Introduction: Relapsed and refractory classic Hodgkin lymphoma (cHL) is typically treated with salvage chemotherapy, followed by high-dose chemotherapy (HD-CT) and autologous stem cell transplantation (ASCT). This standard approach, however, achieves long-term remission in only about 60% of patients. Moreover, severe short- and long-term side effects remain major concerns. Recent studies suggest high response rates of up to 95% and unprecedented progression-free survival (PFS) with anti-programmed cell death protein 1 (PD-1)-based salvage regimens such as pembrolizumab, gemcitabine, vinorelbine, and liposomal doxorubicin (P-GVD). Therefore, we hypothesize that anti-PD1-based chemotherapy combinations might allow patients who achieve a negative PET during therapy to be spared from the highly toxic HD-CT. Methods: Pembro-CORE (NCT04838652) is a multicenter phase II trial investigating a HD-CT free approach for first-relapsed cHL by combining the anti-PD1-antibody pembrolizumab with salvage chemotherapy. Initiated in March 2024 at four German centers, the trial has enrolled 23 patients to date. Patients receive an initial cycle of pembrolizumab followed by two cycles of P-ICE (pembrolizumab, ifosfamide, carboplatin, etoposide). After PET restaging, complete responders continue with two more cycles of P-ICE, while patients failing to achieve a complete response switch to two cycles of P-DHAP (pembrolizumab, dexamethasone, high-dose cytarabine, cisplatin). A second PET restaging after five cycles determines further treatment; PET-positive cases are treated outside the study per standard of care (SOC). Complete responders in the P-DHAP arm may receive two additional cycles of P-DHAP consolidation and undergo a third restaging. Persistent PET positivity at the third restaging leads to SOC treatment. Treatment concludes with eight consolidation cycles of pembrolizumab until final staging. The primary endpoint is the complete metabolic response rate (CMR), defined as the proportion of patients achieving a Deauville score of 1–3 after treatment with one infusion of pembrolizumab followed by either four cycles of P-ICE or two cycles of P-ICE followed by two cycles of P-DHAP. This measures the proportion of patients who can avoid HD-CT. Results: A total of 23 of the planned 29 patients were enrolled at the time of the interim analysis (data cutoff 14th July 2025) (60.9 % male, 39.1 % female; mean age 37.2 ± 10.8 years). At baseline, 73.9 % had ECOG 0 and 26.1 % ECOG 1. At relapse, Ann Arbor stages I–IV were distributed as 8.7 %, 43.5 %, 26.1 % and 21.7 %, respectively; GHSG risk-group at first diagnosis was advanced in 47.8 %, early-unfavorable in 47.8 % and early-favorable in 4.3 %. B-symptoms at relapse occurred in 26.1 %. First-line regimens comprised 2×eBEACOPP + 2×ABVD (47.8 %), eBEACOPP-like (47.8 %) or ABVD-like (4.3 %) protocols, with a median of four cycles (range 2–8) administered. At the first restaging (with n=20 patients evaluable), 50% had a CMR and 50% had a partial response and underwent further treatment with two cycles of P-ICE or P-DHAP, respectively. At the time of data cutoff, 15 patients had already reached the primary endpoint - either four cycles of P-ICE or two cycles of P-ICE followed by two cycles of P-DHAP. At this time point, 93.3 % of patients achieved a complete response. A total of nine serious adverse events were reported. Of these, only one was confirmed as immune-related (immune-mediated colitis). Other events included acute kidney injury (n=2), febrile neutropenia (n=2), respiratory tract infections (n=2), and viral dermatitis (n=1). In addition to the patient with colitis, another patient had to withdraw from the trial due to possibly immune-related elevation of liver enzymes. Four patients had progressive disease in the interim or end-of-treatment staging. Conclusion: The interim analysis of the Pembro-CORE trial demonstrates promising early results for a PET-adapted, HD-CT-free treatment strategy in first-relapsed cHL. A high CMR of 93.3% was observed among evaluable patients reaching the primary endpoint restaging. However, thus far four patients showed relapse in imaging-based assessment. Updated data will be presented at the conference.

In patients with relapse of classical Hodgkin lymphoma (cHL) after autologous stem cell transplant, brentuximab vedotin and anti-PD1 treatment, the outcome is poor. To assess the efficacy of the bispecific anti-CD30/CD16A, NK-cell engaging antibody AFM13 and to select the optimal treatment schedule (arm A-C), we initiated a randomized two-stage phase II trial (NCT02321592). Due to slow recruitment, the trial was terminated after treatment of 25 patients. Treatment with AFM13 was well tolerated: only two treatment-associated serious adverse events (SAEs) were reported; all SAEs resolved completely. With an objective response rate (ORR) of 16.7% (1/5 in arm A, 1/11 in arm B, and 2/8 in arm C) and a 12-month progression-free survival (PFS) of 12.6% (95% CI 3.2-28.9), treatment efficacy of AFM13 monotherapy in all evaluable patients was modest. The continuous application schedule (arm C) might be more effective, but the visit schedule should be better aligned with patients' daily life.

