RT or the Stanford V regimen results in high cure rates and is highly effective. ABVD for 6–8 cycles plus 36 Gy RT remains the US standard of care. Longer follow up is required to assess RT related late effects. Future research efforts should focus on risk stratification to identify; a) the 15–20% of patients destined to relapse after standard therapy and evaluate treatment intensification strategies and b) the 80–85% of patients who are cured with standard therapy and determine whether a subset can achieve the same excellent outcomes with a reduction or elimination of radiation. Planned US cooperative group trials will address these questions, using ABVD as the chemotherapy backbone in conjunction with interim PET imaging for risk stratification. Disclosures: Blum: Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

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Younes, Anas, Francisco Hernandez, R. Gregory Bociek, Yvette L. Kasamon, Peter Lee, Lia Gore und Amanda R. Copeland. „The HDAC Inhibitor Entinostat (SNDX-275) Induces Clinical Responses in Patients with Relapsed and Refractory Hodgkin's Lymphoma: Results of ENGAGE-501 Multicenter Phase 2 Study“. Blood 118, Nr. 21 (18.11.2011): 2715. http://dx.doi.org/10.1182/blood.v118.21.2715.2715.

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Abstract Abstract 2715 Background: Entinostat (ENT) is an oral, class 1 isoform selective HDACi that preclinically has been shown to induce apoptosis in HL cells, block production of tumor growth promoting factors found in the HL microenvironment and up-regulate T cell co-activators important in inducing anti-tumor immune responses. Based on these data and promising activity observed with this class of agents, this phase 2 study was designed to define ENT single agent activity and safety profile in relapsed and refractory HL. Methods: A total of 49 patients (pts) were enrolled on two dosing schemes designed to establish single agent ENT activity for HL. 33 pts received either 10 mg or 15 mg every other week (wk) and 16 pts received 15 mg on days 1, 8, and 15 every 28 days. Primary endpoint was objective response rate (CR+PR), CT/PET scans were conducted every 2 cycles. Blood was obtained at baseline, D1, D8, and D15 of cycle 1 of both schedules for biomarker analysis to determine ENT effects on a panel of immunomodulatory cytokines, chemokines and growth factors. Results: The median age was 33 years (19–73), median prior regimens was 3 (1–10); 30 (61%) pts relapsed after autologous SCT, 4 (8%) after allogeneic SCT and 5 (10%) following both; 17 pts progressed after one or more investigational therapies, 30 (79%) pts had bulky disease (1 or more baseline lesions > 5cm). For the efficacy analysis, 38 pts were evaluable for response. Tumor reductions were observed in 61% of pts (23 (6 PR+17 SD) with preliminary PFS of 3.8 months (mths). Four pts with PR remain on treatment with time on study from 4.4–17 mths and 1 PR went on to SCT. One SD pt became PET negative and remains on ENT in mth 7; an additional SD pt was PET negative and went on to SCT. The majority of pts had some tumor reduction at wk 8, however maximum response often occurred after 4 cycles (wk 16). A similar percentage of patients completed > 2 cycles with both dosing schedules with 15/27 (56%) on the every other wk dosing and 5/11 (45%) on weekly dosing. 9 pts (5 pts on weekly dosing) remain alive without disease progression, and 7 began a new anticancer therapy prior to PD; median PFS is not yet reached for pts on the weekly dosing schedule. The median OS is 22.1 mths for the first 33 pts (not reached for 16 pts dosed weekly). Common G 1/2 AEs regardless of treatment relationship were gastrointestinal, fatigue, and edema. The most common ENT-related events were G 3/4 thrombocytopenia in 27 (55%) patients, G 3/4 neutropenia in 20 (41%) patients, and G 3/4 anemia in 21 (43%) patients. These events were reversible with dose reduction or delay. Conclusions: Single agent ENT was well tolerated and demonstrated antitumor activity in HL pts progressing after SCT with bulky disease in about a third of patients within 2 cycles of therapy. The ORR is consistent with activity demonstrated with other HDACi in HL. Durable responses in bulky disease pts can be achieved with this single agent with tolerable toxicity. ENT provides a non-cross resistant mechanism of action with cytotoxic therapy and study in combination with other agents earlier in the disease course is warranted. Disclosures: Younes: Genentech: Research Funding; SBIO: Research Funding; Syndax: Research Funding; Novartis: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding. Hernandez:Celgene: Consultancy, Honoraria, Research Funding; Millenium Pharmaceuticals: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding. Kasamon:Genentech: Research Funding; Seattle Genetics: Research Funding.

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Tartas, Norma E., Marta Zerga, Maria I. Santos, Graciela Alfonso und Maria Amoroso. „International Prognostic Score (IPS) Is Not Useful in Stages I–II Hodgkin’s Lymphoma (HL) - An Experience of the Buenos Aires Leukemia Group (BALG).“ Blood 108, Nr. 11 (16.11.2006): 4659. http://dx.doi.org/10.1182/blood.v108.11.4659.4659.

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Abstract The International Prognostic Factors Project on advanced HL developed a prognostic score to predict treatment outcome in patients with advanced disease treated with modern chemotherapy,with or without radiotherapy (RT).The score incorporates seven adverse prognostic factors (APF): age ≥45yrs old, male sex, stage IV, hemoglobin<10.5,serum albumin <4 g/dl,leukocytosis≥ 15×109/L and lymphocytopenia (< 0.6× 109/L). Patients with ≤ 2 APF have a two year freedom from progression of 80% while those with 3 or more APF have a worse outcome, each additional factor reduces the prognosis by about 8%. To study the utility of IPS in less advanced disease, we looked into our patients included in the HD 98 protocol for stages I–II HL.According to this protocol, patients without bulky disease,B symptoms or N< 3, received 4 cycles of standard ABVD plus IFRT.Patients with one or more of the unfavourable characteristics received 6–8 cycles of standard ABVD plus RT in areas of bulky or residual disease.Since December 98, ninety two patients have been included, 91 are evaluable for this report.Patient characteristics were as follows: 44 males,47 females, Age 30yr (15–80).Histologic subtypes were: LP:5, NS:64, MC:21, LR:1. Clinical stages IA:13, IAX: 3, IB:1, IBX:3, IIA:34, IIAX:13, IIB:19, IIBX:5. Looking to IPS impact in freedom from progression we have simply considered two subgroup of patients: low risk (<3APF) and high risk (≥ 3APF).Only 6/91 patients belonged to the high risk group. With ABVD 92% of the patients got a CR.Four patients were considered to be primary resistant, we have lost follow up of two patients, three persons have relapsed and two of them got a second CR. Currently 85/91 are alive, with a median FU of 56 months .All patients with a high IPS obtained a prolonged CR . Three patients have relapsed at 7,13 and 30 months;all belonged to the low risk IPS group.Four patients with primary resistant HL have died, three of them had had an autologus bone marrow transplant .All primary resistant HL belonged to the low risk IPS group. We think that IPS is not useful in stages I–II HL, because it is only significantly altered in less than 10% of the patients. One possible explanation might be, that IPS relies on laboratory parameters such as white cell counts in peripheral blood, hemoglobin levels and serum albumin which are less affected, in early stages of the disease .Interestingly 5/6 patients with high risk IPS had B symptoms and 3/5 had bulky or N3 disease, consequently they received 6–8 cycles of ABVD. These facts, might have had influence in our results. In our experience resistance to ABVD have a dismal prognosis in HL. IPS was not a good predictor of progression or resistance in this cohort of patients.

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Martinez, Carmen, Mercedes Rodriguez-Calvillo, María José Terol, Blanca Xicoy, Ramón García-Sanz, Elena Perez-Ceballos, Alberto Cantalapiedra et al. „Salvage Treatment with Ofatumumab and ESHAP (O-ESHAP) for Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma After First-Line Chemotherapy: Interim Analysis of a Phase II Trial of the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO)“. Blood 120, Nr. 21 (16.11.2012): 1630. http://dx.doi.org/10.1182/blood.v120.21.1630.1630.

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Abstract Abstract 1630 The management of recurrent or refractory Hodgkin's lymphoma (HL) remains challenging. Previous published data have suggested that infiltrating normal B lymphocytes in classic HL lesions may contribute to the survival of Hodgkin and Reed-Sternberg cells in vivo. The objective of this prospective, multicenter, phase II trial was to investigate the activity of an anti-CD20 monoclonal antibody, ofatumumab, in combination to a standard platinum-based salvage regimen, ESHAP (O-ESHAP) followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) for patients with classical HL failing to first line chemotherapy. Forty- five patients (25 M / 21 F, median age 34 years, range 18–66) were enrolled in the study between June 2010 and June 2012. Treatment consisted on three cycles of ESHAP plus ofatumumab 1,000 mg days 1 and 8 on first cycle and day 1 on second and third cycles. At the time of study entry, 66% of patients had III-IV Ann Arbor stage, 16% bulky disease, 18% B symptoms, 40% extranodal HL and 52% ≥3 involved nodal areas. We respect to response to first-line therapy, 46% patients had achieved a completed response (CR) and then relapsed, 6% had a partial remission (PR), whereas the remaining 48% were primary refractory. Eighty-one percent patients have received 3 cycles of O-ESHAP as scheduled, three patients 2, and five 1 cycle (1 patient due to toxicity, 1 patient's decision, 2 HL progression, and 4 treatments ongoing). Grade 3–4 WHO hematological toxicity was observed in 16%, 19%, and 20% after cycles 1, 2, and 3, respectively. Non-hematological toxicity was reported in 32%, 10%, and 20%, respectively. Overall response (OR) rate was 63% (49% CR and 14% PR). Response to O-ESHAP according to prior response to first-line chemotherapy is shown in table 1. Adequate PBSCs collection was achieved in 94% mobilized patients. Twenty-six out of 33 patients have already proceeded to ASCT. Two patients died of neutropenic sepsis after ASCT and HL progression, respectively. Preliminary results of this ongoing trial suggest that addition of ofatumumab to ESHAP is safe and has a promising clinical activity in patients with relapsed/refractory HL candidates to ASCT. Table 1. Response to O-ESHAP according to previous response to first-line treatment Response to first-line chemotherapy Relapsed or partial response (n=17) Refractory (n=16) Response after O-ESHAP OR 16 (94%) 7 (44%) CR 14 (82%) 3 (22%) PR 2 (12%) 4 (22%) Refractory 1 (6%) 9 (56%) Disclosures: No relevant conflicts of interest to declare.

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Ouyang, Jing, Annette Plütschow, Elke Pogge, Sabine Ponader, Gabriel Rabinovich, Donna S. Neuberg, Andreas Engert und Margaret A. Shipp. „Galectin-1 Serum Levels Reflect Tumor Burden and Adverse Clinical Features in Hodgkin Lymphoma“. Blood 120, Nr. 21 (16.11.2012): 51. http://dx.doi.org/10.1182/blood.v120.21.51.51.

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Abstract Abstract 51 Galectin-1 (Gal1) is a member of a highly conserved family of carbohydrate-binding proteins that modulate innate and adaptive immune responses and foster tumor immune escape. Through the selective recognition of specific cell-surface glycans (Gal-beta1-4-NAcGlc [N-acetyllactosamine] units on the branches of N- or O-linked glycans), Gal1 induces the apoptosis of Th1 and cytotoxic T cells. Th2 cells have different patterns of sialylation of cell-surface glycoproteins, lack Gal1 ligands, and resist Gal1-induced cell death. Regulatory T (Treg) cells are also resistant to Gal1-mediated apoptosis. In addition, Gal1 promotes hypoxia-driven tumor angiogenesis. Primary Hodgkin lymphomas (HLs) include small numbers of malignant Reed-Sternberg cells within a Th2/Treg-skewed inflammatory infiltrate. In previous studies, we found that Reed-Sternberg cells overexpress Gal1, which selectively kills Th1 and cytotoxic T cells and promotes the immunosuppressive Th2/Treg-predominant HL microenvironment. In HLs, which exhibit constitutive AP-1 activation, Gal1 overexpression is driven in large part by an AP-1-dependent enhancer. Given the immunosuppressive function of Gal1, we reasoned that the secreted protein might be a potent marker of disease activity and a novel therapeutic target. We previously developed a panel of Gal1 monoclonal antibodies and demonstrated the utility of Gal1 as a diagnostic marker of AP-1-dependent lymphoid malignancies. A potent neutralizing Gal1 antibody also protected Th1 and cytotoxic T cells from Gal1-induced apoptosis, abrogated Gal1-associated tumor angiogenesis and limited the growth of Gal1+ tumors in vivo. We have now developed a sandwich ELISA to assess the utility of Gal1 as a serum marker of disease burden in HL. After establishing the sandwich ELISA with purified recombinant Gal1 and the newly developed Gal1 antibodies, we assessed the levels of serum Gal1 in 15 healthy normal donors and 315 newly diagnosed, previously untreated HL patients from the German Hodgkin Study Group. The HL patients were enrolled on 3 tailored, risk-adapted clinical trials: HD13 for early-stage disease (clinical stage [CS] IA-IIB) with no risk factors, 94 pts); HD 14 for early stage disease with risk factors (CS I-IIA with large mediastinal mass, extranodal disease, elevated ESR or > 3 nodal areas and CS IIB with elevated ESR or > 3 nodal areas, 90 pts); and HD18 for bulky localized or advanced stage disease (CS IIB with bulky mediastinal involvement and/or extranodal involvement and CS III or IV, 131 pts). Serum Gal1 levels were significantly elevated in HL patients in comparison to normal controls (median value 2.3 X higher, p <.0001; 100% specificity and 78% sensitivity with a cut-off value of ∼ 50 ng/ml). HL patients on the clinical trial for early-stage low-risk patients (HD13) had significantly lower Gal1 levels than patients on either HD14 or HD18 (p =.0006). We next evaluated the potential association of Gal1 serum levels with Ann Arbor stage and B-symptoms, two major determinants for assigning HL pts to risk-adapted therapy. Gal1 levels were significantly higher in HL pts with advanced-stage disease (stage I/II vs. III/IV, p <.001) and B symptoms (absence vs. presence, p =.03). We also assessed the potential association of Gal1 levels with individual clinical prognostic factors in the Hodgkin Lymphoma International Prognostic Score (IPS). In univariate analyses, Gal1 levels were highly correlated with the following clinical risk factors: extranodal involvement (p =.01); > 3 lymph node areas (p =.0001); elevated erythrocyte sedimentation rate (ESR) (p =.0015); albumin < 4 g/dl (p =.035); hemoglobin < 10.5 g/dl (p =.035); lymphoma count < 600 per mm or < 8% of white cell count (p =.015). Consistent with these observations, HL patients with an IPS score of >= 2 had significantly higher Gal1 levels than patients with an IPS of 0 or 1 (p =.007). Direct analyses of the association between Gal1 levels and outcome await completion of the ongoing HD18 clinical trial. In conclusion, Gal1 serum levels are significantly associated with tumor burden and additional adverse clinical characteristics in newly diagnosed HL patients. Given the demonstrated role of Gal1 in tumor immune evasion and angiogenesis, analyses of circulating Gal1 levels may inform risk-adapted and targeted treatment strategies for HL patients. Disclosures: No relevant conflicts of interest to declare.

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Cedrych, Ida, Slawomir Blamek, Andrzej Deptala und Krzysztof Skladowski. „Skeletal Disorders as Late Complications in Hodgkin Lymphoma Survivors“. Blood 112, Nr. 11 (16.11.2008): 4962. http://dx.doi.org/10.1182/blood.v112.11.4962.4962.

