ALBERT

Beschreibung: Introduction Achieving a PET-negative metabolic (m)CR with salvage chemotherapy prior to autologous stem cell transplantation (ASCT) in relapsed/refractory Hodgkin lymphoma (R/R HL) is a strong predictive factor for long-term progression-free survival (PFS). In a phase I dose-escalation trial we have shown a favorable toxicity profile of 3 cycles of DHAP in combination with brentuximab vedotin (BV) with a high mCR rate (12/12 patients). A subsequent phase II study in 55 patients has been performed; the 6 patients treated at full dose of BV-DHAP in the phase I part were added to the current analysis. Methods BV was given at a fixed dose of 1.8 mg/kg on day (d) 1 of 3 cycles of DHAP q 3 weeks (dexamethasone 40 mg iv d 1-4, cisplatin 100 mg/m² iv d1 and cytarabine 2x2 g/m² iv d2). Cycle 2 was used for stem cell mobilization; after the 1st and 3rd cycle patients received pegylated G-CSF to prevent prolonged neutropenia and dose delays. The primary endpoint of the study was the mCR rate after 3 cycles of BV-DHAP based on central PET-review. Patients with a partial or complete response proceeded to high dose chemotherapy (BEAM) and ASCT. Results Twenty-three of the 61 patients (29 males; median age 29 yrs, range 19-71) had not achieved a CR to 1st line treatment (37%), which consisted of ABVD (n=45), (escalated) BEACOPP (n=11) or other regimens (n=5). The median time from response to 1st line treatment to relapse was 6 months (range 0-160 months); 38 patients (62%) had either primary refractory disease or early relapse (

Beschreibung: Abstract 3078 Introduction Adding rituximab to induction therapy has improved overall survival in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) after high dose chemotherapy followed by autologous stem cell transplantation (AuSCT) to 50–60%. However, there is still room for improvement. Addition of 90Yttrium ibritumomab tiuxetan prior to the BEAM conditioning regimen seems feasible and results in promising data with respect to disease free and overall survival in high risk DLBCL patients even when treated with rituximab containing induction therapy. At the VU University Medical center, rituximab was added to (re-)induction therapy starting July 2001. From 2006 we started to add 90Yttrium ibritumomab tiuxetan (Zevalin®) to BEAM (Z-BEAM) in high risk DLBCL patients. In this retrospective analysis we compare outcome of Z-BEAM versus BEAM, both followed by AuSCT. Patients and methods All high risk DLBCL patients consolidated with high dose (radio-immuno) chemotherapy and AuSCT in CR or PR after rituximab-containing induction therapy were included. High-risk DLBCL was defined as either relapsed or refractory DLBCL or as histological transformation of indolent NHL. AuSCT was preceded by BEAM conditioning and 90Yttrium ibritumomab tiuxetan (0, 4 mCi/kg, max 32 mCi, starting 2006: Z-BEAM group) or by BEAM only (BEAM group). EFS and OS were estimated using the Kaplan-Meier method and compared using the log rank test. Results 43 patients received Z-BEAM and 42 patients received BEAM conditioning. Median age was 56 and 52 years respectively. No significant differences in disease characteristics were seen. Median follow up (range) was 15 months (6–54) and 39 months (0–112) respectively. Overall survival was significantly better in the Z-BEAM group compared with the BEAM group (p=0.02) with an estimated 2 year overall survival of 90% vs. 65%. (fig 1.) In the first 2 years of follow up 7 patients in the Z-BEAM group relapsed compared to 11 in the BEAM group, this did not reach significance (p=0.09). Median time to recovery of neutrophils and thrombocytes was not significantly different. Moreover, there was no significant difference in TRM (no TRM in the Z-BEAM group versus 2 patients in the BEAM group). Patients who relapsed, in both groups, were able to receive re-induction chemotherapy and, if indicated, allogeneic SCT without being compromised by decreased bone marrow reserve or non haematological toxicities. Conclusion Adding 90Yttrium ibritumomab tiuxetan to the BEAM conditioning regimen preceding AuSCT leads to a significant improvement in overall survival in high risk DLBCL patients, even if they have received rituximab during (re)induction. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: [§ share last authorship] Background: In 2000-2010, the first large prospective trials in peripheral T-cell lymphoma (PTCL) showed outcomes burdened by high failure rates during induction. Concurrently, trials with the anti-CD52 monoclonal antibody alemtuzumab (ALZ) yielded promising responses in PTCL while demonstrating the feasibility of combining ALZ with CHOP. Hence, the Nordic Lymphoma Group initiated the randomized ACT-1 trial to test, in younger patients (pts) (18-65yrs), the addition of ALZ to CHOP + autologous stem cell transplant (ASCT). Primary endpoint was the 3 years event-free survival (EFS). Here, we present the final analysis of the ACT-1 trial (ClinicalTrials.gov: NCT00646854). Patients and Methods: Overall, 136 pts were randomized (43% of planned sample size due to slow accrual), five did not receive study treatment, and 131 were analyzed (ALZ-CHOP: 65; CHOP: 66). Due to lack of tumoral CD52 expression, anaplastic large cell lymphomas (ALCL) were not included in the ACT-1 trial. An amendment tapering ALZ dose from 360 mg (30 mg on days 1+2 of each CHOP course) to 120 mg (30 mg on day 1 of CHOP courses 1-4) was introduced early on due to systemic fungal infections in 2 pts. Of the 65 pts treated with ALZ-CHOP, 4 received the pre- and 61 (94%) the post-amendment dose. Monitoring for CMV- and EBV-DNA and antimicrobial prophylaxis were mandatory. Results: The median observation time for the Full Analysis Set was 66 months and the median age 51 yrs. The ALZ-CHOP and CHOP cohorts were well balanced with regard to classical prognostic factors and histological subtypes (PTCL-NOS 58% vs 54%, AILT 21% vs 25%, other 21% vs 21%). Feasibility: Neither CHOP nor ALZ-CHOP pts experienced substantial treatment delay. ALZ exposure did not affect stem cell harvest nor hematopoietic recovery. Grade 4 leucopenia was more frequent in ALZ-CHOP pts (73% vs 35%; p=0.001), whereas the occurrence of grade 3-4 anemia and thrombocytopenia did not differ significantly. After ALZ dose amendment, the frequency of bacterial and fungal infections of grade ≥3 was similar in both treatment arms. ALZ treated pts had more viral events (22/57=42% vs 4/23=17%), mainly due to asymptomatic CMV reactivations. The ratio of serious adverse events per ALZ-CHOP treated patient dropped markedly (from 3.25 to 0.86, comparable with 0.46 for CHOP) after dose amendment. Additional toxicity was mild and similar in both arms. Treatment related mortality was 4% (5% vs 3%). Efficacy: Complete remission (CR) was 52% in ALZ-CHOP vs 42% in CHOP. Primary refractory disease occurred for ALZ-CHOP and CHOP in 23% and 38% of pts, respectively. Overall, females had a significantly better outcome than males (p=0.004), also after adjustment for classical prognostic factors. Analyzing time-related endpoints without knowledge of CD52 expression, 3-years EFS, progression-free, and overall survival (PFS, OS) did not differ significantly between ALZ-CHOP and CHOP (EFS 35% vs 26%, PFS 37% vs 26%, OS 52% vs 50%). Fig.1A shows EFS by treatment arm, by gender, and by gender and treatment arm. Although not significantly different, EFS, PFS and OS values of ALZ-CHOP treated females in the ACT-1 trial were consistently higher than those of non-ALZ treated females or of males regardless of treatment group. RNA sequencing from evaluable pre-therapeutic tumor biopsies defined a signature of differentially expressed genes to be predictive of clinical outcome in ALZ-CHOP but not CHOP treated pts (n=33). Tumor microenvironment genes were prominent in determining response to ALZ. Tumors rich in B-cell milieu showed good responses, while the opposite was observed in tumors with signatures enriched with high endothelial cell genes (p

Beschreibung: Key Points DS4 is recommended as the cutoff value for PET-2 positivity after 2 cycles eBEACOPP for advanced-stage HL.