SummaryReinduction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second‐line standard of care for transplant‐eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high‐dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant‐eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase‐I‐part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end‐point of computed tomography (CT)‐based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT‐based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end‐point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.

High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.

While classical Hodgkin lymphoma (HL) is highly susceptible to anti-programmed death protein 1 (PD1) antibodies, the exact modes of action remain controversial. To elucidate the circulating lymphocyte phenotype and systemic effects during anti-PD1 1st-line HL treatment we applied multicolor flow cytometry, FluoroSpot and NanoString to sequential samples of 81 HL patients from the NIVAHL trial (NCT03004833) compared to healthy controls. HL patients showed a decreased CD4 T-cell fraction, a higher percentage of effector-memory T cells and higher expression of activation markers at baseline. Strikingly, and in contrast to solid cancers, expression for 10 out of 16 analyzed co-inhibitory molecules on T cells (e.g., PD1, LAG3, Tim3) was higher in HL. Overall, we observed a sustained decrease of the exhausted T-cell phenotype during anti-PD1 treatment. FluoroSpot of 42.3% of patients revealed T-cell responses against ≥1 of five analyzed tumor-associated antigens. Importantly, these responses were more frequently observed in samples from patients with early excellent response to anti-PD1 therapy. In summary, an initially exhausted lymphocyte phenotype rapidly reverted during anti-PD1 1st-line treatment. The frequently observed IFN-y responses against shared tumor-associated antigens indicate T-cell-mediated cytotoxicity and could represent an important resource for immune monitoring and cellular therapy of HL.

Hodgkin lymphoma (HL) is a rare malignancy accounting for roughly 15% of all lymphomas and mostly affecting young patients. A second peak is seen in patients above 60 years of age. The history of HL treatment represents a remarkable success story in which HL has turned from an incurable disease to a neoplasm with an excellent prognosis. First-line treatment with stage-adapted treatment consisting of chemotherapy and/or radiotherapy results in cure rates of approximately 80%. Second-line treatment mostly consists of intensive salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Novel approaches such as antibody drug conjugates and immunomodulatory drugs have shown impressive results in clinical trials in refractory and relapsed HL and are now increasingly implemented in earlier treatment lines. This review gives a comprehensive overview on HL addressing epidemiology, pathophysiology and current treatment options as well as recent developments and perspectives.

The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.

Individualizing treatment is key to improve outcome and reduce long-term side-effects in any cancer. In Hodgkin lymphoma (HL), individualization of treatment is hindered by a lack of genomic characterization and technology for sensitive, molecular response assessment. Sequencing of cell-free (cf)DNA is a powerful strategy to understand an individual cancer genome and can be used to develop assays for extremely sensitive disease monitoring. In HL, a high proportion of cfDNA is tumor-derived making it a highly relevant disease model to study the role of cfDNA sequencing in cancer. Here, we introduce our targeted cfDNA sequencing platform and present the largest genomic landscape of HL to date, which was entirely derived by cfDNA sequencing. We comprehensively genotype and assess minimal residual disease in 324 samples from 121 patients, presenting an integrated landscape of mutations and copy number variations in HL. In addition, we perform a deep analysis of mutational processes driving HL, investigate the clonal structure of HL and link several genotypes to HL phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cfDNA sequencing as early as a week after treatment initiation is feasible and predicts overall treatment response allowing highly improved treatment guidance and relapse prediction. Our study also serves as a blueprint showcasing the utility of our platform for other cancers with similar therapeutic challenges.

Purpose: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (Delta MTV and Delta TLG), measured on PET, might provide additional relevant information for response assessment in this setting. Hence, the current analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. Patients and Methods: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arms A and B were assessed for early treatment response after two courses of doxorubicin, vinblastine, and dacarbazine with two concomitant nivolumab infusions per cycle (2 X N-AVD) and 4 X nivolumab, respectively. In the current analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. Results: At interim restaging, we determined a mean DMTV and DTLG of -99.8% each in arm A after 2 X N-AVD, compared with -91.4% and -91.9%, respectively, for treatment group B undergoing 4 X nivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. Conclusions: Our study showed that nivolumab-based first-line treatment leads to rapid, near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PETderived biomarkers might allow reduction or even omission of chemotherapy and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