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Abstract Background: Long-term complications of musculoskeletal system are rare in adult Hodgkin lymphoma (HL) survivors, thus is uncertain whether these complications are treatment-related. Aim: The goal of this study was to analyze risk, frequency and type of skeletal damage in HL survivors. Methods: The study comprises of a retrospective analysis of 170 patients (pts) suffered from HL, and treated in an oncological center in Poland between 1979–2005. There were 88 females and 82 males, median age 30.5 years (range 16–72). According to the Ann Arbor clinical staging system there were 22 cases (12.5%) in CSI, 95 cases (55.8%) in CSII, 26 cases (15.4%) in CSIII and 27 cases (15.8%) in CSIV. Fifty six percent of the patients presented B-symptoms, and 60% had bulky disease. Vast majority of cases were diagnosed as classical HL, with histologic subtypes of nodular sclerosis grade 1 in 45%, nodular sclerosis grade 2 in 14%, mixed cellularity in 21%, lymphocyte depletion in 5.2%, and lymphocyte-rich in 7%. However 5.8% of the cases were unclassified by a histopathologist. Chemotherapy with a median of 6 cycles/patient was given to 93.5% of cases (ABVD – 29.4%, MOPP/ABV – 37.6%, MOPP – 24.1%, other – 2.25%). Chemoradiotherapy was given to 61.8% of pts. Radiotherapy alone (mantle-field or involved-field), with a median dose of 40 Gy (range 21–46.8) received 6.5% of pts. For statistical analysis we used Kaplan-Meier method and log-rank test Results: With a median follow-up of 242 months (range 0–439) a skeletal disorder (SD) was detected in 27 (15.8%) of the patients. Median time to identify SD was 29.5 months. Skeletal disorders were diagnosed as follows: osteoarthritis (11 pts), avascular (aseptic) necrosis of bone (3 pts), osteoporosis (3 pts), osteopenia (3 pts), rheumatoid arthritis (2 pts), vertebral osteochondritis (2 pts), idiopathic (nontraumatic) subluxation of wrist (1 patient), fibrosis of vertebral body (1 patient), and inflammation of nucleus pulposus (1 patient). In the statistical analysis there was no relationship between the risk of SD and: sex, bulky disease, B symptom, involvement of extralymphatic organ, histologic subtype, radiotherapy, chemotherapy, and chemotherapeutic regimen. However, we found an association of SD risk with clinical stage. The difference between CSI and CSIII was statistically significant (p = 0.0235). There were no differences between CSII and CSIII (p = 0.0564), as well as CSIII and CSIV (p = 0.0787). Conclusions: In our group of adult HL survivors skeletal disorders caused substantial amount of long-term complications. We found no relationship between treatment modality and the risk of a skeletal disorder, despite high median dose of radiotherapy and extensive use of alkylating agents. The association between skeletal disorder and more advanced clinical stage is difficult to explain, however it might suggest a possible role of initial tumor burden and excessive crosstalk between cancer and reactive immune/inflammatory cells.

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Potre, Ovidiu, Monica Pescaru, Alexandra Sima, Ioana Ionita, Raluca Tudor, Ema Borsi, Miruna Samfireag und Cristina Potre. „Evaluation of the Relapse Risk and Survival Rate in Patients with Hodgkin Lymphoma: A Monocentric Experience“. Medicina 57, Nr. 10 (27.09.2021): 1026. http://dx.doi.org/10.3390/medicina57101026.

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Background and objectives: Hodgkin lymphoma (HL) is characterized by the presence of malignant Reed Sternberg cells. Although the current curability rate in patients with HL has increased, up to 30% of those in the advanced stages and 5% to 10% of those in limited stages of the disease, relapse. According to the studies, the relapse risk in HL decreases after 2 years. The purpose of this study is to evaluate the relapse risk and event free survival (EFS) in patients with HL treated with Doxorubicin, Bleomycin, Vinblastine and Dacarbazine (ABVD), or treated with Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone (BEACOPP) regimens. Material and methods: In an observational, consecutive-case scenario, 71 patients (median age 32 years; range 16 to 80 years) diagnosed within a 4-year timeframe were enrolled; all patients were treated according to standards of care. The average follow-up duration was 26 months. Results: The risk of relapse, in patients older than 40 years, decreased after 1 year, OR = 0.707 (95% CI 0.506 to 0.988), and 2 years, OR = 0.771 (95% CI 0.459 to 1.295), respectively. Patients in the advanced stages had a higher International Prognostic Score (IPS) (score ≥ 4). The overall survival at 2 years was 57.74% and the disease-specific survival at 2 years was 71.83%. Regardless, the chemotherapy regimen and the EFS time, advanced stage, high IPS and bulky disease were still associated with an increased relapse risk in patients with HL. Conclusions: The use of ABVD chemotherapy regimen followed by 2 years EFS was associated with a reduced relapse risk.

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Shafer, Danielle, Hossein Borghaei, Michael Millenson, Nicos Nicolaou, Tahseen I. Al-Saleem, Nick C. Leasure, Kris Padavic, Mitchell R. Smith und Russell J. Schilder. „Vinblastine, Mitoxantrone and Prednisone (MVP) Followed by Involved Field Radiotherapy (IF-XRT) for Early Clinical Stage Hodgkins’s Lymphoma: Long Term Follow-Up.“ Blood 106, Nr. 11 (16.11.2005): 2677. http://dx.doi.org/10.1182/blood.v106.11.2677.2677.

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Abstract Background: The treatment of early stage Hodgkin’s lymphoma (HL) continues to evolve in attempt to improve the safety profile of the regimens and decrease their long-term toxicities. Treatment related mortality exceeds that from HL after 12 to 15 years. In light of the potential long-term complications associated with irradiation and chemotherapy, particularly pulmonary and cardiac toxicity, alternative approaches minimizing exposure to drugs with long-term organ toxicity have been examined. Objectives: We evaluated a novel regimen of MVP and IF-XRT for non-bulky early-stage HL. The primary outcomes were response rate and freedom from disease progression. Secondary outcomes were toxicity, specifically pulmonary and cardiac dysfunction. Methods: Patients were enrolled in this multi-site phase 2 study between 1995 and 1999. Eligible patients were 18 years of age or older, had ECOG performance status 0–2 and pathologically confirmed, clinically staged non-bulky Stage I or II HL. Patients received a minimum of four cycles of mitoxantrone 8mg/m2 and vinblastine 6 mg/m2 intravenously on days 1 and 15 of each 28-day cycle. Prednisone 100mg was given orally days 1 to 5 and 15 to 19. Chemotherapy was continued for two additional cycles after complete response, up to eight cycles. Patients then received IF-XRT (30.6 Gy-39.6 Gy) four weeks after completion of chemotherapy. G-CSF was not used as primary prophylaxis. Results: Thirty-four patients were evaluated for response in a final review. A total of 32 patients (94%) achieved a complete remission after combined therapy. Thirty patients (88%) achieved a complete response after chemotherapy alone. At a median follow-up of 49 months (range 16.9–79.7 months), 10 patients had relapsed, and three deaths were documented. None of the deaths occurred during treatment. The median time to progression was 30 months. The overall survival and disease-free survival rates at 5 years were 90% (95% confidence interval [CI], 73–97%) and 78% (95% CI, 58–89%), respectively. The treatment was well tolerated without significant grade 3/4 toxicity. (Grade 3/4 leukopenia 18% of patients; neutropenia 28%) There were no significant changes in DLCO or left ventricular ejection fraction at 12 months observed after chemotherapy. Twenty-one patients received only 4 cycles of chemotherapy; the median dose intensity for the entire group was 85%. Conclusions: As the management of early-stage HL continues to evolve in attempt to reduce long-term toxicity, this trial serves as a reminder of the balance required between efficacy and toxicity in this largely curable population. In this relatively well-tolerated regimen, there was minimal long-term toxicity, but a high number of relapses, most of which were successfully salvaged with resultant excellent 5-year overall survival rates. As the treatment for early-stage HL moves forward, there will undoubtedly be further attempts to modify the ABVD backbone. We await those results as well as long term data from the German Hodgkin Study group investigating reduction of combined modality treatment (HD10) in a similar patient population.

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Sobol, Urszula A., Tulio E. Rodriguez, Scott E. Smith, Aileen Go, Ross Vimr, Mala Parthasarathy, Rong Guo und Patrick Stiff. „Long Term Follow-up of Allogeneic Transplantation Using BEAM Chemotherapy for Patients with Hodgkin's Lymphoma Who Relapse After Autologous Transplantation: Importance of Minimal Residual Disease At Transplant.“ Blood 120, Nr. 21 (16.11.2012): 3131. http://dx.doi.org/10.1182/blood.v120.21.3131.3131.

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Abstract Abstract 3131 Patients with relapsed or refractory Hodgkin's Lymphoma (HL) who fail autologous transplantation seldom survive long term and most have exhausted effective therapeutic options. Preliminary data however suggests a role for allogeneic transplantation (allo-SCT) using reduced intensity conditioning (RIC), with 2–5 year progression free survival (PFS) and overall survival (OS) of 20–36% and 28–64%, respectively. Allo-SCT for HL is still uncommon however with CIBMTR data indicating a median of only 2 allografts/center/year (range: 1–13) at US centers. Methods We report 7 year outcome on 31 consecutive patients with HL who failed an autograft who were prospectively enrolled in a single institution trial and treated with BEAM RIC regimen (BCNU 300mg/m2 day -6, Etoposide 100mg/m2 daily and Cytarabine 100mg/m2 BID days -5 to -2, and Melphalan 140mg/m2 day -1). Graft vs host disease (GVHD) prophylaxis was with tacrolimus (0.03mg/kg/day starting day -2) and methotrexate (5mg/m2 days +1,+3,+6). Antithymocyte globulin (ATG 1.5mg/kg/day on days -4, -3) was used in 17 patients who underwent matched unrelated donor (MUD) transplantation and had no cytotoxic chemotherapy in the preceding three months. Results Median time from diagnosis to allo-SCT was 51 months (range: 17–172) and median age was 36 (range: 21–55 years). Patients were heavily pretreated with a median number of 5 prior regimens (including autograft; range: 4–9). Thirteen patients received stem cells from an HLA-matched sibling, 12 MUDs, 5 mismatched unrelated and 1 had mismatched related stem cells. All patients engrafted promptly at a median of 15 days (range: 12–26) defined as an absolute neutrophil count of >0.5 × 109/L and a median of 26 days (range: 10–76) for unsupported platelets >20 × 109/L. 100-day chimerism results were available for 26 patients: 23 (88%) were full donor chimeras (>98% donor DNA), 1 was a mixed chimera at 96% donor DNA, and one patient had graft rejection. The incidence of grade 1–2 acute GVHD was 29% and grade 3–4 was 7%. Incidence of limited stage chronic GVHD (cGVHD) was 56% and extensive stage was 9%. At a median follow up of 7 years the PFS is 36% (95% CI 19–54%) and OS is 42% (95% CI 23–59%), with no relapses seen after 36 months. Non-relapse mortality at one year was 13% (95% CI 5–32%). Significant predictors of improved survival in univariate analysis included chemosensitivity, bulk of disease <2cm, and performance status of 0–1. In multivariate analysis only bulk of disease predicted outcome. Patients transplanted with minimal bulk (<2cm; n=18) had a 4 year PFS and OS of 62% and 75% vs 8% and 8% for patients with bulky disease (p=0.005 for PFS, p=0.001 for OS). To underscore importance of bulk of disease, patients with chemorefractory but non-bulky disease had a favorable 4 year OS of 71% while patients with chemosensitive but bulky disease had a 4 year OS of 33%. Patients with both chemorefractory and bulky disease had the worst outcome with a 100% relapse rate and no survivors after 4 years (Fig 1). Patients with cGVHD had a trend towards lower relapse rates, 43% vs 70% at 4 years (p=0.125). Five patients were treated with donor lymphocyte infusions for relapsed disease after allo-SCT, only 3 achieved a transient PR. Brentuximab vedotin was used in five patients to facilitate allo-SCT, 4 responded (3 PR and 1 CR). Two additional patients who relapsed after allo-SCT received brentuximab vedotin; they are the only survivors with relapsed disease at 29+ and 94+ months, respectively. Conclusion RIC BEAM allogeneic transplantation is safe and effective in producing long term remissions in patients with advanced HL who fail autografts. Bulk of disease is the only significant prognostic factor for a successful outcome regardless of chemosensitivity, thus patients with chemorefractory disease should be offered an allo-SCT after additional therapy has been given to achieve a minimal residual disease state, e.g with brentuximab vedotin and/or involved field radiation. While very preliminary, brentuximab vedotin also appears promising in the treatment of relapsed HL after allograft failure and thus should be further explored as maintenance therapy after engraftment to reduce early relapses while awaiting a potential graft vs Hodgkin's effect. Disclosures: Rodriguez: Seattle Genetics, Inc: Research Funding. Smith:Seattle Genetics, Inc: Consultancy, Research Funding. Stiff:Seattle Genetics, Inc: Research Funding.

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Pavlovsky, Santiago, Claudia S. Corrado, Miguel A. Pavlovsky, Virginia Prates, Lucia Zoppegno, Mario Giunta, Ider Cerutti et al. „Risk-Oriented Therapy in Adults Previously Untreated Hodgkin’s Lymphoma (HL) with ABVD Followed by Involved Field Radiotherapy (IFRT). Final Results of the Argentinian Group for Treatment of Acute Leukemia (GATLA) Phase III Study.“ Blood 108, Nr. 11 (01.11.2006): 2474. http://dx.doi.org/10.1182/blood.v108.11.2474.2474.

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Abstract Introduction: The present goal standard for the treatment of HL is ABVD plus low doses of IFRT. With the purpose of maintaining a high response rate, event-free survival (EFS) and overall survival (OSV) with minimal toxicity we adapted the number of cycles of ABVD and doses of IFRT to the risk at diagnosis and early response. Methods: From December 1996, up to October 2005 a total of 527 patients, 15 to 75 years old (median 28) previously untreated entered the study. Patients with clinical stage I, II, IIIA without bulky tumor (< 10 cm mass or < 1/3 thoraxic diameter) (low-risk) received 3 cycles of ABVD followed by IFRT 25 Gy to all node areas of more than 2 cm at diagnosis. A total of 55 out of 267 patients (21%) with low-risk who failed to achieve complete remission (CR) after 3 cycles of ABVD were included as high-risk completing 6 cycles of ABVD. Patients with clinical stage IIIB and IV or all other stages with bulky disease or persistance lymph nodes areas after 3rd cycle of ABVD (high risk) received 6 cycles of ABVD followed by IFRT 30 Gy to bulky areas at diagnosis or those areas remaining > 2cm after 3 cycles. The dose of ABVD was the standard; Adriamycin 25 mg/m2, Bleomycin 10 IU/m2, Vinblastine 6 mg/m2 and Dacarbacine 375 mg/m2 all IV on day 1 and 15 of each 28 days cycles. Patients who achieved partial remission (PR) were salvage with other regimen mainly ESHAP × 3 cycles followed by high dose therapy with autograft rescue. Results: A total of 211 (99%) out of 212 patients with low-risk achieved CR. One 74 year old patient died of pneumonia after the third ABVD. A total of 277 (87%) of 315 patients with high-risk achieved CR, 28 PR, 9 failed to respond (FR), and 1 died of sepsis (P<0,001). The estimate EFS at 60 months was 91% and 72% (P< 0.001), while the OSV was 99% and 89% (P=0.001) for low and high risk respectively. Of the 28 patients with PR, all received second line therapy followed in 17 by an autograft, 13 patients are in CR, 3 are in PR, 1 alive in progressive disease (PD) and 11 died of PD. Of the 9 who FR, five received an autograft, five are alive (CR 3, PR 2) and four died of PD. One patient developed a MDS/AML after relapsing from an autograft and 8 months after having been rescued with BEACOPP. Eight other second cancer (2 NHL, and 6 solid tumours) appeared after treatment, three died and 6 remain alive, 2 in CR of their HL. Using the IPI HL 205 patients (45%) have scored 0–1, 206 (46%) scored 2–3, and 39 (9%) scored ≥ 4 out of 450 patients. The rate of CR was 97%, 90%, and 87% respectively (P<0.020). The estimated EFS at 60 months was 87%, 76% and 61% respectively (P=0.001). The OSV was 97%, 91% and 78% (P=0.004). Conclusion: This risk-oriented therapy based in cycles of ABVD and doses of IFRT in 527 patients with HL without previous treatment, produced an overall CR rate of 93%, EFS of 80% and OSV of 93% at 60 months.

