We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS ( < .0001) and OS ( = .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (>147 cm) group (n = 46), respectively, vs 92% and 98% in the low-TMTV group (≤147 cm). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe d'Etude des Lymphomes de l'Adulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV≤147+DS1-3; 5-year PFS, 95%), low-intermediate (TMTV>147+DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV≤147+DS4-5; 5-year PFS, 50%), and high (TMTV>147+DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well.

Anti-PD-1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti-PD-1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti-PD-1 therapy, assessed by PET-CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pre-treated before anti-PD-1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti-PD1 therapy were progressive disease (PD) (n=24) and partial response (PR) (n=6). For the 24 PD patients, median anti-PD-1 related PFS was 7.5 months (95%CI, 5.7-11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti-PD-1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow-up of 12.1 months (7-14.7), the median PFS following the initiation of CT was 11 months (95%CI, 6.3; not reached) and the median of overall survival was not reached. These observations in highly pre-treated HL patients suggest that anti-PD-1 therapy might re-sensitize tumor cells to CT. This article is protected by copyright. All rights reserved.

Control of intensity and duration of erythropoietin (Epo) signaling is necessary to tightly regulate red blood cell production. We have recently shown that the ubiquitin/ proteasome system plays a major role in the control of Epo-R signaling. Indeed, after Epo stimulation, Epo-R is ubiquitinated and its intracellular part is degraded by the proteasome, preventing further signal transduction. The remaining part of the receptor and associated Epo are internalized and degraded by the lysosomes. We show that ␤-Trcp is responsible for Epo-R ubiquitination and degradation. After Epo stimulation, ␤-Trcp binds to the Epo-R. This binding, like Epo-R ubiquitination, requires Jak2 activation. The Epo-R contains a typical DSG binding sequence for ␤-Trcp that is highly conserved among species. Interestingly, this sequence is located in a region of the Epo-R that is deleted in patients with familial polycythemia. Mutation of the serine residue of this motif to alanine IntroductionThe glycoprotein hormone erythropoietin (Epo) regulates the proliferation, survival, and differentiation of erythroid progenitor cells leading to the tight control of red blood cell production (reviewed in Lacombe and Mayeux 1 ). The Epo receptor (Epo-R) is a homodimer that belongs to the cytokine receptor superfamilly. Each Epo-R molecule of the dimer is constitutively associated with a Jak2 tyrosine kinase molecule that is absolutely required for Epo signaling. [2][3][4] Association of Jak2 with the Epo-R is also necessary for Epo-R maturation and cell surface expression. 5 Epo binding to its receptor induces a conformational change in the receptor complex that leads to Jak2 activation, subsequent phosphorylation of intracellular Epo-R Tyr residues, and activation of several intracellular signaling pathways, including Stat5, Ras/MAP kinase and PI3 kinase/Akt (reviewed by Damen et al 6 ). At the same time, desensitization processes are activated. The tyrosine phosphatase SHP-1 (SH2 domain-containing protein-tyrosine phosphatase-1) is recruited through phosphorylated Tyr 430 in human Epo-R and it dephosphorylates and deactivates Jak2. 7 CIS/SOCS family members are produced upon Epo stimulation and Cis, Socs-1, and Socs-3 suppress Epo signaling through their binding to the Epo-R complex. [8][9][10] Lastly, Epo and Epo-R are internalized and degraded. [11][12][13] Epo-induced Epo-R down-regulation is a complex process that involves Epo-R ubiquitination, proteasomes, and lysosomes. Epo-R is rapidly ubiquitinated at the cell surface after Epo binding. This process occurs before receptor internalization and requires Jak2 kinase activity. Most of the Epo-R intracellular domain is then degraded by proteasomes. This degradation process removes all the phosphorylated tyrosine residues in the intracellular domain, thereby preventing further signal transduction. The remaining part of the Epo/Epo-R complex is internalized and degraded by the lysosomes. 13 Thus, it appears that Epo-R ubiquitination plays a key role in Epo-R down-regulation during Epo stimulation...