Beschreibung: Abstract 3538 Poster Board III-475 Introduction Recently, Yttrium-90 labeled anti-CD20 (90Y-ibritumomab tiuxetan, Zevalin®) has been introduced as a new therapeutic option in relapsed malignant B cell lymphoma. The results of adding 90Y-ibritumomab tiuxetan to high-dose BEAM with autologous stem-cell transplantation(auSCT) are promising. However, the toxic impact of radioimmunotherapy to the haematopoietic microenvironment, and its effects on stem cell homing and engraftment are largely unknown. Stromal Derived Factor-1 (SDF-1α) is a key regulator of stem cell engraftment. SDF-1α has been found to co-localize with hyaluronan (HA) on human bone marrow sinusoidal endothelium and endosteum, supporting transendothelial migration of human progenitor cells and their final anchorage within specific niches of the BM. External irradiation influences levels of SDF-1α and HA. Therefore, we studied the effect of 90Y-ibritumomab tiuxetan on in vivo SDF-1α and HA levels. Patients and methods Patients with relapsed B cell NHL, treated with Zevalin-BEAM and autologous stem cell transplantation were included after obtaining their informed consent. At 3 different time points, bone marrow aspirates and peripheral blood samples of 9 consecutive patients were analysed: day -22 (before Z-BEAM), day -8 (7 days after Zevalin (0.4 mCi/kg, max. 32 mCi (n=8) or 64 mCi (n=1) (before BEAM)) and day 0 (after BEAM and before auSCT). SDF-1α and HA protein levels were determined in bone marrow and peripheral blood plasma using ELISA. Also, SDF-1α mRNA expression was quantified by real time PCR. Quality of bone marrow stroma was determined by investigating CFU-F after 1 and 2 weeks and the percentage of confluency in cultures after 1, 2 and 3 weeks. Also, in 5 patients dosimetry of Zevalin was performed. Results In 5 patients dosimetry of Zevalin was performed, by using Zirconium-89 labelled Zevalin as surrogate for PET scanning at day 0, +3 and +6 after injection. Patients received 3.4.10 * 6/kg(mean, range 1,9-8,3) CD34+ cells, and all but one showed engraftment. ANC〉0.5 10*9/l was reached at 12,8 days (range 11-15, n=9), platelets〉50 10*9/l at 18 days (range 11-38, n=8) ), being comparable with retrospective data on BEAM transplantation. In the one patient not recovering, a second transplant did not result in platelet recovery. Zevalin alone did not affect bone marrow MNC count (23,3 vs 17,4 10*6/ml, p=0.40), CFU-F capacity (colonies 〉 50 cells: 2,4 vs 8,3, p=0.35) and stromal confluency (41,9 vs 62,1%, p=0.31). In addition, the levels of SDF-1α (4584 vs 5305 pg/ml, p=0.11) and HA (227 vs 247 mcg/ml, p=0.86) were not influenced. Following BEAM, production of SDF-1α (4584 vs 6166 pg/ml, p=0.01) and HA levels (227 vs 356 mcg/ml, p=0.03), significantly increased. A corresponding increase in SDF-1α mRNA copies was observed (0.16 vs 17.2 cps % GAPDH, p=0.02), indicating that induction of SDF-1α gene expression was involved. There was a trend in decreased quality of bone marrow stroma, as determined by MNC count, CFU-F capacity and confluency. Whereas Fibroblast Growth Factor increased the confluence of stromal culture before and after Zevalin, it didn't overcome the harmful effect of the BEAM chemotherapy. Conclusion 90Y-ibritumomab tiuxetan alone did not effect the bone marrow environment as measured by SDF-1α and HA. As expected, significant changes were found after high dose chemotherapy. Engraftment and repopulation after Z-BEAM and auSCT was similar to standard BEAM followed by auSCT. Disclosures: No relevant conflicts of interest to declare.