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Bohlius, Julia, Heinz Haverkamp, Volker Diehl, Houchingue Eghbali, Jeremy Franklin, Beate Pfistner, John Raemaekers, Andreas Engert und Michel Henry-Amar. „Identification of Prognostic Factors in Patients with Early Stage Unfavorable Hodgkin’s Lymphoma: An Individual Patient Data Meta-Analysis.“ Blood 106, Nr. 11 (16.11.2005): 5577. http://dx.doi.org/10.1182/blood.v106.11.5577.5577.

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Abstract Background: In patients with early stage unfavorable Hodgkin’s lymphoma (HL) event-free-survival (EFS) is low compared to patients with early favorable or advanced stage disease. An international collaborative study was initiated to identify prognostic factors that could help to define among early stage unfavorable patients those who might benefit from more intensive treatment. Methods: Medline and Cochrane Library were systematically searched for randomized controlled trials in stage I/II HL. Trials should concern patients with one or more risk factors (age, sex, stage, B-symptoms, bulky disease, number of areas involved, laboratory parameters) receiving 4–6 cycles of ABVD or similar chemotherapy and radiotherapy. Only trials with ≥ 100 patients per study arm were considered. Individual patient data were collected. Results: Six studies were identified: GHSG: HD5, HD8, HD11; EORTC: H6U, H7U, H8U. Data from 4,235 patients enrolled between 08/1982 and 01/2003 were available for analysis. The proportion of missing data was very low for demographic and clinical characteristics (< 1%); it was acceptable (1.5–9%) for laboratory parameters with the exception of albumin (41% missing values, not recorded in 3 trials). Patient characteristics are listed below. The median follow up was 58.4 months (95% CI 56–61). At the time of analysis 612 patients had experienced an event (disease progression, relapse or death) leading to a 5-year EFS rate of 85%. Using an univariate Cox-regression stratified by study and treatment arm several parameters showed significant influence on EFS. Conclusion: The data set available is sufficiently powered to identify relevant prognostic factors. A multivariate analysis using updated data will be presented. Baseline parameter of inlcuded studies Age (median years) Male sex Sage (I/II) B symptoms Bulky disease Hb (median g/dL) All patients, n=4,325 32 2,039 (48.1%) I: 546 (12.9%), II: 3,688 (87.1%) 1,490 (35.2%) 1,936 (45.7%) 12.9 Missing data 1 (< 1%) 0 1 (< 1%) 35 (< 1%) 0 82 (1.9%)

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Dann, Eldad J., Osnat Bairey, Rachel Bar-Shalom, Elinor Sabbag, Marina Izak, Abraham Korenberg, Luiza Akria et al. „Tailored Therapy in Hodgkin Lymphoma, Based on Predefined Risk Factors and Early Interim PET/CT: Israeli H2 Study“. Blood 124, Nr. 21 (06.12.2014): 4409. http://dx.doi.org/10.1182/blood.v124.21.4409.4409.

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Abstract Introduction: The aim of therapy in Hodgkin lymphoma (HL) is to maximize response and minimize long-term toxicity. Methods: This multicenter study prospectively evaluated outcomes of HL patients (pts) recruited between 9/2006-8/2013, whose therapy was chosen according to baseline prognostic factors and tailored based on PET/CT results performed after 2 cycles of chemotherapy (PET-2). Pts with classic HL aged 18-60 years, stages I-IV were eligible. Those with early HL were categorized into early favorable (EFD) and unfavorable (EUD) disease groups. After 2 ABVD cycles, EFD pts with negative PET-2 underwent involved nodal radiation therapy (INRT) and EUD pts received 2 more ABVD cycles (total 4) followed by INRT. At physician's discretion, young pts requiring large-field irradiation could be given a total of 6 ABVD cycles with no RT. Pts with positive PET-2 received 2 additional ABVD cycles (total 4) in EFD and 4 additional cycles (total 6) in EUD followed by RT in both groups. Thus, differences in treatment modality between early disease pts with positive and negative PET-2 included addition of 2 ABVD cycles and mandatory RT for pts with positive PET-2. Pts with advanced HL (B symptoms or stages III/IV) were assigned to therapy based on the International Prognostic Score (IPS). Standard-risk pts (IPS 0-2) initially received 2 ABVD cycles and those with IPS of ≥ 3 received 2 cycles of escalated BEACOPP (EB). If PET-2 was negative or showed minimal residual uptake in a single site, further therapy with 4 ABVD cycles was given and RT to bulky mediastinal masses was omitted. If PET-2 was positive with no evidence of HL progression, therapy was escalated to EB with RT given to bulky mediastinal masses. Results: Data on 356 pts are presented in Table 1. At a median follow-up of 36 months (4-92), 3-y PFS for pts with early disease, overall, and for those with negative and positive PET-2, was 89, 91 and 74%, respectively (p=0.004). For pts with advanced HL, 3-y PFS overall and among those with negative and positive PET-2 was 85, 86 and 75%, respectively (p=0.012). No difference in PFS was observed according to IPS score. RT was given to 45% of pts with early and 12.5% of pts with advanced disease. Three pts died: one during autologous stem cell transplant (SCT), one after allogeneic SCT and one from acute myocardial ischemia. Conclusions: Tailored therapy based on PET-2 is feasible both in early and advanced HL. A positive PET-2 is a marker of inferior prognosis both in early and advanced disease, even when therapy is escalated. For pts with advanced disease and high IPS, initiation of therapy with EB provides a higher rate of negative PET-2 than reported with ABVD. De-escalation of therapy is safe in advanced HL pts with negative PET-2 and does not affect the outcome. RT could be omitted in half of pts with early disease with no difference in PFS. Further follow-up is needed to draw conclusions regarding the long-term efficacy and safety of this personalized approach. Abstract 4409. Table N Pts with negative PET-2 N (%) Predictive value of PET-2Treatment adapted based on PET-2 Pts experiencing disease progression/relapseNPVPPVEscalation/ reductionN (%)Pos/NegPET-2Total356305(86)91%21%20/6146 (13)12/34Early disease173148 (85)92%32%10/018 (10)7/11Favorable2518 (75)94%16%6/02 (8)1/ 1Unfavorable148130 (88)92%37%4/016 (10)6/10Advanced183157 (86)85%22%10/6128 (15)5/23IPS 0-210694 (90)86%33%10/016 (15)3/13IPS ≥37763(81)84%14%0/6112 (15)2/10 PPV = Predictive value of positive PET-2 for relapse/progression Disclosures No relevant conflicts of interest to declare.

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Moccia, Alden A., Felicitas Hitz, Paul Hoskins, Richard Klasa, Maryse Power, Kerry J. Savage, Tamara Shenkier et al. „Gemcitabine, Dexamethasone, and Cisplatin (GDP) Is An Effective and Well-Tolerated out-Patient Salvage Therapy for Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) and Hodgkin Lymphoma (HL)“. Blood 116, Nr. 21 (19.11.2010): 113. http://dx.doi.org/10.1182/blood.v116.21.113.113.

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Abstract Abstract 113 Introduction: DLBCL and HL represent highly curable lymphoid malignancies. Patients (pts) whose lymphoma is refractory to or relapses following initial therapy pose a significant therapeutic challenge. The goal of therapy is to proceed to a non-cross-resistant salvage regimen followed by high dose chemotherapy (HDC) and stem cell transplantation (SCT) for transplant eligible pts. The optimal choice of salvage therapy remains unknown. The combination of gemcitabine, dexamethasone and cisplatin (GDP) has been shown in phase II studies to induce high response rates with minimal toxicity (Baetz T, Ann Oncol, 2003; Crump M, Cancer, 2004). Based on these promising results, British Columbia Cancer Agency (BCCA) policy has recommended GDP as the preferred salvage regimen for pts with relapsed/refractory DLBCL and HL since 2002. Patients and Methods: We conducted a retrospective analysis using the BCCA Lymphoid Cancer Database and included all pts with relapsed/refractory DLBCL and HL who received GDP as salvage therapy between September 2002 and June 2010. Pts were treated with gemcitabine 1000 mg/m2 IV day 1,8; dexamethasone 40 mg PO days 1–4 and cisplatin 75 mg/m2 IV day 1, administered at 3 week intervals (2-3 cycles for transplant eligible patients and up to 6 cycles for non-transplant candidates). Primary endpoints were response rate, PFS (defined as the interval from the beginning of GDP to first progression, relapse or death from any cause) and OS. Results: 235 pts treated with GDP were identified; 152 and 83 pts with relapsed/refractory DLBCL and HL, respectively. Clinical characteristics at time of diagnosis for patients with DLBCL were: 68% male, 65% stage III/IV, 42% bulky disease ≥ 10 cm, 43% B-symptoms, 59% IPI 0–2, 41% IPI 3–5. Median age at time of GDP was 57 y (range 20–79 y). 57 pts (37%) had primary refractory disease to first-line R-CHOP; 144 (95%) were treated with GDP at first relapse/progression; median time from diagnosis to relapse after R-CHOP (excluding primary refractory pts) was 21 m (range 7–139 m). 30 pts (20%) received rituximab with GDP. Detailed radiologic response assessment following GDP(+/−R) was available for 82% pts with response rates as follows: 16% CR/CRu, 33% PR, 17% SD, 34% PD. 9 pts (6%) underwent HDC followed by allogeneic SCT and 57 pts (38%) underwent HDC followed by autologous SCT. With median follow-up of 24 m from start of GDP (range 0–84 m), 51 pts (34%) were alive and 101 pts (66%) have died (99 from lymphoma, 1 treatment toxicity during allogeneic SCT, 1 unrelated cause). 2-y PFS and OS were 21% and 28%, respectively. The 2-y PFS and OS for the subset of patients who underwent HDC/SCT were 36% and 47%, respectively. Clinical characteristics at diagnosis for the 83 pts with relapsed/refractory HL were: 55% male, 59% stage III/IV, 39% bulky disease ≥ 10 cm, 55% B-symptoms, 80% nodular sclerosis, 4% mixed cellularity, 2% nodular lymphocyte predominant, 2% lymphocyte depleted and 12% HL NOS. IPS variables were retrievable on 66% patients: 82% IPS ≤ 3 and 18% IPS ≥ 4. Median age at time of GDP was 31 y (range 17–73 y). 30 pts (36%) had primary refractory HL and 73 (88%) received GDP at first relapse/progression. Median time from diagnosis to relapse following ABVD-like therapy (excluding primary refractory pts) was 20 m (range 9–186 m). Detailed radiologic response assessment following GDP was available in 67% pts with response rates as follows: 7% CR/CRu, 64% PR, 13% SD, 16% PD. In total, 1 pt underwent HDC followed by allogeneic SCT and 69 pts (83%) proceeded to HDC and autologous SCT. With a median follow-up of 30 m from start of GDP (range 0–86 m), 70 pts (84%) were alive and 13 (16%) have died (all from HL). 2-y PFS and OS were 58% and 85%, respectively, and for the subset of pts who underwent HDC/SCT were 57% and 86%, respectively. Hospitalization rates due to complications during GDP were higher in patients with DLBCL than HL (20% vs 7%), likely reflecting differences in age and co-morbidities between the 2 cohorts. No failures of stem cell mobilization were recorded and the only toxic death was a consequence of HDC and allogeneic SCT. Conclusions: GDP is an effective and well-tolerated out-patient salvage regimen for relapsed/refractory DLBCL and HL. Outcomes appear to be comparable to those reported with more aggressive regimens. Results from an ongoing Canadian prospective trial comparing R-GDP to R-DHAP will help clarify the role of GDP in the treatment of relapsed/refractory DLBCL. Disclosures: Connors: Hoffmann-La Roche: Research Funding.

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Totadri, Sidharth, Venkatraman Radhakrishnan, Trivadi S. Ganesan, Prasanth Ganesan, Krishnarathnam Kannan, Kadur Mallaiah Lakshmipathy, Ganesarajah Selvaluxmy und Tenali Gnana Sagar. „Can Radiotherapy Be Omitted in Children With Hodgkin Lymphoma Who Achieve Metabolic Remission on Interim Positron Emission Tomography? Experience of a Tertiary Care Cancer Referral Center“. Journal of Global Oncology, Nr. 4 (Dezember 2018): 1–7. http://dx.doi.org/10.1200/jgo.2017.009340.

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Purpose Treating pediatric Hodgkin lymphoma (HL) involves a delicate balance between cure and reducing late toxicity. Fluorodeoxyglucose positron emission tomography (PET) combined with computed tomography (CT) identifies patients with early response to chemotherapy, for whom radiotherapy may be avoided. The role of PET-CT in upfront risk stratification and response–adapted treatment is evaluated in this study. Methods Patients with HL, who were younger than 18 years, were included. PET-CT was performed at baseline and after two cycles of chemotherapy. Patients were stratified into three risk groups: group 1 (stage I or II with no unfavorable features); group 2 (stage I or II with bulky disease/B symptoms); and group 3 (stage III/IV). A doxorubicin, bleomycin, vinblastine, dacarbazine–based regimen was used in early disease. A cyclophosphamide, vincristine, prednisolone, procarbazine, doxorubicin, bleomycin, vinblastine–based regimen was used in advanced disease. Results Forty-nine patients were included. Fifteen (31%), seven (14%), and 27 (55%) patients were included in groups 1, 2, and 3, respectively. Among 36 patients who underwent staging by PET-CT at diagnosis, seven (19%) patients were upstaged and one (3%) patient was downstaged by PET compared with CT. On the basis of negative interim PET responses, 39 (80%) patients were treated without radiotherapy. The 3-year event-free survival for the entire cohort was 91% (± 5.2%) and overall survival was 100%. Conclusion PET-CT is an excellent stand-alone staging modality in HL. The omission of radiotherapy can be considered in patients who achieve metabolic remission on interim PET.

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Herraez, Ines, Leyre Bento, Jaume Daumal, Alessandra Repetto, Raquel Del Campo, Adriana Sas, Rafael Ramos et al. „Improving Evaluation of Disease Burden at Diagnosis in Hodgkin Lymphoma“. Blood 136, Supplement 1 (05.11.2020): 24–25. http://dx.doi.org/10.1182/blood-2020-141875.

