BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children's Oncology Group

Dose-intensified treatment strategies for Hodgkin lymphoma (HL) have demonstrated improvements in cure but may increase risk for acute and long-term toxicities, particularly in children. The Children's Oncology Group assessed the feasibility of a dose-intensive regimen, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in children with high-risk HL (stage IIB or IIIB with bulk disease, stage IV). Rapidity of response was assessed after 4 cycles of BEACOPP. Rapid responders received consolidation therapy with guidelines to reduce the risk of sex-specific long-term toxicities of therapy. Females received 4 cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine) without involved field radiation therapy (IFRT). Males received 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with IFRT. Slow responders received 4 cycles of BEACOPP and IFRT. Ninety-nine patients were enrolled. Myelosuppression was frequent. Rapid response was achieved by 74% of patients. Five-year event-free-survival is 94%, IFRT with median follow-up of 6.3 years. There were no disease progressions on study therapy. Secondary leukemias occurred in 2 patients. Overall survival is 97%. Early intensification followed by less intense response-based therapy for rapidly responding patients is an effective strategy for achieving high event-free survival in children with high-risk HL. This trial is registered at http://www.clinicaltrials.gov as #NCT00004010.     

Improved outcome of patients with relapsed/refractory Hodgkin lymphoma with a new fotemustine‐based high‐dose chemotherapy regimen

High‐dose chemotherapy (HDT) with autologous stem cell transplantation is the standard of care for relapsed/refractory (RR) Hodgkin lymphoma (HL). Given that HDT may cure a sizeable proportion of patients refractory to first salvage, development of newer conditioning regimens remains a priority. We present the results of a novel HDT regimen in which carmustine was substituted by a third‐generation chloroethylnitrosourea, fotemustine, with improved pharmacokinetics and safety (FEAM; fotemustine, etoposide, cytarabine, melphalan) in 122 patients with RR‐HL accrued into a prospective registry‐based study. Application of FEAM resulted in a 2‐year progression‐free survival (PFS) of 73·8% [95% confidence interval (CI), 0·64–0·81] with median PFS, overall survival and time to progression yet to be reached. The 2‐year risk of progression adjusted for the competitive risk of death was 19·4% (95% CI, 0·12–0·27) for the entire patient population. Most previously established independent risk factors, except for fluorodeoxyglucose (^18FFDG)‐uptake, were unable to predict for disease progression and survival after FEAM. Although 32% of patients had ^18FFDG‐positrin emission tomography‐positive lesions before HDT, the 2‐year risk of progression adjusted for competitive risk of death was 19·4% (95% CI; 0·12–0·27). No unusual acute toxicities or early/late pulmonary adverse events were registered. FEAM emerges as an ideal HDT regimen for RR‐HL patients typically pre‐exposed to lung‐damaging treatments.     

Treatment of acquired immunodeficiency syndrome-related lymphoma with a standard chemotherapy regimen

 Sixty patients with poor-prognosis malignant lymphoma associated with acquired immunodeficiency syndrome (AIDS) were treated with a standard chemotherapy regimen: cyclophosphamide 600 mg/m² i.v., day 1; vincristine 1.4 mg/m² i.v., day 1; epirubicin 70 mg/m² i.v., day 1; and bleomycin 10 mg/m² i.v., on day 14. Granulocyte colony-stimulating factor, 5 μg/kg/day, was administered subcutaneously on days 4–14 to ameliorate severe myelosuppression. All patients were in an advanced stage of AIDS with <200 absolute CD4+ cells/mm³ and the presence of adverse prognostic factors related to lymphoma, such as high or high-intermediate clinical risk, multiple extranodal involvement, presence of bulky disease, and high levels of beta 2 microglobulin. Complete response (CR) was achieved by 33 patients (54%); no partial response was observed, and 27 cases were considered failures. All 27 died secondary to tumor progression without any response to salvage chemotherapy. Twenty patients in CR died of opportunistic infections related to AIDS. Actuarial 5-year survival shows that time to treatment failure for the 13 patients who remain in CR is 3.1 years. However, disease-free survival was 14.5 months. Overall survival for the entire group was 13.6 months. Side effects secondary to chemotherapy were frequent and severe, but no death related to treatment was observed.Infection-related granulocytopenia was observed in 27 cycles (8%). This study indicates that standard chemotherapy could be useful in patients with AIDS-associated lymphoma because CR rate, duration of remission, and survival were similar to those with other intensive, but more toxic, regimens. Until a new and better therapy for AIDS is found, treatment of patients with AIDS-related lymphoma will be regarded as palliative, and less toxic regimens will be considered. The use of a standard regimen appears to be an adequate therapeutic approach in this group of patients. Received: January 27, 1998 / Accepted: August 18, 1998     

Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma

We conducted a randomized trial to compare the intensive conventional chemotherapy regimen ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) with standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in previously untreated patients with poor-risk aggressive lymphoma. Patients aged 61 to 69 years who had aggressive non-Hodgkin lymphoma with at least one prognostic factor of the age-adjusted international prognostic index (IPI) were included. ACVBP consisted of an induction phase of intensified chemotherapy and central nervous system (CNS) prophylaxis followed by a sequential consolidation phase. Of the 708 patients registered for the study, 635 were eligible. The rate of complete response was 58% in the ACVBP group and 56% in the CHOP group (P =.5). Treatment-related death occurred in 13% of the ACVBP group and 7% of the CHOP group (P =.014). At 5 years, the event-free survival was 39% in the ACVBP group and 29% in the CHOP group (P =.005). The overall survival was significantly longer for patients treated with ACVBP, at 5 years it was 46% compared with 38% for patients treated with CHOP (P =.036). CNS progressions or relapses were more frequent in the CHOP group (P =.004). Despite higher toxicity, the ACVBP regimen, used as first-line treatment for patients with poor-risk aggressive lymphoma, is superior to standard CHOP with regard to both event-free survival and overall survival.     

Fertility in male patients with advanced Hodgkin lymphoma treated with BEACOPP: a report of the German Hodgkin Study Group (GHSG)

To date, there is little information on the impact of more aggressive treatment regimen such as BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) on the fertility of male patients with Hodgkin lymphoma (HL). We evaluated the impact of BEACOPP regimen on fertility status in 38 male patients with advanced-stage HL enrolled into trials of the German Hodgkin Study Group (GHSG). Before treatment, 6 (23%) patients had normozoospermia and 20 (77%) patients had dysspermia. After treatment, 34 (89%) patients had azoospermia, 4 (11%) had other dysspermia, and no patients had normozoospermia. There was no difference in azoospermia rate between patients treated with BEACOPP baseline and those given BEACOPP escalated (93% vs 87%, respectively; P > .999). After treatment, most of patients (93%) had abnormal values of follicle-stimulating hormone, whereas the number of patients with abnormal levels of testosterone and luteinizing hormone was less pronounced-57% and 21%, respectively. In univariate analysis, none of the evaluated risk factors (ie, age, clinical stage, elevated erythrocyte sedimentation rate, B symptoms, large mediastinal mass, extranodal disease, and 3 or more lymph nodes) was statistically significant. Male patients with HL are at high risk of infertility after treatment with BEACOPP.     

Survival analysis of patients with Hodgkin lymphoma who failed high dose chemotherapy and autologous stem cell transplant

