It’s all about the CD3+ T-cells: how circulating immune cell subset analyses can predict early relapse in Hodgkin lymphoma

Advances in combination chemotherapy with or without radiation therapy have yielded excellent survival rates amongst patients with classical Hodgkin lymphoma (cHL), with a combined 5-year overall survival for all cHL patients of over 80% [1]. There are highly effective combination chemotherapy regimens available for patients with cHL, resulting in high numbers of complete remission and long-term survival [2–5]. Despite the favorable therapeutic landscape, a significant number of patients with cHL will be resistant to frontline therapy or relapse [6]. Many of these patients will require high dose chemotherapy followed by an autologous hematopoietic stem cell transplantation (auto-HSCT). Although auto-HSCT cures approximately 50% of relapsed cHL patients [7,8] the remaining patients will experience relapse, accordingly, better prognostic and therapeutic tools are still needed to improve outcomes in this cohort. Malignant Hodgkin and Reed Sternberg (HRS) cells only represent 1% of the total tumor mass, with the remaining 99% comprising different immune cells [9]. In a previous study, Chan et al. demonstrated significant biological divergence of gene expression patterns at the time of the initial diagnosis of cHL and at first relapse, developed a novel gene signature as a prognostic tool, attempting to identify the subset of autoHSCT patients at higher risk of relapse [9]. The tumor microenvironment (TME) and its biology is essential, and further investigation into the TME of patients with HL, to improve identification of patients at greater risk of relapse after transplant, and to develop more novel therapeutic agents for their treatment is imperative. In this issue of Leukemia & Lymphoma, Batorov et al. [10] report the results of analysis of circulating immune cells in 79 patients with cHL following an auto-HSCT. Their findings illustrate a dynamic relationship between circulating immune cells and the evolving TME in the post-ASCT setting. The authors systematically recorded relative and absolute counts of several peripheral blood lymphocyte subpopulations in patients with cHL at different time intervals; prior to receiving high dose chemotherapy, on the day of engraftment following auto-HSCT, and at 6 and 12 months after transplantation. The above documentation was performed in 51 responding patients (in CR/PR) and in another 15 who had relapsed after auto-HSCT. Most patients who relapsed did so early on after a median time of 5.5 months (interquartile range: 3.8–6.8 months) [10]. With a median follow-up of 19.2 months post auto-HSCT, they observed significantly elevated absolute CD3þ and CD8þ T cell counts at engraftment in patients with early relapse or progression (p1⁄4 .0028 and p1⁄4 .0072, respectively). Importantly, no other patient or disease characteristics were different in relapsing patients and those who remained disease – free; and these factors included age, disease stage or number of CD 34þ HSCs infused. The alterations in the absolute CD3þ T cell counts were similar to those recorded by other authors [10], but their association with early relapse and clinical progression is a novel finding, and contrary to previous reports as discussed by Batorov et al. [10]. Notably, the authors logistic regression models revealed that the elevated CD3þ T-cell counts trended toward early relapse/progression (OR: 1.76, 95% CI: 1.05–3.25; p1⁄4 .069) [10]. The authors suggest that the significance of this analysis is probably limited because of the decrease in patient numbers from the time of enrollment compared to 12 months after an ASCT,