BACKGROUND:Individualization of treatment in Hodgkin's lymphoma is necessary to improve cure rates and reduce treatment side effects. Currently, it is hindered by a lack of genomic characterization and sensitive molecular response assessment. Sequencing of cell-free DNA is a powerful strategy to understand the cancer genome and can be used for extremely sensitive disease monitoring. In Hodgkin's lymphoma, a high proportion of cell-free DNA is tumor-derived, whereas traditional tumor biopsies only contain a little tumor-derived DNA. METHODS:We comprehensively genotype and assess minimal residual disease in 121 patients with baseline plasma as well as 77 follow-up samples from a subset of patients with our targeted cell-free DNA sequencing platform. FINDINGS:We present an integrated landscape of mutations and copy number variations in Hodgkin's lymphoma. In addition, we perform a deep analysis of mutational processes driving Hodgkin's lymphoma, investigate the clonal structure of Hodgkin's lymphoma, and link several genotypes to Hodgkin's lymphoma phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cell-free DNA sequencing, as early as a week after treatment initiation, predicts treatment response and progression-free survival, allowing highly improved treatment guidance and relapse prediction. CONCLUSIONS:Our targeted cell-free DNA sequencing platform reveals the genomic landscape of Hodgkin's lymphoma and facilitates ultrasensitive detection of minimal residual disease. FUNDING:Mildred Scheel School of Oncology Aachen-Bonn-Cologne-Düsseldorf MD Research Stipend, Next Generation Sequencing Competence Network grant 423957469, Deutsche Krebshilfe grant 70112502, Deutsche Forschungsgemeinschaft (DFG) grant EN 179/13-1, the HL MRD consortium, and the Frau-Weiskam und Christel Ruranski-Stiftung.

Background The primary analysis of the investigator-sponsored randomized multicenter phase II GHSG NIVAHL trial showed feasibility and excellent short-term efficacy of anti-PD1 based 1st-line treatment of early-stage unfavorable classical Hodgkin lymphoma (cHL). Achieving long-term disease control without excessive treatment-related morbidity is of utmost importance when developing innovative 1st-line cHL therapies. Duration of response and development of persisting immune-related toxicities are of concern in the setting of 1st-line anti-PD1 treatment. Methods NIVAHL enrolled treatment naïve early-stage unfavorable cHL patients at 28 German centers and individuals were randomized to either receive fully concomitant 4x Nivo-AVD (group A) or sequential 4xnivolumab, followed by 2x Nivo-AVD and 2x AVD (group B). Both groups received consolidative 30Gy IS-RT and the primary endpoint was complete response (CR) rate at end of study treatment. Detailed methods, patient characteristics and the primary endpoint analysis of NIVAHL have been recently published (Bröckelmann PJ et al. JAMA Oncol 2020). Herein we present extended follow-up of the NIVAHL trial to assess efficacy in terms of 2-year progression-free (PFS) and overall survival (OS) as well as safety with regards to long-term toxicities or organ impairment documented during the first year of follow-up after treatment. Results A total of 109 patients with cHL confirmed by central pathology review were enrolled between 04/2017 - 10/2018 and followed for a median of 20 and 21 months in groups A (n=55) and B (n=54), respectively, for the present analysis. All of the 7 patients deemed in partial remission (PR) at end of study treatment (EOT) converted into an ongoing CR after end of study without additional treatment during follow-up. With no relapse and no death observed since the primary analysis, the 2-year PFS estimates are 100% and 98% (95%CI 88-100%) in groups A and B, respectively, and the 2-year OS is 100% in both groups. With a median observation time for late-toxicities of 14 months after EOT (range 6-26 months) among 103 patients, any potentially treatment-related AE during follow-up was reported in 65% of patients (A: 74%, B: 56%). The highest documented CTCAE grade of late AEs was °I in 33%, °II in 25% and °III in 7% of patients with no °IV-V AEs observed. A total of 54% had at least one late event related to AVD, 47% to nivolumab and 32% to RT, with multiple relations attributable per event. Mean FEV1 and DLCOc did not decrease from baseline (91.1% -> 96.4% and 86.2% -> 83.3%, respectively). Decreased LVEF after EOT was reported in 2/56 patients with available data (4%). After EOT, 18% of patients required medication for adverse events. Corticosteroid ≥ and < 10mg prednisolone equivalent was required in 3% and 2% of patients, respectively, for a toxicity at any time during follow-up. No patient required corticosteroid treatment at last available follow-up. Most frequent toxicities reported after EOT included fatigue (21%), hypothyroidism (17%), respiratory tract disorders (16%), leukopenia (14%) and nervous system disorders (14%). Hypothyroidism was the event most frequently solely attributed to nivolumab during follow-up. The median time to onset after EOT was 5 months and affected patients nearly exclusively female (15/16 [94%]). After median follow-up of 10 months (range 0-21), hypothyroidism remained unchanged in 10 of 16 affected patients and resolved in 3 patients. Conclusion The excellent disease control of concomitant and sequential nivolumab and AVD in early-stage unfavorable cHL is confirmed with the currently available follow-up. Treatment-related toxicities ongoing or emerging during follow-up are predominantly associated with chemo- and/or RT. The most frequent nivolumab-associated late toxicity is hypothyroidism. No patient currently requires chronic corticosteroid treatment. Disclosures Bröckelmann: Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD Sharp & Dohme: Research Funding. Keller:Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau. Meissner:Celgene: Other: Travel support; Bristol Myers Squibb: Other: Travel support; Takeda: Other: Travel support; Merck Sharp & Dohme: Other: Travel support; Hexal: Other: Travel support. Trautmann:Bristol Myers Squibb: Honoraria. Kerkhoff:BMS: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Lead Discovery Center GmbH: Consultancy; Seattle Genetics: Research Funding; Gilead: Honoraria; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zimmermann:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb: Other: Travel Expenses; MSD: Other: Travel Expenses; Novartis: Other: Travel Expenses. Fuchs:Bristol Myers Squibb: Honoraria, Research Funding; Affimed: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria. von Tresckow:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD Sharp & Dohme: Honoraria, Research Funding; Roche: Honoraria; Kite/Gilead: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Borchmann:Takeda: Research Funding; Bristol Myers Squibb: Research Funding. Engert:Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Takeda: Honoraria, Research Funding; MSD Sharp & Dohme: Honoraria; AstraZeneca: Honoraria; Sandoz: Honoraria. OffLabel Disclosure: Nivolumab 240mg Q2W alone or in combination with AVD for 1st-line treatment of classical Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action.

