The online version of this article has a Supplementary Appendix. BackgroundPlasma thymus and activation-regulated chemokine is a potential biomarker for classical Hodgkin's lymphoma. To define its value as a marker to monitor treatment response, we correlated serial plasma thymus and activation-regulated chemokine levels with clinical response in newly diagnosed and relapsed classical Hodgkin's lymphoma patients. Design and MethodsPlasma was collected from 60 (39 early stage and 21 advanced stage) newly diagnosed classical Hodgkin's lymphoma patients before, during, and after treatment, and from 12 relapsed patients before and after treatment. Plasma thymus and activation-regulated chemokine levels were determined by enzyme-linked immunosorbent assay and were related to pre-treatment metabolic tumor volume, as measured by quantification of 2-[18F]fluoro-2-deoxyglucose positron emission tomography images, and to treatment response. ResultsBaseline plasma thymus and activation-regulated chemokine levels correlated with stage of disease and bulky disease, and more closely with metabolic tumor volume. Response to treatment was observed among 38 of 39 early stage and 19 of 21 advanced stage patients. Reduction in plasma thymus and activation-regulated chemokine to normal range levels could be observed as early as after one cycle of chemotherapy in all responsive patients, while plasma levels remained elevated during and after treatment in the 3 non-responsive patients. Plasma thymus and activation-regulated chemokine was elevated in all 12 relapsed patients at time of relapse and remained elevated after salvage treatment in the 4 non-responsive patients. ConclusionsBaseline plasma thymus and activation-regulated chemokine levels correlate with classical Hodgkin's lymphoma tumor burden and serial levels correlate with response to treatment in patients with classical Hodgkin's lymphoma.Key words: Hodgkin's lymphoma, plasma thymus, chemokine, tumor burden, serial plasma. 's lymphoma. Haematologica 2012;97(3):410-415. doi:10.3324/haematol.2011 Citation: Plattel WJ, van den Berg A, Visser L, van der Graaf A-M, Pruim J, Vos H, Hepkema B, Diepstra A, and van Imhoff GW. Plasma thymus and activation-regulated chemokine as an early response marker in classical Hodgkin

Background Few studies have examined the impact of treatment-related morbidity on long-term, cause-specific mortality in Hodgkin lymphoma (HL) patients. Methods This multicenter cohort included 4919 HL patients, treated before age 51 years between 1965 and 2000, with a median follow-up of 20.2 years. Standardized mortality ratios, absolute excess mortality (AEM) per 10 000 person-years, and cause-specific cumulative mortality by stage and primary treatment, accounting for competing risks, were calculated. Results HL patients experienced a 5.1-fold (AEM = 123 excess deaths per 10 000 person-years) higher risk of death due to causes other than HL. This risk remained increased in 40-year survivors (standardized mortality ratio = 5.2, 95% confidence interval [CI] = 4.2 to 6.5, AEM = 619). At age 54 years, HL survivors experienced similar cumulative mortality (20.0%) from causes other than HL to 71-year-old individuals from the general population. Whereas HL mortality statistically significantly decreased over the calendar period (P < .001), solid tumor mortality did not change in the most recent treatment era. Patients treated in 1989-2000 had lower 25-year cardiovascular disease mortality than patients treated in 1965-1976 (4.3% vs 5.7%; subdistribution hazard ratio = 0.65, 95% CI = 0.46 to 0.93). Infectious disease mortality was not only increased after splenectomy but also after spleen irradiation (hazard ratio = 2.81, 95% CI = 1.55 to 5.07). For stage I-II, primary treatment with chemotherapy (CT) alone was associated with statistically significantly higher HL mortality (P < .001 for CT vs radiotherapy [RT]; P = .04 for CT vs RT+CT) but lower 30-year mortality from causes other than HL (15.8%, 95% CI = 9.7% to 23.3%) compared with RT alone (36.9%, 95% CI = 34.0% to 39.8%, P = .001) and RT and CT combined (29.8%, 95% CI = 26.8% to 32.9%, P = .02). Conclusions Compared with the general population, HL survivors have a substantially reduced life expectancy. Optimal selection of patients for primary CT is crucial, weighing risks of HL relapse and long-term toxicity.