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Introduction: Hodgkin lymphoma (HL) is a hematological malignancy, with an inflammatory majority component of reactive cells and a few (1-2%) Reed-Sternberg cells (RSC). A high percentage of patients are cured with conventional strategies but approximately 15-30% relapse or progress. The standard tool to assess disease burden is the Ann Arbor Stage that classically categorizes HL in early (I-II) and advanced stages (III-IV). However, AA staging lacks accuracy in predicting outcome. New ways to asses tumor burden, such as baseline fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT), detect active disease with higher sensitivity in comparison with computed tomography (CT). Additionally, different volumetric parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), may be obtained from FDG PET/TC. We aim to improve disease burden testing using FDG PET/TC-related parameters, to better stratify HL patients at the time of diagnosis. Methods: We retrospectively selected patients with HL, homogeneously treated with ABVD +/- RT, at Son Espases and Son Llatzer University Hospitals in Palma de Mallorca from the databases of Pharmacy, Pathology and Nuclear Medicine Departments, to avoid selection bias. FDG PET/TC was done at baseline. MTV was measured with a semiautomatic method using a 41% maximum standardized uptake value (SUVmax) threshold and represents the sum of metabolic volumes of tumor tissues with increased FDG uptake. TLG was calculated by multiplying MTV and the mean SUV (SUVmean) of the MTV and was representative of the metabolic activity throughout the entire tumor. We used receiver operating curves (ROC) analysis to obtain the optimal cutoff for progression or death of all experimental FDG PET/TC-related variables. Standard clinical prognostic variables were obtained from medical records (age, gender, stage, bulky and ECOG PS) and main prognostic scores (IPS, EORTC and GHSG) were calculated. Progression-free survival (PFS) was considered the time from diagnosis to disease progression or death of any cause. Univariate survival analysis was done using Kaplan-meier plots and comparison between variables with log-rank test. Results: From August-2011 to November-2018, we included 101 patients. Table 1 shows main characteristics of patients. Median age was 37 years (14-83 years), 53% of patients had an advanced stage and 10% had bulky disease. With a median follow-up of 45 months (11-90), median PFS was 78%. The optimal cuttoffs obtained for MTV, TLG and SUVmax were 32.5, 167.8 and 10.4, respectively. In the univariate survival analysis, PFS was significantly influenced by MTV (p=0,007) and TLG (p=0.003), but not AA stage (Table 2). OS was significantly influenced by TLG (p=0.007) and SUVmax (p=0.001). With the three FDG PET/TC-related variables influencing HL survival we designed a FDG PET/TC score as follows: 1 point for high level of MTV, TLG or SUVmax (from 0 to 3). As shown in Table 2, this new FDG PET/TC score had a much better risk assessment that standard AA stage, being able to differentiate three risk groups with 100%, 84% and 65% 4-y PFS and 100%, 84% and 75% OS. Conclusions: The combination of functional 3D measurement of tumor burden (MTV, TLG and SUVmax) obtained from the FDG PET/TC at diagnosis, in HL, could be a valuable tool to better stratify the risk patients from tumor burden at the moment of diagnosis, when compared with standard AA staging. Disclosures No relevant conflicts of interest to declare.

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Pavlovsky, Santiago, Claudia S. Corrado, Miguel A. Pavlovsky, Mario Giunta, Lucia Zoppegno, Virginia Prates, Francisco Lastiri et al. „Risk-Adapted Therapy in Adults Previously Untreated Hodgkin’s Lymphoma (HL) with ABVD Followed by Involved Field Radiotherapy (IFRT).“ Blood 104, Nr. 11 (16.11.2004): 1310. http://dx.doi.org/10.1182/blood.v104.11.1310.1310.

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Abstract Background: The present goal for the treatment of HL is to develop a combined modality therapy with high response rate, disease-free survival (DFS) and overall survival (OSV) with minimal toxicity. Methods: On December 1996, the GATLA started a non randomized protocol for 15 to 75 years old (median 28) patients previously untreated. Patients with clinical stage I, II, IIIA without bulky tumor (< 10 cm mass or < 1/3 thoraxic diameter) (low risk) received 3 cycles of ABVD followed by IFRT 25 Gy to all node areas of more than 2 cm at diagnosis. A total of 46 out of 218 patients (21%) with low risk who failed to achieve complete remission (CR) after 3 cycles of ABVD were included as high risk completing 6 cycles of ABVD. Patients with clinical stage IIIB and IV or all other stages with bulky disease or persistance lymph nodes areas after 3rd cycle of ABVD (high risk) received 6 cycles of ABVD followed by IFRT 30 Gy to residual areas after the third cycle of ABVD or bulky areas at diagnosis. The dose of ABVD was the standard; Adriamycin 25 mg/m2, Bleomycin 10 IU/m2, Vinblastine 6 mg/m2 and Dacarbacine 375 mg/m2 all IV on day 1 and 15 of each 28 days cycles. Patients who achieved partial remission (PR) were salvage with other regimen mainly ESHAP x 3 cycles followed by high dose therapy with autograft rescue. Results: A total of 171 (99%) out of 172 patients with low risk achieved CR. One 74 year old patient died of pneumonia after the third ABVD. A total of 187 (85%) of 219 patients with high-risk achieved CR, 25 PR, and 7 failed to respond (FR) (P<0,001). The estimate DFS at 60 months was 92% and 67% (P< 0.001), while the OS was 98% and 89% (P=0.004) for low and high risk respectivelly. Of the 25 patients with PR, all received second line therapy followed in 15 by an autograft. Twelve patients are in CR, 5 are in PR, 2 in progressive disease and 6 died. Of the seven who FR, four died of PD an three are alive with the disease. One patient developed a MDS/AML after relapsing from an autograft and 8 months after having been rescued with BEACOPP. Five other second cancer (1 ovary, 2 NHL, 1 lung, 1 colon) appeared after treatment, two died and 3 remain in CR of their HL. Using the IPI HL 165 patients (48%) have scored 0–1, 145 (43%) scored 2–3, and 30 (9%) scored 3–4. The rate of CR was 96%, 88% and 87% respectively (P<0.016). The EFS at 60 months was 89%, 72% and 55% respectively (P=0.004). The OSV was 98%, 89% and 86% (P=0.037). Conclusions: We can conclude by saying that with risk-adapted therapy, 92% of the 391 patients achieved CR, with a CR + PR response of 98%. A total of 78% are event-free and 93% are alive at 60 months with remarkable low-toxicity.

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Abramson, Jeremy S., Robert A. Redd, Jeffrey A. Barnes, Elizabeth Bengtson, Ronald W. Takvorian, Lubomir Sokol, Frederick Lansigan et al. „A Phase II Study of Brentuximab Vedotin Plus Adriamycin and Dacarbazine without Radiation in Non-Bulky Limited Stage Classical Hodgkin Lymphoma“. Blood 132, Supplement 1 (29.11.2018): 1654. http://dx.doi.org/10.1182/blood-2018-99-115173.

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Abstract BACKGROUND: ABVD with or without radiation is standard therapy for limited stage HL, but carries risks of bleomycin-lung injury and radiation toxicity. Brentuximab vedotin (BV) is an anti-CD30 antibody drug conjugate which is highly active in relapsed classical HL. We previously combined BV with AVD in limited stage non-bulky classical HL which resulted in a high CR rate, but at the cost of increased neutropenia, neutropenic fever, and neuropathy, likely related to the overlapping toxicity profile with vinblastine. Similar toxicity findings were also observed with BV-AVD in advanced stage classical Hodgkin lymphoma. We therefore evaluated BV plus AD (BV-AD) without radiation therapy for non-bulky stage I-II classical HL with the goal of reducing toxicity and maintaining high rates of inducing CR. METHODS: This is a multicenter single arm open label phase 2 study. Patients received BV 1.2 mg/kg plus standard dose adriamycin and dacarbazine on days 1 and 15 of each 28 day cycle. GCSF prophylaxis was not included. Patients received 4 or 6 cycles of BV-AD based on the results of an interim PETCT scan performed following cycle 2. PET negativity was defined as Deauville scores 1-3. Patients in CR on interim PETCT received 4 total cycles of therapy; patients in PR completed 6 cycles. The primary endpoint is complete response rate (CRR) at end of treatment. A sample size of 34 was required to detect an end of treatment CRR of 95% with 91% power and alpha error of 0.09. RESULTS: 34 patients were enrolled. Median age is 36 (range 18-63). Stage is IA (3), IB (1), IIA (29) and IIB (1). Risk is classified per the GHSG criteria as early unfavorable in 47%, and favorable in 53%. The interim CR rate is 94%. Accordingly, 32 interim PET negative patients (94%) received 4 total cycles of therapy, and 2 interim PET positive patients (6%) received 6 total cycles of therapy. No patients received consolidative radiation therapy, per protocol. The primary endpoint of end of treatment CR rate is 100%. At a median follow-up of 15 months, the FFS, PFS and OS are all 100%. The most common adverse events of any grade are nausea (79%), peripheral sensory neuropathy (56%), fatigue (50%), constipation (38%), alopecia (35%) and neutropenia (24%). Most toxicities were low grade, with only 15% of subjects experiencing any grade 3 toxicity, and there were no grade 4 or 5 toxicities. Specifically, 2 patients had grade 3 neutropenia, and 1 patient each had grade 3 nausea/vomiting, pneumonia and thromboembolic event. Peripheral sensory neuropathy was grade 1 in 17 patients, and grade 2 in 2 patients. There were no cases of neutropenic fever. CONCLUSIONS: BV-AD for 4-6 cycles induces high interim and end of treatment CR rates of 94% and 100%, respectively, allowing 4 total cycles of therapy in most patients. The PFS, FFS and OS are all 100% at last follow up. Toxicity appears mild and notable for a low incidence of neutropenia, alopecia, and moderate peripheral neuropathy. This promising regimen avoids bleomycin, vinblastine, radiation and primary GCSF prophylaxis with resultant low toxicity and preserved high efficacy rates in patients with early favorable and early unfavorable non-bulky limited stage classical Hodgkin lymphoma. Follow up for this trial is ongoing. Figure. Figure. Disclosures Abramson: Merck: Consultancy; Seattle Genetics: Consultancy; Karyopharm: Consultancy; Verastem: Consultancy; Amgen: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board.

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Cheng, Phoebe Tsz Man, Diego Villa, Alina S. Gerrie, Ciara L. Freeman, Graham W. Slack, David W. Scott, Joseph M. Connors, Laurie Helen Sehn und Kerry J. Savage. „Outcome of elderly patients with classical Hodgkin lymphoma (HL) in British Columbia.“ Journal of Clinical Oncology 38, Nr. 15_suppl (20.05.2020): 8031. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.8031.

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8031 Background: Outcomes in elderly patients (pts) with Hodgkin lymphoma (HL) have traditionally been poor. We evaluated the survival of elderly pts (>60 years [y]) with classical HL in British Columbia (BC). Methods: All pts aged >60 y newly diagnosed with classical HL from 1961 to 2019 were identified in the BC Cancer Lymphoid Cancer Database. Limited stage was defined as non-bulky (<10 cm) stage 1A/IB or 2A (before 2000 1B = advanced stage), with the remainder considered advanced stage. Results: Following exclusions (HIV positive n=4, incomplete data n=21, prior or concurrent other lymphoproliferative disease n=67), 713 pts were identified. With a median follow up of 6.0 y (0.1 - 24.0 y) in living pts, there has been an improvement in 5 y DSS/OS (both p<.001) by decade comparison: 1960s (n=52) 25%/17%; 1970s (n=75) 38%/31%; 1980s (n=90) 51%/43%; 1990s (n=115) 53%/42%; 2000s (n=180) 66%/57%; 2010s (n=201) 63%/53%. To account for advances in diagnosis, staging, supportive care, and therapy in the modern era, we evaluated the outcome of pts diagnosed since 01/1995. A total of 368 pts were treated with curative intent (Table). Most pts received multi-agent chemotherapy (n=359, 98%: ABVD[like] n=351, alkylator-based n=7, CHOP n=1), 8 pts had radiotherapy (RT) alone, and 1 pt had surgery (primary CNS HL). The 5 y DSS, PFS, and OS were 74%, 57%, and 62%, respectively. Increasing age was associated with inferior outcomes (5 y DSS/PFS/OS): 61-70 y (81%/70%/74%), 71-80 y (69%/47%/52%), and >80 y (59%/27%/31%) (DSS p=.011; PFS p<.0001; OS p<.0001). Of 318 pts that received bleomycin, 60 (19%) developed pulmonary toxicity, including 22 cases that occurred after cycles 1 and 2. Overall, 24/368 pts (7%) died of acute treatment toxicity (pulmonary [bleomycin n=10, radiation n=1], infection n=10, cardiac n=3). There was no association between age and developing bleomycin (p=.80) or lethal treatment toxicities (p=.74). Conclusions: The outcome of elderly pts with HL has improved in recent decades. However, treatment related toxicity remains a concern and use of multi-agent chemotherapy, particularly bleomycin-containing regimens, should be undertaken with caution. [Table: see text]

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Dunleavy, Kieron, Stefania Pittaluga, John Janik, Nicole Grant, Seth Steinberg, Louis Staudt, Elaine Jaffe und Wyndham H. Wilson. „Primary Mediastinal Large B-Cell Lymphoma (PMBL) Outcome Is Significantly Improved by the Addition of Rituximab to Dose Adjusted (DA)-EPOCH and Overcomes the Need for Radiation.“ Blood 106, Nr. 11 (16.11.2005): 929. http://dx.doi.org/10.1182/blood.v106.11.929.929.

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Abstract Gene expression profiling has revealed that over one third of genes more highly expressed in PMBL than other DLBCLs are characteristically expressed in classical Hodgkin Lymphoma (HL) suggesting a biological relationship (J Exp Med198:851, 2003). PMBL and HL also share mediastinal presentation, young age, female predominance, prominent sclerosis and CD30 expression. Although some cases lie in a pathological “grey zone” between HL and PMBL, the latter is distinguished by robust CD20 expression. Like HL, local mediastinal failure after doxorubicin-based regimens has led to routine mediastinal xRT, which is associated with secondary malignancies and coronary disease. We analyzed the outcome of DA-EPOCH in 36 untreated PMBLs. No pts received xRT except for CNS PMBL. DA-EPOCH was administered with G-CSF for 2 cycles beyond CR for 6 to 8 cycles as described (Blood99:2685, 2002). The first 14 pts were on a DA-EPOCH study and the last 22 on a DA-EPOCH-Rituximab study. Most pts had adverse prognostic features with bulky disease, elevated LDH and extranodal sites, which were balanced among the 2 series. IHC in 34 cases was consistent with gene expression profiling of PMBL with frequent CD20+ 33/33 (100%), infrequent CD10+ 1/26 (4%) and variable BCL-6+ 17/24 (71%) and MUM-1+ 8/22 (36%) expression. Tumor proliferation by MIB-1 was high with a median (range) of 82% (54–98). IHC markers were similar among the 2 series. EFS and OS are shown below with a median follow-up of 8.6 and 3.4 yrs, respectively, for pts receiving DA-EPOCH −/+ R. Rituximab was associated with a significantly improved EFS (p=0.036) and trend in improved OS (p=0.10) by 2-tailed exact log-rank test. In conclusion, pt characteristics were consistent with the clinical-pathological and molecular definition of PMBL and prognostic features were similar to other series (Haematologica87:1258, 2002). These results suggest for the first time that rituximab significantly improves the outcome of PMBL and that DA-EPOCH-R obviates routine mediastinal xRT. DA-EPOCH-R may be more effective than CHOP-based treatment because it overcomes high tumor proliferation and employs pharmacodynamic dosing. Although needing confirmation, our results suggest DA-EPOCH-R without xRT is highly effective for PMBL. Patient Characteristics Patient Characteristics Characteristics All Patients DA-EPOCH DA-EPOCH-R Total Patients 36 14 22 Gender (F/M) 23/13 (1.77) 9/5 (1.8) 14/8 (1.75) Median age, y (range) 33 (12–70) 34 (20–62) 33 (12–70) Median Mass cm (range) 8.9 (3–16) 8.4 (5.1–15.7) 10 (3–16) Bulky mass > 6 cm 29 (83%) 11 (85%) 18 (82%) ECOG PS > 1 4 (11%) 2 (14%) 2 (9%) Stage III or IV 15 (42%) 7 (50%) 8 (36%) LDH > Normal 26 (72%) 12 (86%) 14 (64%) Extranodal sites 20 (56%) 7 (50%) 13 (59%) Pleural effusion 9 (25%) 3 (21%) 6 (27%) Figure Figure

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Vanazzi, Anna, Fedro Peccatori, Barbara Buonomo, Di Loreto Eugenia, Giovanna Scarfone, Stefano A. Pileri und Corrado Tarella. „Lymphoma Occurring during Pregnancy: Obstetric Outcome and Overall Survival in a Series of 19 Patients“. Blood 134, Supplement_1 (13.11.2019): 5289. http://dx.doi.org/10.1182/blood-2019-127391.