Hodgkin lymphoma (HL) patients failing after high dose chemotherapy (HDC) and auto-SCT have a poor outcome. Some patients may still benefit from further treatments. From 1996 to 2016, 137 HL patients (39.5%) out of 347 transplanted experienced post auto-SCT failure. Males/female 61%:39%, median age at auto-SCT 23.4 years and median follow-up 55.6 months (9–153). Type of failure was progressive (46%), relapsed (35%) or persistent disease/refractory disease (19%). Median overall survival (OS) from the time of failure is 20 months; 35 patients (25.5%) are alive. One hundred and four patients received treatment; the response rate was 45%; complete remission in 41 (30%) and partial remission in 21 (15%) patients. 1st interventions post auto-SCT were chemotherapy (39%), radiation therapy (35%) or best supportive care (24%). Twenty-seven patients with 2nd-SCT (allogeneic (15), auto-SCT (2)) and/or brentuximab (18 patients) had superior OS (50.6 months) vs other treatments (22.5 months, P value 0.037). COX regression multivariate analysis identified post auto-SCT treatment failure before 12 months (hazard ratio (HR) 3.37, CI 1.7–6.6, P value <?0.001), presence of B symptoms (HR 2.55, CI 1.4–4.6, P value 0.002), stages III–IV (HR 2.7, CI 1.5–4.9, P value 0.001), albumin <?4 g/dl (HR 1.76, CI 1.1–2.9, P value 0.027) and tumor >?5 cm (HR 1.1.9, CI 1.13–3.25, P value 0.015) as significant risk factors; P value <?0.001. KM OS with 0–1 factor (148.6 months): 2 factors (23.6 months) and 3–5 factors (9.4 months) (P value <?0.001). OS was 63%:25%:7% respectively with 0–1:2:3–5 factors respectively (P value <?0.001). Despite high-risk factors, 2nd-SCT/brentuximab use post HDC auto-SCT failure may result in durable survival.     

Whole-slide image analysis of the tumor microenvironment identifies low B-cell content as a predictor of adverse outcome in patients with advanced-stage classical Hodgkin lymphoma treated with BEACOPP

Asubset of patients with advanced-stage classical Hodgkin lymphoma (cHL) relapse or progress following standard treatment. Given their dismal prognosis, identifying this group of patients upfront represents an important medical need. While prior research has identified characteristics of the tumor microenvironment, which are associated with cHL outcomes, biomarkers that are developed and validated in this high-risk group are still lacking. Here, we applied wholeslide image analysis (WSI), a quantitative, large-scale assessment of tumor composition that utilizes conventional histopathology slides. We conducted WSI on pre-treatment biopsies from 340 patients with advanced-stage cHL enrolled in the HD12 and HD15 trials of the German Hodgkin Study Group (GHSG), and tested our results in a validation cohort of 147 advanced-stage cHL patients within the GHSG HD18 trial. All patients were treated with BEACOPP-based regimens. By quantifying T cells, B cells, Hodgkin and Reed-Sternberg cells and macrophages with WSI, 80% of all cells in the tumor tissue were identified. Crucially, low B-cell count was associated with significantly reduced progression-free survival and overall survival, while the content of T cells, macrophages and Hodgkin and Reed-Sternberg cells was not associated with the risk of progression or relapse in the study cohort. We further validated low Bcell content as a prognostic factor for progression-free survival and overall survival in the validation cohort and demonstrated the good interobserver agreement of WSI. WSI may represent a key tool for risk stratification of advanced-stage cHL and can easily be added to the standard diagnostic histopathology work-up.     

努力提高恶性淋巴瘤规范化治疗的水平

恶性淋巴瘤 (ＭＬ)包括霍奇金淋巴瘤 (ＨＬ)和非霍奇金淋巴瘤 (ＮＨＬ)两大类。近年来ＮＨＬ的发病率明显升高 ,而ＨＬ则有所下降 ,ＭＬ已成为人们关注的重要疾病之一。一、ＭＬ病理分类的演进196 5年制定的ＨＬ的Ｒａｙ分类一直使用了 30多年。ＮＨＬ的分类则经历了几次较大的变化 ,2 0世纪 70年代以前的分类基础是形态学和组织病理学 ,以后出现了几种基于免疫分型的分类方法。 1994年提出了修改的欧美淋巴瘤分类 (ＲＥＡＬ分类 ) [1] ,在此基础上 ,ＷＨＯ于 2 0 0 0年提出了淋巴造血系统肿瘤的新的病理分类方法。这一分类包含了所有淋巴造…     

A variant of ProMACE-CytaBOM chemotherapy for non-Hodgkin's lymphoma with threefold higher drug dose size but identical cumulative dose intensity. A pilot study of the Italian lymphoma study group (GISL)