Achieving a metabolic complete response (mCR) before high-dose chemotherapy (HDC) and autologous peripheral blood stem-cell transplant (auto-PBSCT) predicts progression free survival (PFS) in relapsed/refractory classical Hodgkin lymphoma (R/R cHL). We added brentuximab vedotin (BV) to DHAP to improve the mCR rate. In a Phase I dose-escalation part in 12 patients, we showed that BV-DHAP is feasible. This Phase II study included 55 R/R cHL patients (23 primary refractory). Treatment consisted of three 21-day cycles of BV 1.8 mg/kg on day 1, and DHAP (dexamethasone 40mg days 1-4, cisplatin 100mg/m2; day 1 and cytarabine 2x2g/m2; day 2). Patients with a metabolic partial response (mPR) or mCR proceeded to HDC/auto-PBSCT. Based on independent central FDG-PET-CT review, 42 of 52 evaluable patients (81% [95% CI: 67-90]) achieved an mCR before HDC/auto-PBSCT, five had an mPR and five had progressive disease (three were not evaluable). After HDC/auto-PBSCT, four patients with an mPR converted to an mCR. The 2-year PFS was 74% [95% CI: 63-86], and the overall survival 95% [95% CI: 90-100]. Toxicity was manageable and mainly consisted of grade 3/4 hematological toxicity, fever, nephrotoxicity, ototoxicity (grade 1/2) and transiently elevated liver enzymes during BV-DHAP. Eighteen patients developed new onset peripheral neuropathy (maximum grade 1/2) and all recovered. In conclusion, BV-DHAP is a very effective salvage regimen in R/R cHL patients, but patients should be monitored closely for toxicity. ClinicalTrials.gov identifier: NCT02280993.

Soluble Galectin-1 (sGal-1, also termed LGALS1), soluble CD163 (sCD163) and soluble CD30 (sCD30) have been reported to be elevated in plasma or serum of patients with classical Hodgkin lymphoma (cHL). We aimed to determine the clinical utility of these biomarkers for evaluation of treatment response compared to thymus and activation regulated chemokine (TARC, also termed CCL17). Plasma or serum samples were prospectively collected among 103 newly diagnosed cHL patients before and after treatment. Levels of sGal-1, sCD163, sCD30 and TARC were correlated with disease characteristics and clinical treatment response. Elevated plasma levels of sGal-1, sCD163, sCD30 and TARC were found in 67%, 21%, 91% and 93% of cHL patients respectively. Mean plasma levels of sGal-1 and sCD30 decreased after treatment but sCD163 did not decrease after treatment. There was no correlation with change of these markers and clinical treatment response in individual patients. TARC levels strongly correlated with disease characteristics and metabolic volume. TARC remained high in 6 out of 7 non-responsive patients and dramatically decreased in 95 out of 96 responsive patients. In summary, elevated pre-treatment levels of sGal-1, sCD163, sCD30 and TARC can be found in patients with cHL. However, only plasma TARC accurately reflects disease activity and correlates with clinical treatment response.

The interaction between the tumor cells in classical Hodgkin lymphoma (cHL) and the microenvironment includes aberrant activity of receptor tyrosine kinases. In this study we evaluated the expression, functionality and prognostic significance of Insulin-like growth factor-1 receptor (IGF-1R) in cHL. IGF-1R was overexpressed in 55% (44/80) of cHL patients. Phosphorylated IGF-1R was detectable in a minority of the IGF-1R positive tumor cells. The overall survival (OS, 98%) and 5-year progression-free survival (PFS, 93%) was significantly higher in IGF-1R positive cHL patients compared to IGF-1R negative patients (OS 83%, p = .029 and PFS 77%, p = .047, respectively). Three cHL cell lines showed expression of IGF-1R, with strong staining especially in the mitotic cells and expression of IGF-1. IGF-1 treatment had a prominent effect on the cell growth of L428 and L1236 cells and resulted in an increased phosphorylation of IGF1R, Akt and ERK. Inhibition of IGF-1R with cyclolignan picropodophyllin (PPP) decreased cell growth and induced a G2/M cell cycle arrest in all three cell lines. Moreover, a decrease in pCcd2 and an increase in CyclinB1 levels were observed which is consistent with the G2/M cell cycle arrest. In conclusion, IGF-1R expression in HRS cells predicts a favorable outcome, despite the oncogenic effect of IGF-1R in cHL cell lines.

Summary Serum thymus and activation regulated chemokine (TARC) levels reflect classical Hodgkin lymphoma (cHL) disease activity and correspond with treatment response. We compared mid‐treatment interim TARC (iTARC) with interim 18 F‐fluorodeoxyglucose positron‐emission tomography (iPET) imaging to predict modified progression‐free survival (mPFS) in a group of 95 patients with cHL. High iTARC levels were found in nine and positive iPET in 17 patients. The positive predictive value (PPV) of iTARC for a 5‐year mPFS event was 88% compared to 47% for iPET. The negative predictive value was comparable at 86% for iTARC and 85% for iPET. Serum iTARC levels more accurately reflect treatment response with a higher PPV compared to iPET.