Beschreibung: Background: Patients with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. Treatment with salvage chemotherapy has generally been disappointing. In many centers in the Netherlands the oral PECC regimen is used for such patients. 90Y-ibritumomab tiuxetan (Zevalin®, Spectrum Pharmaceuticals) radioimmunotherapy (RIT) is clinically active as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating salvage therapy with Rituximab (R)-PECC, in responsive patients followed by 90Y-ibritumomab tiuxetan consolidation. Methods: Adult patients with refractory/relapsed DLBCL, more than one year after or not eligible for ASCT, were treated with R-PECC (Prednisone 40 mg/m2 po D1-5; Etoposide 100 mg/m2 po D1-5; Chlorambucil 8 mg/m2 po D1-5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1) q 28 days for 4 cycles. Complete (CR) or partial responders (PR) received consolidation with a single dose 90Y-ibritumomab tiuxetan (15 MBq/kg, 0.4 mCi/kg). Response was evaluated according to the revised Cheson criteria (2007). Results: Between November 2008 and February 2012 62 patients were enrolled. Median age was 70 years (range, 45-82). Secondary IPI score was high-intermediate or high in 42% patients. All patients had received CHOP at first-line, 12 without rituximab. Prior therapies consisted of (R)-CHOP (65%), R-CHOP and R-DHAP/VIM (24%) or R-CHOP and R-DHAP/VIM plus ASCT (11%). Fourteen patients (23%) were refractory to the last prior therapy. After 4 cycles of R-PECC the overall response rate (ORR) was 31/62 (50%), with 14 of 62 (23%) patients achieving a CR and 17 of 62 (27%) achieving a PR, 13 of 62 (21%) patients had progressive disease. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (63% vs 7%, p=0.0001). 29 of 31 responsive patients received consolidation with RIT. The remaining two patients with PR did not proceed to RIT because of one toxic death and one misinterpretation of the response. The ORR after the end of the entire treatment was 29% (23% CR, 6% PR), RIT consolidation improved the overall best response (from PR to CR) in 5 of the 17 PR pts after the R-PECC only regimen. The median follow-up time of patients still alive is 48 months (range, 0-67 months). The median response duration in the patients that received R-PECC only was 9 months (range 3-63 months). The median response duration in the patients that received RIT consolidation was 20 months (range 0-59 months). The failure free survival at 1 yr from start of RIT consolidation was 52% (95% CI=[33%,68%]) and the overall survival 62% (95% CI=[42%,77%]). There was one treatment related death, due to sepsis and pneumonia after the first R-PECC cycle. The R-PECC regimen was well tolerated by most patients. The most common grade 3 or 4 adverse events during R-PECC treatment were hematological toxicity (27%), infection (19%) and malaise (11%). Adverse events after RIT were primarily hematologic. Grade 3 to 4 trombocytopenia and neutropenia occurred in 8 patients (28%) and 5 patients (17%), respectively. Eight patients received platelet transfusions and 6 patients red blood cell transfusions. Conclusions: The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Consolidation with RIT was well tolerated and resulted in long response durations in half of the patients. Disclosures Lugtenburg: Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Roche: Consultancy; Celgene: Consultancy. Off Label Use: 90Ytrium-ibritumomab tiuxetan for diffuse large B-cell lymphoma. Zijlstra:Celgene: Consultancy; Roche: Consultancy. Doorduijn:Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Hoogendoorn:Gilead: Consultancy; Novartis: Consultancy.