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INTRODUCTION AND BACKGROUND: Lymphoma during pregnancy is a rare and highly challenging condition. Recent evidences show that chemotherapy can be safely administered during pregnancy, however the effects on obstetric and neonatal outcomes are still largely unknown. Aim of this study is to illustrate the oncologic management and to investigate the obstetric, neonatal and maternal outcomes in a series of cases diagnosed with lymphomas during pregnancy. PATIENTS AND METHODS: A retrospective analysis has been conducted in a cohort of pregnant patients diagnosed with Hodgkin lymphoma (HL) and non-Hodgkin Lymphoma (NHL) between 2006 and 2019. Data were collected from the clinical databases and medical records at Istituto Europeo di Oncologia and IRCCS Policlinico di Milano (Milano, Italy). Data on maternal disease, treatments, obstetric complications, fetal and maternal outcomes were analyzed. RESULTS: We identified 19 pregnant patients diagnosed with HL and NHL. Their median age at diagnosis was 29 years (range 23-39). Nodular sclerosis HL was the most common histological subtype (9 patients); primary Mediastinal B-cell lymphoma (PMBCL) was diagnosed in 4 patients, Diffuse Large B Cell NHL in 2 patients, whereas Burkitt lymphoma, Anaplastic Large Cell Lymphoma (ALCL), Follicular NHL and primary cutaneous ALCL were diagnosed in one patient for each of these subtypes. Seven women were diagnosed with advanced disease, with bulky presentation in 5 of them and B symptoms in 3 patients. The median gestational age at diagnosis was 22 weeks (range 7-30). Three patients were diagnosed in the first trimester of pregnancy. Two of them opted for a termination of pregnancy in order to initiate immediate treatment. The remaining 17 pregnancies ended in a live birth. Overall, 8 pregnant women received antenatal chemotherapy, started at a median gestational age of 23 weeks (range 23-33). Treatment included ABVD in 4 patients, CEOP in 3 patients, CHOP in 1 patient (rituximab delayed after delivery in 4 patients). One additional patient received radiotherapy on cutaneous lesion delivered at 33 weeks (primary cutaneous ALCL). Seven out of 9 patients treated during pregnancy obtained a complete response (CR). In eight patients treatment was postponed (due to indolent histology or asymptomatic and non-bulky disease). Obstetric complications occurred during chemotherapy at week 33 in 1 patient with intrauterine growth restriction (IUGR) and oligohydramnios. After a median follow up of 32 months, 13/19 patients are alive and free of disease, 1 patient relapsed 6 y after diagnosis of HL and she is presently undergoing salvage treatment, 1 patient non yet evaluable, 4 patients lost at follow-up. CONCLUSIONS: Treating lymphomas during pregnancy is feasible, however the management of a pregnant patient with lymphoma requires multidisciplinary approach. In case of low risk disease and/or disease occurring in late gestational phase, therapy can be deferred to post-partum. If required, standard chemotherapeutic regimens can be administered during the 2nd and 3rd trimester, with minimal maternal or fetal complications. Starting treatment during pregnancy does not imply an adverse long-term outcome. Disclosures No relevant conflicts of interest to declare.

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Ramadan, Khaled M., und Joseph M. Connors. „Long Term Follow-Up Results for Patients with Hodgkin Lymphoma after First Remission of Longer Than Ten Years: A Population Based Study of 954 Patients from the British Columbia Cancer Agency.“ Blood 108, Nr. 11 (01.11.2006): 2269. http://dx.doi.org/10.1182/blood.v108.11.2269.2269.

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Abstract Background Little information is available regarding the long-term follow-up results in patients with Hodgkin lymphoma (HL) after a first remission for 10 years or longer. The aim of this study is to evaluate the risk of disease relapse, secondary malignancy and causes of mortality in this cohort of patients. Results 954 patients with HL were identified by searching the BC Lymphoid Cancer Database for all patients diagnosed between 1960 and 1995 who had maintained a first remission of greater than 10 y. Median age at diagnosis was 27 y (range 3–73 y) with 83% of patients less than 44 y. Male:female ratio was 1.2:1. The clinicopathological characteristics of the whole cohort are summarized in table 1. The 20- and 30-year OS for the whole cohort were 84% and 64%, respectively. The 20- and 30-year DSS for the whole group were 99% and 98%, respectively. Significant risk factors for lower OS were male gender (20-year OS for males 81%, females 87%, p=0.03), age >44 at diagnosis (20-year OS for age >44 was 51%, <44 was 93%, p<.00001) and mixed cellularity (MC) (20-year OS 81%) compared with nodular sclerosing (NS) (20-year OS 90%), p=0.007. Those factors (sex, age and histological subtype) had no significant impact on the 20-year DSS or PFS. Disease stage and B symptoms had no impact on survival (OS, DSS and PFS). There is no significant difference in the 20- and 30-year OS, DSS or PFS between patients initially treated with radiotherapy alone, chemotherapy alone or a combination of both. Only 24 patients (2.5% of the whole group) had a HL relapse. Six patients had been treated with radiotherapy only, one with radio-chemotherapy and 17 with chemotherapy only. Twelve of these patients have died due to various causes (HL: 7, cardiac disease: 4, lung cancer: 1). There were no risk factors predictive for late relapse (age, stage, histologic type, initial treatment). Secondary cancer was observed in 169 patients (17%) with a median age at cancer diagnosis of 52 years. Extended field radiotherapy (n=108, 64%) and MOPP-like chemotherapy (n=72, 43%) were the most prevalent 2 factors in this group. Breast cancer was the most common malignancy (n=31, median age at diagnosis 47 years), followed by lung (n=25), gastrointestinal (n=21), gynecological (n=20), genitourinary (n=16), hematopoietic (n=15), and thyroid (n=6). In total, 165 patients (17% of the whole group) died after remission of more than 10 y of whom 113 (13% of the whole group) died due to potential complications of primary treatment. The two most common causes of death were secondary malignancies (n=79) and heart diseases (n=34). Only seven patients (0.7%) died due to HL relapse. Conclusion HL relapse is a rare event (< 3%) and death from HL very rare (< 1%) in those who remain in first remission for more than 10 y. Treatment related complications, such as secondary malignancy or ischemic heart disease, are the major causes of mortality. Summary of clinicopathological parameters of patients with HL in first remission for longer than 10 y Parameter Number (954)(%) *Limited: stage I/II, non-bulky (<10 cm in diameter) and no B symptoms. Histology Classical HL 858(90) Nodular sclerosing 610(65) Mixed cellularity 193(20) Lymphocyte-rich/depleted 42/13(4/1) Nodular lym. pred. 11(1) HL not specified 85(9) Stage:Limited*/advanced 445/509(47/53) B symptoms 239(25) Treatment Radiotherapy alone 357(37) Chemotherapy alone 258(27) Combination 337(35)

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Bruno, F., E. Pronello, S. Bortolani, R. Palmiero, A. Melcarne, A. Chiappella, C. Mantovani, R. Soffietti und R. Rudà. „P14.85 Brain metastasis from Hodgkin’s Lymphoma: case report and literature review“. Neuro-Oncology 21, Supplement_3 (August 2019): iii87—iii88. http://dx.doi.org/10.1093/neuonc/noz126.320.

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Abstract BACKGROUND Central nervous system (CNS) metastases from Hodgkin’s Lymphoma (HL) are very rare, occurring in 0.02–0.5% of cases. They are usually associated to systemic relapse of the disease. Treatment options for HL brain metastases include surgery, radiotherapy, and systemic chemotherapy. CASE REPORT A 54 year-old woman presented with thoracic pain and dyspnea. Chest CT showed a thoracic bulky mass larger than 10 cm. Biopsy confirmed HL stage IIA, nodular sclerosing variant. No typical B symptoms, such as fever, night sweats or weight loss, were observed. The patient underwent chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD scheme), followed by 30Gy mediastinic radiotherapy (RT), which led to complete remission in September 2017. After 3 months, she presented with headache and rapidly progressing gait disorder. MRI showed a contrast-enhanced lesion in the right occipital lobe, with central necrosis and massive edema. Total-body CT scan and FDG-PET ruled out either the presence of new solid tumors or systemic relapses of HL. Gross total resection of the brain lesion was carried out, and HL histology was confirmed. CSF analysis from lumbar puncture was normal. Afterwards, the patient underwent 2 cycles of high dose cytarabine, but she rapidly progressed, and received salvage RT (30 Gy). Nevertheless, further systemic progression occurred: the patient developed headache, diplopia and dysphagia and, unfortunately, she died 6 months after the diagnosis of brain metastasis. DISCUSSION Thus far, only 45 cases of CNS HL have been reported from 2000 to 2018. Whole brain radiotherapy, with or without chemotherapy, was the most common treatment. In our patient, we chose surgical resection for the solitary brain metastasis followed by chemotherapy, delaying RT at recurrence. In the literature, median overall survival of patients diagnosed with brain metastases from HL is 18 months (1–273): 17 patients (38%) showed a progression (local / systemic: 12/17 - 71%), while 28 (62%) showed complete remission after a median follow-up of 20 months (6–273). CONCLUSION Intracranial localisation of Hodgkin’s Lymphoma is a rare entity but still has to be taken into account. Advanced brain imaging could be of help in case of uncertain radiological presentation. A multidisciplinary approach is needed as there is no consensus on the best treatment to choose: surgery, radiotherapy and chemotherapy should be considered on individual basis.

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Abbadessa, Antonio, Salvatore Iaccarino, Giuseppe Monaco, Maria Luigia Vigliotti, Mario Troiano und Enrico Attingenti. „Rapid Transformation to Aggressive B-Cell Lymphoma, in a Case of Mixed Cellularity Hodgkin Lymphoma Subtype : A Rare Event“. Blood 112, Nr. 11 (16.11.2008): 4831. http://dx.doi.org/10.1182/blood.v112.11.4831.4831.

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Abstract BACKGROUND. Several histological subtypes of lymphoma can occur in the same patient. This event may happen sequentially or simultaneously. We describe a case of sequential diffuse large B-cells lymphoma (DLBCL), occurred shortly after therapy and rapidly fatal, after primary mixed cellularity Hodgkin lymphoma subtype (MCHLs). CASE REPORT. A 24-year-old woman was admitted in March 2006 to our Unit with fever, loss of weight and left sovraclavear lymphoadenopathy. On admission, chest radiography and total body computerized tomography (TB-CT) evidenced bulky mediastinal disease, lung involment, pericardial and pleural effusion. Left sovraclavear limphoadenopaty biopsy was performed and histology revealed MCHLs. Clinical stage was IVB with mediastinal bulky disease (Ann-Arbor Classification). Chemotherapy with doxorubicin-bleomycin-vinblastin- dacarbazine (ABVD) was starded. After 2 cycles TB-CT and PET showed reduced involvement of mediastinum and middle lobe of right lung. We decided to continue with further 4 cycles of ABVD chemotherapy. At restaging, TB-CT was negative; yet TB-PET was again positive with further strong reduction of mediastinal captation and absence of pulmonary involvment. Radiotherapy involved field (RT-IF) on mediastinum was started. Treatment was not well tolerated because infectious episodes occurred. After 3 weeks since the end of radiotherapy the patient showed fever and catarrhal cough. In the suspect of the bronchopneumonia, we performed cultural examination of sputum and hemoculture, turned out negative; broad-spectrum antibiotic and antimicotic therapy was started. TB-CT, performed after a month, showed an oval lesion on right lung, mediastinal ipercaptation, right pleural effusion, sub-diaphragmatic lymphoadenopathies, cystic lesions of kidneys. The patient underwent medistinal biopsy with histologic diagnosis of DLBCL, but she died a week later for heart and respiratory failure. Overall survival was only of 12 months. DISCUSSION. Possibility of development in the same patient of various types of lymphomas has been recognized for some time. To explain this occurrence, the term of multiple histology lymphomas (MHL) has been coined. MHLs may be sequential (different lymphomas at different times) or simultaneus (different lymphomas occurring at same time in the same lymphnode or at different sites). This event is mostly observed in non Hodgkin lymphoma (NHL). (Tucci et al, Haematologica 2005). Eventuality of a NHL after a primitive Hodgkin lymphoma (HL) is very rare (less than 1% of cases), with a variable time of insorgence (incidence is higher in the first 2 years from diagnosis of HL). Simultaneous HLs and NHLs are also very rare. All HL subtypes may evolve in a NHL DLBCL is main histology subtype of NHL from primary HL, with frequent extranodal involvement. Prognosis is poorer than primary NHLs. (Rueffer et al, JCO 2001). Our case shows a quick transformation to DLBCL of a MHLs. This event happened 3 weeks about for the end of therapy. Latent period is very short to consider DLBCL like a secondary neoplasm. Most reliable hypothesis is the common B-cellular derivation of HL and B-NHL, such as it has recently been demonstrated (Fraga M et al, Histol Histopathol 2007). CONCLUSION. The transformation of a HL into a NHL is a very rare event. Since HL is probably a B-cell derived lymphoma, the transformation into an aggressive NHL has to be suspected in presence of dubious images and symptoms and a biopsy has to be performed and standard therapy for NHL quickly started.

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Gallamini, A., M. Hutchings, L. Rigacci, L. Specht, F. Merli, F. D’Amore, L. Nassi et al. „Advanced Stage Hodgkin Lymphoma: The Predictive Value on Treatment Outcome of Early FDG-PET Scan Is Independent of and Superior to IPS Score.“ Blood 108, Nr. 11 (16.11.2006): 4592. http://dx.doi.org/10.1182/blood.v108.11.4592.4592.

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Abstract Background: FDG-PET scan performed early during chemotherapy (CT) is a powerful prognostic tool in lymphoma management. This study aimed to compare the predictive value on treatment outcome of the International Prognostic Score (IPS) with that of FDG-PET scan performed after two courses of standard CT in untreated advanced stage (AS) HL patients. Patients: From December 2001, 202 new AS HL patients were consecutively admitted to 11 Italian and 3 Danish hematological centers, on behalf of Intergruppo Italiano Linfomi and Danish Lymphoma Cooperative Group. The mean age was 35.5 years (14–79), the male/female ratio 105/97; AS (IIB–IVB) was present in 153, and unfavorable stage IIA (> 3 nodal sites involved or sub-diaphragmatic presentation or bulky disease or ESR > 40) in 49. Bulky and extranodal disease was recorded in 71 and 58 patients, respectively. All patients had FDG-PET at baseline (PET-0) and after 2 courses of CT (PET-2). 192 patients were treated with ABVD, 8 with ABVD-like CT, 2 with BEACOPP. 102 patients received consolidation radiotherapy after CT. All patients were given the therapy programmed at baseline, except in case of overt progression. Results: The mean time from the diagnosis to latest follow-up was 796 days (range 91–1716). 164 patients attained CR while 38 were chemoresistant: 34 showed disease progression during CT and 4 showed early relapse (within 6 months) after CR entry: (+28 – +178 days). 4 out of the 164 pts attaining CR relapsed later than 6 months. In univariate analyses, both PET-2 (p<0.0001) and IPS (p<0.001) were significantly associated with a higher probability of treatment failure. However, in a multivariate analysis only PET-2 was independently predictive of relapse/progression probability (51.0; 95 % C.I. 20.9 – 124.2). The sensitivity of PET-2 for treatment failure was 85%, the specificity 96% and the overall accuracy 94%. The 2-y FFS probability for PET-2 negative and for PET-2 positive patients were 96% and 14%, respectively (log Rank test, p<0.0001; Fig. 1). Conclusions: so far, FDG-PET after two cycles of CT is the most powerful tool available for predicting treatment outcome in AS HL. Figure Figure

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Dann, Eldad J., Rebeca Lopez-Alonso, Shunan Qi, Tania Mashiach, Michal Weiler-Sagie und Joachim Yahalom. „Should a Bulky Mediastinal Mass ≥7cm in the Longest Dimension be Considered an Adverse Prognostic Factor in Patients with Advanced Hodgkin Lymphoma and Negative Interim PET/CT?“ Blood 134, Supplement_1 (13.11.2019): 4051. http://dx.doi.org/10.1182/blood-2019-122824.