BACKGROUND AND OBJECTIVE: The positive results of high-dose chemotherapy followed by rescue with bone marrow progenitor cell transplantation are generally ascribed to the high dose size (DS) of the drugs given. However, a concomitant marked increase in dose intensity (DI) is always involved. With the aim of comparing the role of DS and DI in non-Hodgkin's lymphomas, a variant of Fisher's ProMACE-CytaBOM regimen was designed in which the projected cumulative drug DIs remained the same as in the original schedule but the DSs were tripled. DESIGN AND METHODS: Dosages in mg/m(2), route and days of administration were the following: cyclophosphamide 1,950 i.v. on days 1, 64; methotrexate 360 i.v. days 15, 78; vincristine 1.4 iv days 15, 78, 43, 106; etoposide 360 i.v. days 29, 92; epirubicin 120 i.v. days 29, 92; bleomycin 15 i.v. days 43, 106; cytarabine 900 i.v. days 50, 113. Thirty-six outpatients with intermediate- and high-grade non-Hodgkin's lymphomas entered the pilot study; 29 were untreated and 7 had relapse disease. Clinical stage was I in 1 patient, II in 7, III in 5 and IV in 23; 10 had B symptoms; the IPI score was 0-2 in 29 cases and > or =3 in the remaining 7. RESULTS: Of the 29 previously untreated patients, 16 achieved complete remission, 8 partial remission, 4 developed progressive disease and 1 was withdrawn early from the study because of acute viral hepatitis; subsequently 4 relapsed and 3 died (2 of disease progression, 1 of causes unrelated to the disease). In the pre-treated group 3 patients obtained complete remission, 2 partial remission and in 1 patient the disease progressed; 3 of these pre-treated patients died (1 of progressive disease, 1 of a new relapse, 1 of myocardial infarction during therapy). With a 20-month median follow-up, the 30-month overall and relapse-free survival were 0.58 and 0.70, respectively. G-CSF was administered to all but 2 patients, with median delivery throughout the whole regimen of 8, 400 microg per patient. Actual cumulative DI was 0.82+/-0.11. Grade 3-4 hematologic toxicity consisted of anemia in 3 cases, of leukopenia in 8 and of thrombocytopenia in 2; the same grade of non-hematologic toxicity involved the liver in 2 cases, the heart in 1 (the above mentioned death), the digestive mucosa in 2 and the peripheral nerves in 1 patient. INTERPRETATION AND CONCLUSIONS: The iso-DI sequential variant of the ProMACE-CytaBOM regimen can be considered feasibile, relatively non-toxic, and can be given on an out-patient basis. Limited use of G-CSF is required (about 3 vials after each drug administration). Thus, a randomized trial with the original ProMACE-CytaBOM regimen can be designed.     

Combination chemotherapy of advanced diffuse histiocytic lymphoma with the six-drug COP-BLAM regimen

A new multiple-drug protocol consisting of cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine, known as COP-BLAM, was administered to 48 patients with stage III or IV diffuse histiocytic lymphoma. Twenty-four of the 33 previously untreated patients had a complete remission, and eight patients had a partial response. The median survival for all previously untreated patients has not yet been reached at 23 months. Median survival for complte responders has not yet been attained at 26 months, although survival of partial responders is 12.5 months. There were no patients with a complete response who had a central nervous system relapse. The COP-BLAM therapy is an easily administered outpatient program capable of inducing a high frequency of durable complete remissions in advanced diffuse histiocytic lymphoma, a malignancy formerly considered to have a poor prognosis.     

Intermediate dose gemcitabine–cisplatin combination chemotherapy without treatment delay for cytopenia followed by autografting—a new standard of care in relapsed or refractory Hodgkin lymphoma?