Beschreibung: Abstract 2729 Background. Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after- or not eligible for autologous stem cell transplantation (ASCT) have a poor prognosis. The optimum salvage therapy for these patients is not known. Treatment results with second-line chemotherapy have generally been disappointing. In some centers in the Netherlands PECC (Prednisone, Etoposide, Chlorambucil and Lomustine) combination chemotherapy is used as salvage treatment for such patients. PECC is a completely oral schedule. The efficacy and toxicity of PECC in this patient category has not been evaluated systematically before. 90Y-ibritumomab tiuxetan (Zevalin®) showed clinical activity as a single agent in relapsed DLBCL. We conducted a prospective multi-center phase II study evaluating induction therapy with Rituximab (R)-PECC followed in responsive patients by 90Y-ibritumomab tiuxetan consolidation. Methods. Patients aged ≥ 18 years with refractory CD20 positive DLBCL or first or second relapse, more than one year after or not eligible for ASCT, were enrolled. Treatment consisted of R-PECC (Prednisone 40 mg/m2 po D1–5; Etoposide 100 mg/m2 po D1–5; Chlorambucil 8 mg/m2 po D1–5; Lomustine 80 mg/m2 po D1 and Rituximab 375 mg/m2 iv D1), every 28 days for 4 cycles. Patients with progressive disease after 2 cycles went off protocol. Patients in complete or partial remission after 4 cycles received consolidation treatment with 90Y-ibritumomab tiuxetan at the standard single dose of 15 MBq/kg (0.4 mCi/kg) 6 to 12 weeks after start of the last R-PECC cycle. Response to treatment was evaluated according to the revised 2007 Cheson criteria. Results. Between November 2008 and February 2012 64 patients were enrolled. We report preliminary data for the first 50 patients evaluable for response and toxicity after the induction treatment with R-PECC. The median age was 70 years (range, 45–82) and median time since first diagnosis was 17 months (range 3–172). All patients had been treated with CHOP as first-line treatment and 8 patients (16%) had not been exposed to rituximab at first-line. Prior therapies consisted of (R)-CHOP (72%), R-CHOP and R-DHAP/VIM (16%) or R-CHOP and R-DHAP/VIM plus ASCT (12%). Eleven patients (22%) were refractory to their last prior systemic therapy. According to the secondary IPI, 26%, 28%, 34% and 8% of the patients belonged to the low-, low-intermediate-, high-intermediate-, and high risk group, respectively. Median relative dose intensities for the myelosuppressive agents of the PECC regimen were 93.7% (90% CI = 62.8–106.9%), 94.3% (90% CI = 71.6–104.7%) and 97.4% (90% CI 76.0–104.7%) for Lomustin, Etoposide and Chlorambucil, respectively. Progressive disease occurred in 14 patients (28%). Overall response rate (ORR) after induction treatment was 52%, including 34% complete response and 18% partial response. ORR of relapsed patients was significantly higher than that of patients refractory to their last prior treatment (64% vs. 9%, p=0.099). Patients more than one year from start of upfront treatment had a significant higher ORR than that of patients less than one year from start of upfront treatment (81% vs 21%, p=0.005). Median response duration was 13 months. One patient died because of treatment related toxicity due to sepsis and pneumonia after the first R-PECC cycle. The most common grade 3 or 4 adverse event was haematological toxicity (42%), followed by infection (14%), malaise (13%) and gastro-intestinal toxicity (6%). Eighteen serious adverse events (SAEs) occurred in 14 patients, 14 of the SAEs were possibly related to treatment (mainly hospitalisations because of infections). Approximately half of the patients (46%) have entered the 90Y-ibritumomab tiuxetan consolidation phase of the study. Conclusions. The R-PECC regimen shows good clinical activity in relapsed DLBCL patients. Its activity in refractory patients is low. This largely oral regimen provides patients not eligible for high-dose salvage treatment with a convenient treatment schedule with an acceptable safety profile. Disclosures: Off Label Use: 90Y-ibritumomab tiuxetan is not registered for DLBCL.