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Introduction: Nowadays, treatment decision making in advanced Hodgkin lymphoma (ad-HL) is based on pre-therapy risk factors and interim PET/CT (PET-2) results, used as a platform for therapy modification. In the past, a bulky mediastinal mass (BMM) was not found to be a significant risk factor and was not included in the final version of the International Prognostic Score (IPS) system (Hasenclever, NEJM 1998). The current study aimed to assess the effect of BMM presence on relapse-free survival (RFS) in patients (pts) with ad-HL and to determine the optimal cutoff of the mass size for outcome prediction in the PET/CT era. Methods: The Israeli Hodgkin Lymphoma Study Group selected to initiate therapy with standard BEACOPP (SB: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) or ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) in HL pts with IPS 0-2 and with intensified therapy using escalated BEACOPP (EB: bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) in pts with IPS ≥3. Treatment was modified according to PET-2 results. To pts with negative PET-2 another 4 cycles of SB/ABVD were administered. PET-2 positive pts received 4 EB cycles followed by radiation therapy (Dann, Blood 2007). In the present study, disease bulkiness, assessed using baseline PET/CT, was retrospectively evaluated in a cohort of HL pts. The data included measurements of the longest diameter of either the biggest single mass or a conglomerate of lymph node masses in the transverse or coronal plane in the PET/CT image. Prognostic values of mediastinal mass cutoffs of ≥5 cm, ≥7 cm, >10 cm for RFS and progression-free survival (PFS) were compared. Results: One hundred and ninety six pts (female/male: 46/54%) with ad-HL [stage IIB - 28, stage III - 74, stage IV - 94; IPS 0-2 - 104; IPS 3-7 - 92; median age 31 years (16-85)] treated at the Rambam Health Care Campus (n=121) and Memorial Sloan Kettering Cancer Center (n=75) between 2000-2016 were included in the analysis. Mediastinal masses ≥5 cm, ≥7 cm and >10 cm were observed in 125 (63%), 82 (42%), 36 (18%) pts, respectively. PET-2 was negative in 79% of pts. At a median follow-up of 66.5 (1-222) months [80 (4-222) for pts without disease progression and 12 (1-62) for those with relapse or progression], estimated 5-year RFS and PFS for the entire group were 82% and 79%, respectively. A mass of up to 7 cm was found in 62 % of pts (n=123); 22% (n=44) had a mass measuring between 7 and 9.9 cm and 15% (n=29) had a mass ≥10 cm. Mediastinal masses were prevalent in 126/196 (64%) pts; in 58 (30%) of them the mediastinal mass, while being biggest, did not exceed 7 cm, and 68 (34%) had BMM of ≥7 cm. We found no effect of bulky disease, either mediastinal or non-mediastinal, on the outcome of the PET-2 positive group. Univariate analysis showed that in pts with negative PET-2, BMM ≥7 cm was a significant adverse prognostic factor for both 5-year RFS and PFS (HR 2.85; 95% CI 1.09-7.41; p=0.032 and HR 2.86; 95% CI 1.1-7.45; p=0.032, respectively). Outcome comparison of PET-2 negative pts with BMM (≥7 cm) to pts with negative PET-2 and either non-mediastinal or mediastinal non-bulky (<7cm) masses (reference group) revealed an inferior 5-year RFS of 73% versus 89% (HR 2.97; 95% CI 1.37-6.42; p=0.006) in the former group. Of note, both groups received an ABVD/SB regimen. HR for RFS was insignificant when a mass size cutoff of ≥5 cm or >10 cm was used. The HR for RFS was particularly high in the comparison between the subgroup of PET-2 negative pts with IPS 0-2 and BMM (≥7 cm) and those with IPS 0-2 in the reference group, demonstrating a 5-year RFS of 59% versus 89% with HR of 4.20 (95% CI 1.59-11.05; p=0.004). PET-2 negative pts with IPS 3-7 and BMM (≥7 cm) did not have an inferior outcome compared to pts with IPS 3-7 from the reference group (5-year RFS of 82% versus 89%). Notably, the two groups were treated with an EB-containing regimen. Our results indicate that BMM is an important adverse prognostic factor predominantly for pts with IPS 0-2. Multivariate Cox regression analysis identified BMM ≥7 cm as the most significant adverse prognostic factor for RFS (Table 1; Fig. 1). Conclusions: In PET-2 negative pts with ad-HL, mediastinal masses ≥7 cm in any plane are associated with the highest risk for HL progression. These findings should be incorporated in a new prognostic scoring system upon more extensive evaluation in a larger cohort. Disclosures No relevant conflicts of interest to declare.

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Mauro, Francesca R., Mara Riminucci, Davide Rossi, Francesca Paoloni, Luca Laurenti, Anna M. Frustaci, Giuseppe Cimino et al. „Role of PET/CT in the Diagnostic Work-up of Patients with Chronic Lymphocytic Leukemia (CLL) and Clinical Signs of Disease Progression“. Blood 120, Nr. 21 (16.11.2012): 3888. http://dx.doi.org/10.1182/blood.v120.21.3888.3888.

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Abstract Abstract 3888 Chronic lymphocytic leukemia (CLL) is a heterogeneous leukemia with a very variable outcome. The occurrence of a second malignancy (SM) or of a disease transformation (DT) may complicate the course of the disease. An aggressive diffuse large B-cell lymphoma (DLBCL) and, less frequently, a Hodgkin's lymphoma (HL) are the most commonly observed forms of DT, defined as Richter's syndrome (RS). Since the presence of enlarged “bulky nodes”, as well as the observation of extra-nodal lesions, can lead both to the suspicion of a CLL progression and to the possibility of a DT or of a SM, a biopsy of the involved tissue is the only appropriate approach for a correct diagnosis. Positron emission tomography/computed tomography (PET/CT) is currently used for the initial staging and restaging of HL and DLBCL, as well as for the identification of other malignancies. In a previous report by Bruzzi et al. (JNM, 2006), PET/CT showed a high predictive value in demonstrating or excluding DT. The same finding has been observed in single case reports, where in patients with CLL a high 18F-FDG uptake was associated with the presence of a DLBCL. With the aim of discriminating the presence of a DT or a SM malignancy, between June 2008 and June 2012, a PET/CT exam followed by the biopsy of the involved tissue was performed in CLL patients from 4 Italian centers. Patients included in this study showed disease progression requiring treatment according to the 2008 revised IWCLL criteria and clinical signs suggestive of the presence of a more aggressive disease, such as rapidly enlarging or bulky lymph nodes (diameter ≥5 cm) and/or extra-nodal lesions associated with at least one additional sign including B systemic symptoms, increased serum lactate dehydrogenase (LDH), increased β2 microglobulin (B2M). The 18F-FDG uptake was correlated with the histologic findings and, for the purpose of this study, a maximum standardized uptake value (SUVmax) ≥5 was considered highly suggestive of a more aggressive disease. Data on 64 CLL patients (median age, 66 years, range, 35–85) were retrospectively analyzed. At the time of PET/CT, the median follow-up from CLL diagnosis was 73 months (range, 3– 227 months) and a Binet C stage was observed in 16 cases (25%). Twenty-three (36%) patients were treatment-naïve and 41 (64%) had been previously treated (median number of prior treatments, 2; range, 1–4), including 14 (22%) refractory cases. Systemic symptoms were recorded in 25% of cases, LDH was increased in 41% and B2M in 72%. The majority of patients (61%) were IGVH unmutated, 45% CD38 positive and 56% ZAP-70 positive. Bulky lymph nodes (diameter ≥5 cm) and/or marked splenomegaly (longitudinal diameter ≥17 cm) were observed in 30 cases (47%). Evidence of extra-nodal disease was recorded in 8 cases (12.5%): thyroid, 2 cases; uterine fundus, 1; gastric,1; bone, 1; nasopharynx, 1; skin infiltrates, 2. The biopsy confirmed a SLL/CLL diagnosis in 44 cases, a DT in 15 (DLBCL, 10; HL, 5) and SM in 5 (thyroid cancer + SLL/CLL, 2 cases; lymph node metastasis of carcynoid + SLL/CLL, 1; lymph-node metastasis of a squamous cancer, 1; lejomioma of the uterine fundus,1). Sites of abnormal 18F-FDG uptake having a SUVmax ≥5 were recorded in a total number of 30 cases, in 13/44 cases (30%) with a SLL/CLL histology, in 13/15 with DT (87%), including 9/10 (90%) cases of DLBCL and 4/5 (80%) HL. An abnormal uptake was recorded also in 4/5 patients with SM. Based on these results, for the diagnosis of a DT or SM, PET/CTPET/CT showed an overall sensitivity, specificity, positive and negative predictive values of 85% 70%, 57% and 91%, respectively, while for the diagnosis of a DT (DLBCL+HL) the sensitivity, specificity, positive and negative predictive values were 87%, 65%, 43% and 94%, respectively. The cases with a SLL/CLL histology having a SUVmax ≥5 were characterized by a higher Ki-67% expression (p=0.0001) suggesting a high rate of cell turnover. Our results show that a PET/CT performed in CLL patients at the time of disease progression can detect cases with a high likelihood of DT or SM, representing therefore a very helpful imaging technique in guiding the appropriate site that should be considered for biopsy. Disclosures: No relevant conflicts of interest to declare.

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Corazzelli, Gaetano, Filippo Russo, Ferdinando Frigeri, Francesco Volzone, Gaetana Capobianco, Manuela Arcamone, Emanuela Morelli et al. „Dose- and time-intensified ABVD without radiotherapy (RT) for advanced-stage Hodgkin lymphoma (HL) with mediastinal bulky disease (MBD).“ Journal of Clinical Oncology 30, Nr. 15_suppl (20.05.2012): 8066. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.8066.

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8066 Background: The role of consolidation RT on MBD after upfront chemotheraphy for advanced HL is debated, also given the supradditive iatrogenic risk. We present the results achieved in the subset of patients (pts) with MBD (max width > 1/3 of thoracic diameter) accrued in a phase II study of an intensified ABVD program without RT. Methods: The current analysis derives from the final evaluation of our trial for advanced HL (stage IIXB-IV) conducted from 06/2004 to 03/2010 (Russo et al, ASH 2009 abst 715). Pts were scheduled to 6 cycles of a ‘time-densified’ ABVD (3-week intercycle, drugs on days 1 and 11) with the first 4 cycles being also ‘dose-intensified’: doxorubicin (ADM) 35 mg/m2, days 1 and 11 and G-CSF on days 6-8 and 17-19. Results: Of 82 accrued pts, 39 had BMD at presentation. Median age was 29yrs (r 16-58); male 46%; stage IIB 48%, III 8%, IV 43%; B-sympt 87%, E-disease 53%; IP Score ≥3 51%. All pts completed the intensified program. Median actual dose intensities for ADM, bleomycin, vinblastine and dacarbazine were 23.12, 6.69, 3.96 and 245 mg/week, respectively; the increase over conventional ABVD was 85% for ADM and averaged 32% for the other agents. PET2 negativity was achieved in 36/39 (92%; 95% CI 79-98), complete responses (CR) in 37/39 [94%; 95% CI 82-99]. At a median f.u. of 54 mo.s (r 20-91) all pts are alive with an event-free survival of 89% (95% CI, 80-98). Events were: <CR (n=1, CS IVB), progression (n=1, CS IIIA), relapse [n=2; at 10 (CS IVA ) and 15 (CS IIB) months after treatment]; all these pts had isolated mediastinal recurrence. CTCAE v3.0 toxicity: Grade (G) 2 nail changes (31%), G2-G3 hemorrhoids (12%-3%), G3 infection (13%) and constipation (5%), G3-G4 stomatitis (7%-2%). No acute or delayed G3-G4 cardiac events, nor G3-G4 decline in pulmonary function (FEV1, DLCO,FEF25-75) were seen. Conclusions: Intensified ABVD can achieve PET2 negativity in a very high proportion of pts with MBD and ensure a long-term disease-free status even without RT. While results need confirmation on a randomized basis, the low mediastinal failure rate seems in line with recent suggestions that RT could be omitted in MBD when CR is achieved upon intensified chemotheraphy.

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Danilov, Alexey V., Hongli Li, Oliver W. Press, Ilan Shapira, Lode J. Swinnen, Ariela Noy, Erin Reid, Sonali M. Smith und Jonathan W. Friedberg. „Feasibility of Interim PET-Adapted Therapy in HIV-Positive Patients with Advanced Hodgkin Lymphoma (HL): Sub-Analysis of SWOG S0816 Phase 2 Trial“. Blood 126, Nr. 23 (03.12.2015): 1498. http://dx.doi.org/10.1182/blood.v126.23.1498.1498.