Ten percent to 20% of patients with Hodgkin Lymphoma (HL) are refractory to first-line therapy or relapse. Existing salvage regimens have response rates of 60–85%, considerable toxicity and frequent treatment delay or dose reduction. We report a gemcitabine, cisplatin, and dexamethasone regimen (GemCis) with intensive growth factor and platelet support and no treatment delay. Seventeen patients with relapsed or refractory biopsy proven HL were treated. Toxicity, transfusion requirement, stem cell harvesting and engraftment data were collected. Response assessment was by computed tomography and positron emission tomography. Overall and complete response rates were high (94% and 65%, respectively). There were no episodes of febrile neutropenia, treatment delays or hospital admissions. All 15 patients intended for autograft were successfully harvested. All engrafted successfully with a median time for the entire group to neutrophil engraftment of 14 days. With a median follow-up of 22 months, the median survival has not yet been reached, and the estimated 2-year survival is 88%. GemCis is a well-tolerated outpatient regimen for relapsed/ refractory Hodgkin lymphoma which does not inhibit stem cell mobilisation, gives excellent response rates and compares favourably with previously published salvage regimens using these or other chemotherapy agents.     

Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma

The proteasome inhibitor, bortezomib, potentially increases cell sensitivity to chemotherapy. This study was performed to determine the overall response rate (ORR), overall survival (OS), progression‐free survival (PFS) and toxicity of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) compared to CHOP + bortezomib chemotherapy in mantle cell lymphoma (MCL) patients at first relapse. Forty‐six patients were randomly assigned to standard dose CHOP ± bortezomib 1·6 mg/m² given on a 21‐d cycle for up to eight cycles of treatment. Median age was 71 years (CHOP arm) and 69 years (CHOP‐bortezomib arm). Median Eastern Cooperative Oncology Group performance status was 1 (CHOP) and 0 (CHOP‐bortezomib) with 65% and 52%, respectively, having a disease stage of IV. ORR was 47·8% (CHOP) and 82·6% (CHOP‐bortezomib). Complete response rate was 21·7% (CHOP) vs. 34·8% (CHOP‐bortezomib); partial response rate was 26·1% (CHOP) vs. 47·8% (CHOP‐bortezomib). Median OS was 11·8 months (CHOP) and 35·6 months (CHOP‐bortezomib) (P = 0·01, Hazard ratio [HR] 0·37 [95% confidence interval (CI) 0·16–0·83)] and there was a non‐significant improvement in PFS: 8·1 months (CHOP) and 16·5 months (CHOP‐bortezomib) [P = 0·12, HR 0·60 (95% CI 0·31–1·15)]. Severe (≥grade 3) sensory neuropathy was similar in both arms (4·3% CHOP vs. 6·5% CHOP‐bortezomib). We conclude that the addition of bortezomib to CHOP chemotherapy for relapsed MCL significantly improves outcome with a manageable increase in toxicity.     

Effect of cumulative etoposide doses on the outcome of autologous peripheral-blood progenitor-cell transplantation for lymphoma

Studies evaluating the effects of previous chemotherapy on stem-cell yield and hematological recovery after autologous peripheral-blood progenitor-cell transplantation (PBPCT) have shown conflicting results. We have retrospectively analyzed 103 consecutive lymphoma patients treated with the BEAM regimen and autologous PBPCT. The impact of the different chemotherapeutic drugs (cumulative doses) on stem-cell yield and transplant-related toxicity was investigated. Highly significant differences in platelet recovery (>20 x 10(9)/l) were observed between patients receiving less or more than 750 mg/m(2) of etoposide before transplant (15 vs 29 days, P=0.001), and between patients receiving less or more than 1.2 x 10(6)/kg CD34(+) cells (27 vs 14 days, P<0.001). Differences in neutrophil engraftment between groups were not clinically significant. Pre-transplant cumulative doses of etoposide >750 mg/m(2) were associated with low CD34(+) cell collections on multivariate analysis. The actuarial incidence of transplant-related mortality (TRM) was 14% at 5 years. Pre-transplant cumulative doses of etoposide >350 mg/m(2) and previous administration of procarbazine were found to be independent prognostic factors for TRM.     