Beschreibung: A total of 239 patients with relapsed/progressive aggressive CD20+ NHL after/during adriamycin containing regimens, were recruited to the randomized HOVON-44 trial comparing DHAP-VIM-DHAP followed by BEAM and autologous stem cell re-infusion (ASCT)(“DHAP-arm”) with DHAP-VIM-DHAP in conjunction with Rituximab (375 mg/m2) and ASCT (“R-DHAP arm”). Of the included patients, 202 were evaluable and randomized to the DHAP arm (n=101) or R-DHAP arm (n=101). Only patients with CR/PR after two courses of intensive chemotherapy were eligible for ASCT. Patients were well balanced for risk factors. In both arms the majority of patients had not been exposed to Rituximab during first line treatment. As of July 2006, median follow-up of all patients still alive is 24.5 months. After two courses of chemotherapy PR/CR was obtained in 49 % of the patients in the DHAP arm and 77% in the R-DHAP arm (p=

Beschreibung: Introduction Autologous stem cell transplantation (AuSCT) is widely used in patients with histologic transformation of indolent lymphoma. Although probably superior to standard chemotherapy, there is still room for improvement. We are currently studying the effect of the addition of 90Yttrium ibritumomab tiuxetan (Zevalin) to BEAM conditioning followed by an AuSCT on survival in a prospective phase 2 trial. It is known that, after rituximab-BEAM-AuSCT, recovery of T cells occurs after 4 months and of B cells after 9 months, with normal levels only being reached after 1 and 2 years, respectively. (1,2) It is however unclear if, in patients uniformly pre-treated with rituximab-chemotherapy, followed by BEAM and AuSCT, the addition of Zevalin further hampers immune reconstitution. Materials and methods Patients (n=14) with histologically proven transformed lymphoma were included in this prospective phase 2 trial when conditioning for AuSCT was started. AuSCT was planned when CR or PR was reached after (re)induction containing a minimum of 6 courses of rituximab (375 mg/m2) and chemotherapy. Patients subsequently received pre-doses of rituximab on day -15 and -8 (250 mg/m2), Zevalin on day -8 (0.4 mCi/kg) and BEAM conditioning on day -7 to -1, followed by AuSCT at day 0. Blood samples were taken before the first predose of rituximab (day -15,t=0) and 3-6, 12-18 and 24-30 months after AuSCT. Absolute neutrophils were counted and samples were analyzed for NK-, B- and T-cell subsets using multicolor flowcytometry. T cells were defined using CD3 combined with either CD4 or CD8. NK cells were defined as CD45+, CD3-, CD56+ and/or CD16+, B cells as CD45+, CD3-, CD19+, memory B cells CD19+,CD27+. Recovery was defined as: Neutrophils 〉 0.5 x 109/l, CD19+ B cells 〉0,07 x 109/l (CD27+ B cells 〉0,03 x 109/l) CD4〉0,4 x 109/l,CD8〉0,13 x 109/l, NK cell 〉 0,08 x 109/l. (1,2) All infections after neutrophil recovery following AuSCT were registered. IgG levels were measured at baseline and after 2 years. Results A median of 3 (range 1-4) measurements were obtained depending on length of follow up. The median follow up was 26 months (range 3-30 months). Median time to neutrophil recovery was 22 days after AuSCT (range 17-29 days). As expected, patients were already severely B-cell depleted at start of consolidation (t=0, figure 1).B cells started to appear after nine months and reached (low) normal values after 12-18 months. T cell and NK cell recovery started after 3 months and took one year to normalize. (figure 1) All patients had IgG levels 〉5 g/l after AuSCT, without support. Only three infectious episodes were reported in 14 patients. In one patient an episode of herpes simplex virus infection with diarrhea was reported two months after AuSCT. In another patient a pneumonia was diagnosed two months after recovery from AuSCT (cultures stayed negative). Both had enough neutrophils but B cells and CD4 cells were not yet recovered. Both patients recovered completely after antiviral and empirical antibiotic and antimycotic therapy, respectively. One patient developed a herpes zoster virus infection at 2 years after AuSCT, recovering