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Abstract Background: The risk of HL is 10-fold higher in HIV-infected individuals than in the background population. Patients with HIV-HL typically present with advanced stage disease and frequent extranodal sites of involvement, accounting for higher risk scores than HIV-negative counterparts. Despite that, the prognosis of HIV-HL in the HAART era has been favorable. Standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) results in complete response rates (74%) and five-year overall survival (80%) similar to those in non-HIV-HL. Thus, as in HIV-negative HL, exploration of response-adapted therapy in HIV-HL is well-justified. PET imaging after 2 cycles of chemotherapy was found to be a strong predictor of treatment outcome in patients with non-HIV-HL. Here, for the first time, we report on the outcomes of HIV-positive patients enrolled on S0816, a multicenter Phase 2 trial of response-adapted therapy of stage III-IV HL using interim FDG-PET imaging. Methods: HIV-positive patients aged 18-60 with previously untreated stage III-IV classical HL were eligible. Patients with multi-drug resistant HIV or concurrent AIDS-defining conditions were excluded. All patients received 2 cycles of ABVD followed by an interim PET, reviewed centrally. Patients with negative PET (Deauville≤3) subsequently received 4 additional cycles of ABVD, while PET-positive patients received 6 cycles of BEACOPP standard regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone). Results: 12 patients with HIV-HL received study treatment. Median age was 44.6 years (range, 25 to 50 years), 83.3% were male. 11/12 (91.6%) patients presented with bulky lymphadenopathy (≥10 cm) and 50% had poor risk international prognostic score (IPS≥4). 6/12 (50%) patients manifested B-symptoms and 33.3% had bone marrow involvement by HL. Where information was available, most patients (7/9, 77.8%) received concurrent HAART during chemotherapy. Median CD4 count prior to registration was 165/µL (range, 22-400/µL), and <100/µL in 5/12 pts (41.7%). All HIV-HL patients successfully completed 2 initial cycles of ABVD. Gr 4 neutropenia and gr 3 febrile neutropenia were common during this treatment (66% and 25%, respectively). 10/12 (83.3%) patients achieved PET-negative status and 2 remained PET-positive with Deauville scores of 4 and 5. All PET-negative patients continued therapy with ABVD. Of those, nine completed the 4 cycles of treatment and one discontinued early for progressive disease 4 months after registration on study. Of the PET-positive patients, one elected to receive ABVD therapy off the study protocol, while the other completed 6 cycles of BEACOPP; both achieved a partial response. Thus, following ABVD therapy, 82% of patients achieved complete response and 18% - partial response. With median follow-up of 31 months (range, 5.4-38.1 months) all study patients are alive. Two patients developed progressive disease, with the estimated progression-free survival of 83% at 2 years (95% CI, 46.1 to 95.3%). Most grade 3-4 adverse events with continued therapy were neutropenia (72.7%) and febrile neutropenia (27.2%), while other toxicities were uncommon (see Table). All 12 patients experienced at least one grade 3-4 toxicity during study treatment. 3 patients (25%) required dose reductions due to febrile neutropenia (N=2) and neuropathy (N=1). Conclusions. ABVD is highly effective in patients with advanced stage poor-risk HIV-HL and induces PET-negative responses at a similar rate without undue added toxicity as compared to non-HIV patients in a prospective trial setting. As response-adapted therapy evolves to be a standard approach for HIV-negative patients with advanced stage HL, the results of S0816 study presented here support a similar investigative approach in patients with HIV-HL, with the goal of reducing long-term toxicity. The role of intensified chemotherapy regimens in patients with HIV-HL who do not achieve PET-negative status needs further study.Table 1.ToxicityGrade 3, N (%)Grade 4, N (%)Anemia2 (18.2)2 (18.2)Febrile neutropenia3 (27.2)-Lymphopenia1 (9.1)2 (18.2)Neutropenia2 (18.2)6 (54.5)Thrombocytopenia1 (9.1)-Infection2 (18.2)-Anorexia1 (9.1)-Dizziness1 (9.1)-Fatigue1 (9.1)-Hypophosphatemia1 (9.1)-Musculoskeletal pain1 (9.1)-Thrombosis1 (9.1)- Disclosures Smith: Pharmacyclics: Consultancy; Celgene: Consultancy.

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Sethi, Tarsheen K., Van T. Nguyen, David S. Morgan, John P. Greer und Nishitha M. Reddy. „Interim Absolute Lymphocyte Count (ALC) As a Predictor of Survival in Hodgkin Lymphoma“. Blood 126, Nr. 23 (03.12.2015): 2640. http://dx.doi.org/10.1182/blood.v126.23.2640.2640.

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Abstract Introduction: Patients with Hodgkin lymphoma (HL) have excellent response to current chemotherapy, however, up to 20% may have relapsed/refractory disease. Lymphocytopenia at diagnosis has been found to be predictive of survival in patients with advanced stage HL. An ALC of <600/μlat diagnosis as part of the Hasenclever predictive score is associated with a poorer prognosis. Furthermore, lymphocyte count at the time of apheresis and at day 15 after autologous SCT has been found to be predictive of survival in patients of HL. ALC is considered a surrogate indicator for the tumor microenvironment as well as immune recovery post treatment. There are no large studies evaluating the clinical significance of ALC recovery in patients with HL during initial chemotherapy treatment. In this study, we evaluated the role of lymphocyte recovery during and after standard chemotherapy in patients with HL. Patients and Methods: We analyzed 183 patients with Classical Hodgkin lymphoma treated at our institution between 1996 and 2014 following IRB approval. Complete data was available for 115 patients. We evaluated the absolute lymphocyte count at diagnosis, interim staging (after 2 cycles, Òinterim ALCÓ), at time of completion of chemotherapy and at 6 weeks and 3 months post completion of chemotherapy. Patients were categorized into two groups based on ALC where lymphocytopenia was defined as an ALC of <1x103/µl for adults based on standard criteria. Differences between the two groups were analyzed using Chi- square and t -Student tests. Statistical significance was set at P <0.05. Kaplan Meier method was used to calculate the Progression-free survival (PFS) and overall survival (OS). Log-rank test was used to determine the differences in survival. Statistical analysis was performed using SPSS.22 software. Results: The median age of patients was 31 years (yrs.) (range: 17-76 yrs.) and 53% of patients were male. 100% patients had an ECOG status of 0-1. 48% patients presented with B symptoms, 42% had advanced stage disease (Stage III and IV) and 22% had bulky disease (defined as a mass > 10 cm or mediastinal mass >1/3 of diameter of thorax at T5-T6). In terms of histology, 68% patients had classical nodular sclerosis HL, 19% syncytial variant of nodular sclerosis HL, 8% mixed cellularity HL and 5% Classical HL (NOS). 90% patients received ABVD as their initial chemotherapy, 2% received Stanford V and 1% received MOPP. The remaining patients were treated on a clinical trial. In the analysis of the 115 patients for whom the lymphocyte data was available, at a median follow up of 40 months, 57% in the ALC <1x103/µl group versus 66% in the ALC >1x103/µlgroup had not progressed. The median overall survival was not reached in the two groups. In the multivariate analysis, for PFS, interim ALC predicted survival independent of the interim staging response. The ALC at the time of interim staging scan (interim ALC) was associated with a significantly superior PFS in the group with ALC>1x103/µl(HR=4.16, 95% CI 2.37 to 7.28, P=0.024). There was no difference in overall survival between the groups (Fig. 1&2,P=0.28). For ALC at other time points, no statistically significant differences in PFS or OS were found in the two groups based on ALC at diagnosis, completion of therapy, six weeks and three months post therapy. Discussion: In summary, our results suggest that for patients across all stages and histopathologic subtypes of classical HL receiving first line chemotherapy, interim ALC >1x103/µl (after 2 cycles) is associated with a superior PFS as compared with ALC <1 x103/µl and this is independent of the interim staging response. This did not translate into a difference in OS. Further studies are underway to determine the role of immune effector cells in the context of newer therapeutic agents. Figure 1. PFS (months) in patients with interim ALC >1x103/ μlvs. <1x103/ μl Figure 1. PFS (months) in patients with interim ALC >1x103/ μlvs. <1x103/ μl Figure 2. OS (months) in patients with interim ALC >1x103/ μlvs. <1x103/ μl Figure 2. OS (months) in patients with interim ALC >1x103/ μlvs. <1x103/ μl Disclosures Reddy: Gilead: Other: Speaker; Seattle Genetics: Consultancy; ImmunoGen: Consultancy; PCYC: Consultancy; Celgene: Consultancy, Research Funding.

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Gallamini, Andrea, Alberto Biggi, Stephane Chauvie, Alexandru Stancu, Federico Fallanca, Agostino Chiaravalloti, Michele Gregianin et al. „Interim-PET Scan Interpretation In the Ongoing Prospective Clinical Trial HD 0607, In Advanced-Stage Hodgkin Lymphoma: Results of the the Expert Panel Review“. Blood 116, Nr. 21 (19.11.2010): 3891. http://dx.doi.org/10.1182/blood.v116.21.3891.3891.

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Abstract Abstract 3891 Background: several PET response-adapted prospective clinical trials are running at the moment, aimed at assessing the role of chemotherapy intensification in ABVD-treated Hodgkin Lymphoma (HL) patients with interim PET-positive after 2 cycles (PET-2). Standard interim-PET interpretation rules are still lacking, and expert review panels for PET interpretation have been implemented in these trials. We report here the results of PET-2 review in the HD 0607 trial. Patients and methods: starting from July 2008 till now, 236 advanced-stage HL patients have been consecutively enrolled in the Italian GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter clinical trial HD 0607 (NCT Identifier: NCT00795613). Advanced-stage (IIB-IVB) HL patients are first treated with 2 ABVD courses and PET-2 performed afterwards. All the non-negative PET-2 scan are reviewed by the expert panel. Non-negative PET-2 is defined as any scan with any residual FDG uptake outside the physiological areas of the tracer concentration. All the non-negative PET-2 according to the local centers (PET-2loc) are uploaded on the dedicated website (http://magic5.to.infn.it/gitil), along with the baseline scans. Six independent reviewers re-interpret the scans according to the 5-point semiquantitative score with mediastinum and liver as reference organs for residual fluorodeoxyglucose (FDG) uptake (Deauville score, Meignan 2009). The first three reviewers replying within 72 hours from PET upload determine the panel final decision; the remaining three report the scans later. Patients with a score 4 or 5 shifted to BEACOPP or Rituximab-BEACOPP escalated treatment; patients with score 1–3 continued with ABVD. Patient with bulky lesion (defined as a nodal mass with the largest diameter 3 6 cm) were treated with IF-RT. Results: 199/236 patients performed a PET-2 scan: 131 (66%) showed a negative, 68 (33%) a non-negative scan. These 68 PET-2loc were reviewed (PET-2rev.); the clinical characteristics of patients with a reviewed and unreviewed PET-2loc were the following: mean age 32 vs.35, Stage III 19/68 (28%) and 61/131(46%), Stage IV 26/68 (39%) and 45/131 (34%), Bulky 44/68 (65%) and 93/131 (71%), IPS 3 or more 20/68 (29%) and 20/131 (15%), respectively. As a result of review there were 32 positive PET-2rev. and 36 negative PET-2rev. The median PET-2 review time from the uploading in the website to the third reviewer's report was 48 hours (1-90). The 32 positive PET-2rev scans showed a single residual focus in 28 and multiple foci of residual FDG uptake in 4 cases (all score 5). 22 showed a single lesion in the mediastinum, 4 in superficial lymph nodes and 2 in the lung. In 25/28 (89%) patients the single residual FDG uptake was within a bulky lesion and in 3/28 was outside it. The concordance rate among couples of reviewers for a positive vs. negative scan, measured with Cohen's Kappa, ranged between 0.76 (substantial agreement) and 0.92 (almost perfect agreement). The overall concordance rate measured with Krippendorf's Alpha, (assuming chance = 0 and perfect agreement =1) was 0.82. Lower concordance among reviewers was found in scans showing FDG residual uptake in anatomical structures not clearly related to lymphoma (brown fat, large vessels, bowel, tonsil, and inflammatory lung lesions). Conclusions: these data show that (1) the preliminary reports of a very high binary and overall concordance rate among reviewers using the Deauville score for PET-2 reporting (Barrington 2010) have been confirmed; (2) the online review process for PET-2 scan is feasible and simple; (3) most of the positive PET-2 scan showed a residual FDG uptake in the site of bulky disease, mostly in mediastinum. Disclosures: No relevant conflicts of interest to declare.

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Straus, David J., Brandelyn Pitcher, Lale Kostakoglu, John C. Grecula, Eric D. Hsi, Heiko Schoder, Sin-Ho Jung et al. „Initial Results of US Intergroup Trial of Response-Adapted Chemotherapy or Chemotherapy/Radiation Therapy Based on PET for Non-Bulky Stage I and II Hodgkin Lymphoma (HL) (CALGB/Alliance 50604)“. Blood 126, Nr. 23 (03.12.2015): 578. http://dx.doi.org/10.1182/blood.v126.23.578.578.

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Abstract Introduction Interim positron-emission tomography (PET) following 1-3 cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) in newly-diagnosed, non-bulky stage I and II HL patients (pts) is a useful biomarker that predicts relapse rates of ≤10% for PET- pts. Relapse rates are higher in pts who are PET+ (J Clin Oncol 2014 32: 2705-11; N Engl J Med 2015 372: 1598-607). Interim PET thus provides an opportunity to minimize treatment for the majority of pts who are interim PET - and only intensify treatment for those who are PET+. This strategy could reduce short and long term treatment toxicity for the majority of pts. To test this hypothesis, the US Intergroup conducted a phase II clinical trial, CALGB/Alliance 50604, for newly-diagnosed non-bulky stage I and II HL pts. Methods Between 5/15/10 and 5/4/12, 164 previously untreated pts with non-bulky stages I/II HL were enrolled. Pts received 2 cycles of ABVD followed by PET. Deauville scores 1-3 were negative (≤ liver uptake), while scores of 4-5 were positive, based on central review. PET- pts received 2 more cycles of ABVD, and PET+ pts received 2 cycles of dose-intense bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escalated BEACOPP) + 3060 cGy involved-field radiation therapy (IF RT). Prophylactic growth factor use was permitted only after grade 3/4 febrile neutropenic events, with or without infection. Results Median age was 31 years (18-58). There were 88 males and 76 females. Pt. stages were IA (16), IB (4), IIA (90), IIB (35), IIAE 4, and IIBE (3). All pts were PET+ prior to treatment. 144/164 patients had cycle 2 PET and adequate follow-up for assessment: 131 (91%) were PET- and 13 (9%) PET+. Of 20 not analyzed, 13 were excluded (6 never treated and 2 treated with < 2 cycles) and 7 had insufficient follow up. At a median follow-up time of 2 years, 8/131 (6%) PET- pts relapsed or progressed with an estimated 3-year progression-free-survival (PFS) of 92%. 4/13 (31%) PET+ pts. failed (3 relapsed, 1 suicide) with an estimated 3-year PFS of 66%. By Cox model, observed hazard ratio comparing PET- and PET+ PFS for pts is 6.04 (1.82, 20.08). It is likely that the trial will meet the primary objective of 3-year PFS of at least 85% (79%, 92%) for PET- pts treated with 2 additional cycles of ABVD. It is unlikely that the results will meet secondary objective of improving the 3-year PFS of PET+ pts treated with 2 cycles of escalated BEACOPP + IF RT to the pre-set level considered to be of clinical interest in comparison with PET- pts treated with 2 additional cycles of ABVD (HR< 3.84). There was 1 death (suicide). Toxicity for all pts was minimal: Neutropenia: 29% grade 3 and 42% grade 4; Febrile neutropenia: 5% grade 3; Decreased CO diffusing capacity: 1% grade 3; Decreased left ventricular ejection fraction: 1% grade 3; Sensory neuropathy: 2% grade 3 and 1% grade 4; Motor neuropathy: 1% grade 4. Conclusions These early results confirm interim PET as a potential biomarker for prediction of relapse with ABVD in patients with non-bulky, stages I/II HL. Importantly, this study demonstrates that defining PET- as Deauville scores of 1-3 results in only 9% of pts. remaining PET+ after 2 ABVD cycles and excellent PFS for the PET-majority. More intensive treatment with 2 cycles of escalated BEACOPP and IF RT for the 9% of pts who are interim PET+ will be unlikely to improve 3-year PFS to the level considered to be of clinical interest in this trial. Interpretation may be limited by small numbers and lack of randomized control comparison. Fortunately, exciting new treatment approaches may provide an opportunity to improve outcomes for the minority of interim PET+ pts in the future. Kaplan Meier Plot of PFS for PET-negative and PET-positive patients For Alliance for Clinical Trials in Oncology, Eastern Cooperative Oncology Group, and Southwest Oncology Group; Supported in part by U10CA180821, U10CA180820, and U10CA180888 Figure 1. Figure 1. Disclosures Straus: Millenium Pharmaceuticals: Research Funding. Hsi:Abbvie: Research Funding; Cellerent Therapeutics: Research Funding; Eli Lilly: Research Funding; Onyx: Honoraria; Seattle Genetics: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Cheson:Gilead: Consultancy, Research Funding; Teva: Research Funding; Celgene: Consultancy, Research Funding; Ascenta: Research Funding; Astellas: Consultancy; Pharmacyclics: Consultancy, Research Funding; Spectrum: Consultancy; AstraZeneca: Consultancy; Roche/Genentech: Consultancy, Research Funding; MedImmune: Research Funding. Bartlett:Janssen: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; ImaginAB: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Millenium: Research Funding; Celgene: Research Funding; Gilead: Consultancy; Seattle Genetics: Consultancy, Research Funding.