High-dose chemotherapy and autologous stem cell transplantation for primary refractory or relapsed Hodgkin lymphoma: long-term outcome in the first 100 patients treated in Vancouver

Beginning in 1985, patients in British Columbia with Hodgkin lymphoma (HL) that was not controlled by conventional chemotherapy routinely underwent high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). Long-term complications of HD-ASCT have become apparent as more patients survive without recurrence of HL. Data were obtained retrospectively on the first 100 patients that underwent HD-ASCT for HL in Vancouver, focusing on relapse, treatment-related complications, and the occurrence of late events. Fifty-three patients remain alive (median follow-up, 11.4 years [range, 10.0-17.4 years]) with an overall survival (OAS) of 54% at 15 years. OAS was significantly better in patients in first relapse (67%) than in patients with primary refractory-induction failure (39%) and advanced disease (29%) (P = .002). The major cause of death was progression of HL (32% at 15 years). Treatment-related mortality, including death from second malignancy, was 17% at 15 years. Cumulative risk of a second malignancy was 9% at 15 years. Karnofsky performance status was at least 90% in 47 patients although hypogonadism (20 patients), hypothyroidism (12 patients), unusual infections (10 patients), anxiety or depression (7 patients), and cardiac disease (5 patients) were not uncommon in survivors. HD-ASCT can lead to durable remissions in relapsed or refractory HL with acceptable but definite late toxicity. The occurrence of late events necessitates lifelong medical surveillance.     

A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children

Important predictors of adverse outcomes of thrombosis in children, including postthrombotic syndrome (PTS), have recently been identified. Given this knowledge and the encouraging preliminary pediatric experience with systemic thrombolysis, we sought to retrospectively analyze our institutional experience with a thrombolytic regimen versus standard anticoagulation for acute, occlusive deep venous thrombosis (DVT) of the proximal lower extremities in children in whom plasma factor VIII activity and/or D-dimer concentration were elevated at diagnosis, from within a longitudinal pediatric cohort. Nine children who underwent the thrombolytic regimen and 13 who received standard anticoagulation alone were followed from time of diagnosis with serial clinical evaluation and standardized PTS outcome assessments conducted in uniform fashion. The thrombolytic regimen was associated with a markedly decreased odds of PTS at 18 to 24 months compared with standard anticoagulation alone, which persisted after adjustment for significant covariates of age and lag time to therapy (odds ratio [OR] = 0.018, 95% confidence interval [CI] = < 0.001-0.483; P = .02). Major bleeding developed in 1 child, clinically judged as not directly related to thrombolysis for DVT. These findings suggest that the use of a thrombolysis regimen may safely and substantially reduce the risk of PTS in children with occlusive lower-extremity acute DVT, providing the basis for a future clinical trial.     

Tumor microenvironment and mitotic checkpoint are key factors in the outcome of classic Hodgkin lymphoma

Around 20% to 30% of patients with Hodgkin lymphoma (HL) do not benefit from standard therapies and finally succumb to their disease. The factors that influence the outcome of HL have not been elucidated, underscoring the demand for the identification of biologic risk factors and new therapeutic targets. We analyzed the gene expression profiles of samples from 29 patients with advanced classic HL treated with standard therapy and compared the expression profiles of patients with favorable and unfavorable clinical outcome. Using supervised methods, we identified 145 genes associated with outcome, which were grouped into 4 signatures representing genes expressed by either the tumoral cells (genes involved in the regulation of mitosis and cell growth/apoptosis) or the tumor microenvironment. The relationship between the expression of 8 representative genes and survival was successfully validated in an independent series of 235 patients by quantification of protein expression levels on tissue microarrays. Analysis of centrosomes and mitotic checkpoint confirmed the existence of an abnormal transition through mitosis in HL cells. Therefore, genes related to tumor microenvironment, cell growth/apoptosis, and regulation of mitosis are associated with treatment response and outcome of patients with HL.     

An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome

Objective

The classical Hodgkin lymphoma (cHL) tumor microenvironment shows an ongoing inflammatory response consisting of varying degrees of infiltrating eosinophils, mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.

Methods

Tumor‐infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.

Results

The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9‐year follow‐up) in age‐adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05‐3‐15). Epstein‐Barr virus (EBV)‐positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.

Conclusions

Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.