completely after antiviral therapy. Conclusion Compared to figures reported in literature (1,2), the addition of Zevalin to consolidation with BEAM and AuSCT after (re)induction with R-chemotherapy does not seem to lead to an increase of infectious complications or delayed immune-reconstitution as analyzed by T cell, B cell and NK cell recovery. References Kasamon YL, Jones RJ, Brodsky RA, Fuchs EJ, Matsui W, Luznik L, Powell D, Blackford AL, Goodrich A, Gocke CD, Abrams RA, Amvinder RF, Flinn IW. Immunologic recovery following autologous stem-cell transplantation with pre-and posttransplantation rituximab for low-grade or mantle cell lymphoma. Ann Oncol 2009: 1-8 van der Velden AMT, Claessen AME, van Velzen-Blad H, de Groot MR, Kramer MHH, Biesma DH, Rijkers GT. Vaccination responses and lymphocyte subsets after autologous stem cell transplantation.Vaccine 2007:8512-8517 Figure 1 Figure 1. Disclosures Wondergem: spectrum pharmaceuticals: Research Funding. Visser:spectrum pharmaceuticals: Research Funding.

Beschreibung: Background: Primary progressive disease still remains an unmet medical need in Hodgkin Lymphoma (HL). Due to missing data on treatment effects and survival there is no established standard of care. We thus performed a retrospective analysis using the German Hodgkin Study Group (GHSG) database to improve the knowledge on the course of primary progressive HL patients. Methods: Patients aged between 18 and 60 years treated within the GHSG first-line trials HD13-HD15 were screened for primary progressive HL. Primary progression was defined as progressive disease during ongoing therapy, within 3 months after the end of treatment, or up to 6 months after the end of treatment in patients with partial response or stable disease in the final restaging. We investigated types and outcome of second-line treatment approaches and overall survival, which was calculated from first diagnosis of HL (OS) and from diagnosis of first progression or relapse (OSp). Results: We analyzed 5,126 patients, of whom 112 (2.2%) were identified with primary progressive disease. Of those, 62 (55%) patients had initially been treated for advanced-stage HL with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) variants, 30 (27%) for early-stage unfavorable HL with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)- or BEACOPP-like regimens (24 and 6 patients, respectively) and 20 (18%) for early-stage favorable HL with ABVD variants. The median age at the time of progression was 33 years. 3 patients (3%) died before a salvage therapy was started. Second-line treatment strategies included reinduction with intensified salvage regimens (77%), conventional chemotherapy (14%), and radiotherapy (8%). Autologous stem cell transplantation (ASCT) was performed in 76% of the patients who had received intensified reinduction chemotherapy, and allogeneic stem cell transplantation in ten (9%) patients. After the first salvage therapy, 42% of all patients achieved a complete remission (CR) and did not require further treatment. In total, 66% of the patient cohort achieved a CR after one or more second-line approaches. Median duration of the first CR was 61 months. After a median observation time of 7 years, 55 of the patients with primary progressive disease (49%) had died, mostly from progressive or relapsed HL (n=36) or toxicity of salvage treatment (n=10). The majority of the 57 survivors was in CR at the time of analysis; 2 were under treatment for HL and there was no information available for one patient. Median OSp for the entire cohort was 83 months, 5-year OSp was 55.4% (95%-CI, 46% to 65%). Since OSp differed among patients of different initial stages and types of pre-treatment (early-stage favorable and unfavorable patients treated with ABVD variants, OSp 74.2% [61%-87%] vs. higher-stage patients treated with BEACOPP variants, OSp 42.9% [31% - 55%]), treatment groups were analyzed for survival separately. In both groups, patients responding to the first salvage therapy had a significantly better OSp compared to those not responding (each p