The online version of this article has a Supplementary Appendix. BackgroundThe c-Met signaling pathway regulates a variety of biological processes, including proliferation, survival and migration. Deregulated c-Met activation has been implicated in the pathogenesis and prognosis of many human malignancies. We studied the function and prognostic significance of c-Met and hepatocyte growth factor protein expression in patients with classical Hodgkin's lymphoma. Design and MethodsExpression of c-Met and its ligand, hepatocyte growth factor, were determined by immunohistochemistry. Prognostic values were defined in cohorts of German and Dutch patients with classical Hodgkin's lymphoma. Functional studies were performed on Hodgkin's lymphoma cell lines. ResultsExpression of c-Met was detected in the tumor cells of 52% (80/153) of the patients and expression of its ligand, hepatocyte growth factor, in 8% (10/121) of the patients. c-Met expression correlated with a 5-year freedom from tumor progression of 94%, whereas lack of expression correlated with a 5-year freedom from tumor progression of 73% (P<0.001) in the combined cohort. In multivariate analysis both c-Met (hazard ratio 5.0, 95% confidence interval 1.9-13.3, P<0.001) and stage (hazard ratio 2.8, 95% confidence interval 1.2-6.4, P=0.014) were independent predictors for freedom from tumor progression. In functional studies activation with hepatocyte growth factor did not affect cell growth, while the c-Met inhibitor SU11274 suppressed cell growth by inducing G2/M cell cycle arrest. ConclusionsAlthough functional studies showed an oncogenic role of the hepatocyte growth factor/c-Met signaling pathway in cell cycle progression, expression of c-Met in tumor cells from patients with classical Hodgkin's lymphoma strongly correlated with a favorable prognosis in two independent cohorts.

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 (<1 year). All patients received the 1st cycle of BV-DHAP, 90% completed all 3 cycles and 87% underwent ASCT. G-CSF mobilized stem cells were harvested successfully after the 2nd cycle with 1 apheresis in all patients (median yield: 6x106 CD34+/kg; range: 2-23). Based on intention to treat analysis 48 patients achieved a metabolic CR after 3x BV-DHAP (mCR rate 79% (n=48/61)), 5 patients had a metabolic PR (8%) and 4 had PD (6.5%). Four patients went off study before the first evaluation (1 PD after cycle 1, 1 liver function abnormalities after cycle 2, 2 withdrew because of emotional problems). After ASCT 4 out of 5 patients with mPR converted to an mCR. At a median follow-up of 20.9 months the 2-year PFS is 76% (95% CI 65-89), and the OS projected at 2 years is 92% (95% CI 84-100). Hematologic toxicity after BV-DHAP consisted of neutropenia grade 3/4 in up to 63% of patients and thrombocytopenia grade 3/4 in up to 81% of patients. Only 3 patients had a bleeding event (epistaxis (n=2) and menorrhagia (n=1), all recovered without sequelae after platelet transfusion). Febrile neutropenia or infections after BV-DHAP occurred in 18 patients (15 grade 3 and 3 grade 4). A total of 21 SAE's other than fever/infections were reported, with kidney dysfunction (n=4; most likely related to cisplatin), malaise (n=3), nausea/vomiting (n=3) and liver function abnormalities (n=3) occurring in 3 or more patients. 11 patients had peripheral neuropathy (PN) already at baseline (10 grade 1, 1 grade 2); worsening of PN was not observed in those patients. New onset PN was seen in 19 patients (15 grade 1, 4 grade 2); no grade 3/4 PN was observed. Three deaths occurred during the study period, 1 encephalitis (exact cause unknown), 1 veno-occlusive disease, both after BEAM/ASCT and 1 trauma capitis (unrelated). One patient who refused further treatment after cycle 1 and went off study died of progressive disease. Conclusions Salvage immunochemotherapy with 3 cycles of BV-DHAP induces a high mCR rate of 79% in patients with R/R HL, which is an optimal starting point for consolidation with BEAM and ASCT and may contribute to a higher cure rate. The toxicity of combining BV and DHAP is acceptable and mainly consists of manageable hematologic toxicity and fever/infections. Figure. Figure. Disclosures Hagenbeek: Millennium/Takeda: Consultancy, Honoraria, Research Funding. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lugtenburg:Millennium/Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Roche: Consultancy; BMS: Consultancy; Sandoz: Consultancy; Genmab: Consultancy. Gastinne:Millennium/Takeda: Honoraria. Tonino:Takeda: Consultancy, Honoraria. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; Kite Pharma: Honoraria; Novartis: Honoraria.