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Gisselbrecht, Christian, Nicolas Mounier, Olivier Casanovas, O. Reman, Catherine Sebban, Marine Divine, Pauline Brice et al. „Prognostic Factors in Localized Hodgkin’s Lymphoma: How To Define Intermediate/Unfavourable Disease?.“ Blood 104, Nr. 11 (16.11.2004): 3122. http://dx.doi.org/10.1182/blood.v104.11.3122.3122.

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Abstract Actually, the prognosis of localized Hodgkin’s lymphoma (HL) patients may be assessed by different scoring systems. Although many similar characteristics have been identified, these scoring systems are not easy to relate to advanced stage HL. The aim of the present study was to refine the assessment of risk using the published scoring systems and to construct a statistical model for predicting risk of death. We report here the results of the EORTC, GHSG and Canadian-ECOG scoring systems obtained in 1156 patients for whom hematological data were available among the 1390 patients with localized HL prospectively treated within GELA centres in H8 (518 pts) and H9 (638 pts) trials. The International prognostic score (IPS) was available only for the H9 subset. All patients have been treated with radio-chemotherapy of different intensity or duration according to their prognostic factors. Median age was 30 yr [14–69] and age≥45yr.: 18%, female 50%; stage 1: 25%; stage 2: 75%; B symptoms with elevated ESR: 40%; number of nodal sites 1–2: 52%; ≥3: 48%; extra nodal involvement: 8%, bulky mediastinum> 0.35, 28%; elevated ESR> 50:33%; Hb< 10.5 g/dl: 7%; Lymphocytes < 600/μl: 6%; WBC > 15000/μl:11 %; albumin< 40g/l: 37%. With the EORTC scoring system 36% of patients had favourable HL, with GHSG 35% and with Canadian-ECOG 38%. The IPS was 0 in 19% and 1 in 45%. With a median follow up of 42 months, 54 patients died. Survival curves according to the different scoring systems significantly discriminated favourable and unfavourable patients outcomes (5 yrs OS 95% vs 92%, p=0.01). By multivariate Cox analysis, age > 45yr (RR=2.0), sex male (RR=2.5), haemoglobin <10.5g/dl (RR=2.3), lymphocytes < 600/μL (RR=3.6), B symptoms with elevated ESR (RR=3.6), extra nodal sites (RR=1.2) retained a significant prognostic value. The 5 yrs OS was 99%, 98%, 92%, 82%, 73% for patients with 0,1, 2, 3, 4–5 factors respectively (p< 0.0001, see figure). 10% of the patients had 3–5 factors. The covariates selection was validated by the bootstrap method. The introduction of albumin< 40g/l in the H9 subset population did not bring more significant information. In conclusion, these factors are similar with those described in the IPS when stages 3–4 are replaced by extra nodal (E) localization. They should be validated in other prospective trials because such a scoring system could unify the assessment of the prognosis for HL patients and facilitate the treatment choice. Figure Figure

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Suleiman, Moyosore M., Ankit Mangla, Hussein Hamad, Romy Thekekkara, Kalid Adab und Rosalind Catchatourian. „Staging Bone Marrow Biopsy Does Not Alter Management in Patients with Hodgkin Lymphoma and May Not be Necessary:a 10yr Single Institutional Retrospective Review of Patients with Hodgkin Lymphoma with Bone Marrow Involvement 2004-2013“. Blood 124, Nr. 21 (06.12.2014): 5361. http://dx.doi.org/10.1182/blood.v124.21.5361.5361.

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Abstract Introduction: The incidence of bone marrow involvement (BMI) in patients diagnosed with Hodgkin Lymphoma (HL) is relatively low varying from 4-14% in different series occurring mainly in patients with advanced disease (stage III-IV). Ann Arbor staging system with Cotswolds modification in 1989 recommend staging bone marrow in patients with clinical stage III-IV and stage II patients with adverse risk features. It’s utility is now questionable and no longer recommended by many authors as it does not alter the way patients are managed. The advent of 18F-fluoro-2 –deoxy-D-glucose positive emission tomography (FDG-PET) scan use in the staging of patients has improved the prediction of possible bone marrow involvement obviating further the need for bone marrow biopsy. While BMI is said to be an independent prognostic factor in the survival of patient with HL, more studies have shown that BMI alone in patients with Stage IV disease does not influence survival or freedom from disease progression. Because staging bone marrow biopsy (BMB) use in HL varies from one institution to another, we performed a retrospective review in our institution in order to determine its incidence, risk factors and effect in the management of patients. Methods: We performed a retrospective search in John H Stroger, Jr. Hospital database of patients with HL seen from 2004 to 2013. 237 adult (18yr and above) patients were screened. 185 patients had BMB done as part of work up. Results: BMI was detected in 21%(38 of 185) of patients who had BMB as part of work up. M:F ratio was 2.5:1. Mean age was 39.8 +/- 11.5yrs. 51%(95 of 185) of patients who had BMB had advanced disease. 94%(33 out of 35) of patients with BMI had advanced disease prior to BMB. 3 patients with BMI were incompletely staged. Advanced disease was significantly more likely to be associated with BMI than early stage disease (OR 20.2 95% CI 4.6-87.6 p=0.0001). Less than 1%(2 out of 78) of patients with early stage disease were upstaged .The 2 patients that were upstaged had Stage IIB disease prior to BMB.38%(14 of 37) of patients with BMI were HIV positive which was higher compared to 12%(16 of 129) of patients without BMI that were HIV positive (OR 5.8 95% CI 2.4-14.0 p=0.0001). 5 of 38 patients with BMI had staging FDG-PET and all showed positivity in the skeletal system. Patients with BMI in our review were managed with 6-8cycles of chemotherapy (CT)-Adriamycin, Bleomycin, Vinblastine and Dacarbazine regimen (ABVD). 5 cases were relapsed disease. 4 of these patients with relapsed disease received Platinum/Gemcitabine regimen and one patient received Mechlorethamine, Vincristine, Procarbazine and Prednisone regimen (MOPP). Radiation Therapy (RT) was part of the management in 4 patients done for cord compression (2), bulky mediastinal disease (1) and for residual disease after chemotherapy (1). Conclusions: The incidence of BMI was high in our retrospective review compared to other series, however majority of involvement were in patients with advanced disease as in most series. Patients were rarely upstaged from early stage to advanced stage with bone marrow biopsy. This occurred in less than 1% in our retrospective review. Staging FDG-PET although done in few of our patients with BMI was predictive. Management of these patients was not significantly altered based on BMI. They were managed mainly with CT. RT needed in some of these patients was justified (cord compression, and bulky mediastinal disease). RT for residual disease is not a standard of care. Risks factors identified for BMI includes advanced disease and associated HIV infection. BMB does not alter patient management and its sole prognostic significance in patients with stage IV disease is controversial. It is therefore not necessary in the staging of newly diagnosed patients with HL. Disclosures No relevant conflicts of interest to declare.

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Christian, Beth, Anne Kopko, Todd A. Fehniger, Nancy L. Bartlett und Kristie A. Blum. „A Phase I Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL)“. Blood 120, Nr. 21 (16.11.2012): 1644. http://dx.doi.org/10.1182/blood.v120.21.1644.1644.

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Abstract Abstract 1644 Introduction: Previous phase 2 single agent trials with the immunomodulatory agent, lenalidomide, in patients with relapsed or refractory HL demonstrated overall response rates (ORR) of 14–29%, with a median duration of response of 6 months. Likewise, a single agent trial utilizing the orally available HDAC inhibitor, panobinostat, in 127 patients with relapsed/refractory HL after prior autologous stem cell transplant (ASCT) demonstrated an ORR of 27% with a median duration of response of 6.9 months. Based on the encouraging single agent activity of these agents and in vitro synergy of combined panobinostat and lenalidomide in myeloma cell lines, we are conducting a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with this combination and results of the phase I study are presented. Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy are eligibile. Measurable disease ≥1 cm in at least one dimension, ejection fraction ≥45%, ECOG PS 0–2, QTc on ECG ≤ 450 msec, ANC ≥1200/mm3, platelets ≥100,000/mm3, AST/ALT ≤ 2.5 × the upper limit of normal (ULN), bilirubin ≤ 1.5 × ULN, and creatinine clearance ≥60 ml/min are required at study entry. Prior ASCT, lenalidomide, and panobinostat are permitted. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly are combined with lenalidomide 25 mg days 1–21 utilizing a cohorts of 3 design. DLT is defined during cycle 1 and includes grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, and other grade 3–4 non-hematologic toxicity. Six patients will be enrolled at the MTD to ensure patient safety prior to phase 2 enrollment. Twenty-eight days defines a cycle and patients may remain on therapy until disease progression or unacceptable toxicity. Response is assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 2007). Results: Seven patients (6 males) with cHL (n=6) and LP HL (n=1) and a median age of 31 (range 24–72) have been enrolled. Patients received a median of 3 prior therapies (range 3–5), 1 patient received prior radiotherapy, 3 patients were refractory to their most recent therapy, 3 patients had prior ASCT, 6 patients had received prior brentuximab vedotin, and no patients had prior lenalidomide or panobinostat. Other characteristics included stage III-IV disease in 100% (57% stage IV), bulky adenopathy ≥5 cm in 14%, and bone marrow involvement in 14%. Seven patients have completed one or more cycles of therapy (median 3, range 1–4) with either 15 mg (n=3) or 20 mg (n=4) of panobinostat + 25 mg lenalidomide. Four patients discontinued therapy for progressive disease (PD) after 4 cycles (n=3) and 1 cycle (n=1), respectively. Three patients continue to receive protocol treatment, all receiving panobinostat 20 mg days 1, 3, and 5 weekly. No DLTs have been observed. Grade 3–4 events included neutropenia (43%), lymphopenia (29%), thrombocytopenia (29%), and hypophosphatemia (29%). No QTc prolongation has been observed. Dose reductions from 15 mg panobinostat days 1, 3, and 5 weekly + lenalidomide 25 mg to 15 mg panobinostat days 1, 3, and 5 weeks 1 and 3 only + 20 mg lenalidomide were required in 2 patients for grade 3–4 neutropenia during cycles 3 and 4. ORR is 33% in 6 evaluable patients with a complete response in 1 patient with cHL and partial response in 1 patient with LP HL. One patient has not yet undergone restaging scans. Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL without dose limiting myelosuppression, cardiac toxicity, QTc prolongation, or other grade 3–4 non-hematologic toxicity. Study accrual continues, 2 additional patients will be added to the highest dose level (panobinostat 20 mg days 1, 3, and 5 weekly for 4 weeks + lenalidomide 25 mg days 1–21) to complete the phase I trial and will be followed by anticipated enrollment of a maximum of 25 patients to a two-stage phase 2 trial targeting an ORR of 30% or higher. Disclosures: Blum: Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of HL.

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Kanoun, Salim, Cedric Rossi, Alina Berriolo-Riedinger, Olivier Humbert, Inna Dygay-Cochet, Marie-Lorraine Chretien, Caroline Legouge, Louis Berthet, Jean-Noel Bastie und Rene-Olivier Casasnovas. „Metabolic Tumor Volume Is an Independent Prognosis Factor Predicting patient's Outcome in Hodgkin Lymphoma“. Blood 120, Nr. 21 (16.11.2012): 3631. http://dx.doi.org/10.1182/blood.v120.21.3631.3631.

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Abstract Abstract 3631 Positron emission tomography with [18F]fluorodeoxyglucose (PET) performed after two cycles of chemotherapy allows to predict treatment outcome in Hodgkin lymphoma (HL) with a pretty good accuracy specifically when the SUVmax reduction (DSUVmax) of the most hypermetabolic lesion is used to interpret interim PET. However, about 15% of false negative and 30% of false positive interim PET results are observed. To investigate the prognosis impact of the metabolic tumor volume at baseline (MTV0) we compared the respective clinical usefulness and prognosis value of the MTV0 and the SUVmax reduction between baseline PET (PET0) and interim PET (PET2) performed after 2 cycles of chemotherapy (DSUVmaxPET0–2) in a retrospective single centre study. From January 2007 to January 2010, 59 consecutive patients with a first diagnosis of HL were treated in our institution. All patients received 4 to 8 cycles of chemotherapy including ABVD in 50 cases (85%) and BEACOPP in 9 cases. Radiotherapy was performed in 14 responding patients with localized disease. PET was done at baseline (PET0) and after 2cycles of chemotherapy (PET2) and therapeutic strategy was not modified according to PET2 result. All PET scans were reviewed by SK, ABR and IDC. MTV0 was measured with a semi-automatic method using various volume shapes and systematic 41% SUVmax thresholding. Based on a receiver operating characteristics approach patients with a MTV0 >225 cc were considered to have a hypermetabolic bulky disease. Interim PET were interpreted using DSUVmaxPET0–2 and patients with a DSUVmaxPET0–2 >71% were considered as good responders after 2 cycles. Progression-free survival (PFS) and freedom from treatment failure (FFTF) were analyzed according to MTV0 and DSUVmaxPET0–2.Median follow-up was 39 months (range: 6–62). Median MTV0 was 120 cc (range: 10 – 1610) and 17 patients (29%) had a MTV0 >225 cc. Patients with a MTV0 >225 cc had more frequently a bulky tumor>10 cm (41% vs 5%; p = 0.0021). MTV0 (≤ 225 vs > 225) was predictive of 3-year PFS (85% vs 42%; p = 0.001) and FFTF (88% vs 45%; p = 0.0015). Bulky tumor was also predictive of 3-year PFS (44% vs 78%, p <0.04), but of border line significance for 3-year FFTF (80% vs 53%, p = 0.09). In multivariate analysis, using the international prognosis score, DSUVmaxPET0–2, MTV0 and bulky tumor as covariates, only DSUVmaxPET0–2 and MTV0 remained independent predictors for PFS (p= 0.0005; RR=6.4, and p<0.007; RR= 4.2, for DSUVmaxPET0–2 and MTV0 respectively) and FFTF (p= 0.0002; RR= 8.2,and p= 0.01; RR= 4.4, for DSUVmaxPET0–2 and MTV0 respectively). Then, 3 prognosis groups could be identified (Figure 1): patients with either DSUVmaxPET0–2>71 and MTV0≤225 (n = 37; 63%), or DSUVmaxPET0–2<71 or MTV0>225 (n = 17; 29%), or DSUVmaxPET0–2<71 and MTV0>225 (n = 5; 8%), had a 92%, 48%, and 20% 3-year PFS (p<0.0001) and a 94%, 54% and 20% 3-year FFTF (p<0.0001) respectively. MTV0 is more relevant that tumor bulk to predict outcome of patients with Hodgkin lymphoma, and adds significant prognosis insights to interim PET response assessment. The combination of MTV0 with DSUVmaxPET0–2 allows identifying 3 subsets of HL patients with significantly different outcomes that may help clinicians to guide therapeutic strategy. Figure 1: PFS according to DSUVmaxPET0–2 and MTV0 results Figure 1:. PFS according to DSUVmaxPET0–2 and MTV0 results Solid line: patients with DSUVmaxPET0–2 >71 and MTV0 ≤225. Dashed line: patients with DSUVmaxPET0–2 <71 or MTV0 >225. Dotted line: patients with DSUVmaxPET0–2 <71 and MTV0 >225. Disclosures: No relevant conflicts of interest to declare.

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