PURPOSE The optimal treatment of newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is ill defined. We therefore conducted a retrospective analysis using the database of the German Hodgkin Study Group (GHSG).PATIENTS AND METHODS The long-term course of 471 patients with NLPHL (early stages, n = 251; intermediate stages, n = 76; advanced stages, n = 144) who had received stage-adapted first-line treatment in the randomized GHSG HD7 to HD15 studies was investigated. Treatment consisted of radiotherapy alone, chemotherapy alone, or combined-modality approaches.RESULTS The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Patients were mostly male (75.8%). The median observation time was 9.2 years. At 10 years, progression-free survival and overall survival estimates were 75.5% and 92.1% (early stages, 79.7% and 93.3%; intermediate stages, 72.1% and 96.2%; advanced stages, 69.8% and 87.4%), respectively. A total of 48 patients (10.2%) developed a second malignancy during follow-up (non-Hodgkin lymphoma, n = 13; leukemia, n = 6; solid tumor, n = 25; unspecified malignancy, n = 4). Death occurred in 43 patients (9.1%). However, only a minority of deaths were NLPHL related (n = 10), whereas second malignancies (n = 20) and nonmalignant conditions possibly associated with radiotherapy or chemotherapy (n = 13) caused the death in the majority of patients.CONCLUSION The overall outcome of patients with NLPHL who had received Hodgkin lymphoma-directed first-line treatment in randomized GHSG trial protocols was good. Nonetheless, treatment optimization is still necessary to reduce toxicity in standard-risk patients and to improve the prognosis in high-risk patients. (C) 2019 by American Society of Clinical Oncology

Importance In early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL. Objective To evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL. Design, Setting, and Participants This was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible. Interventions Systemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy. Main Outcomes and Measures Complete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group. Results Of 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy. Conclusions and Relevance Both strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL. Trial Registration ClinicalTrials.gov Identifier:NCT03004833

Venetoclax plus rituximab or obinutuzumab after allogeneic hematopoietic stem cell transplantation in chronic lymphocytic leukemiaFor several decades, allogeneic hematopoietic stem cell transplantation (alloHCT) has been a therapeutic option in patients with chronic lymphocytic leukemia (CLL) with high-risk features such as del(17p) and/or TP53 mutations, complex aberrant karyotype, or chemotherapy-resistant disease.With the advent of new targeted agents, like ibrutinib, idelalisib, or venetoclax, an increasing number of patients with CLL is now managed without undergoing alloHCT. 1,2While alloHCT has curative potential, many patients with CLL are not eligible for transplant due to age and co-existing conditions, as the procedure can entail con-siderable treatment-related morbidity and mortality.Moreover, up to 50% of patients may experience relapsed disease after transplantation. 3,4enetoclax, a BH3-mimetic that inhibits Bcl-2, has shown profound efficacy in patients with CLL.It is currently approved for treatment of patients with relapsed/refractory CLL, including patients with high-risk genetic abnormalities like del(17p) or TP53 mutations. 5Several clinical trials are investigating its use in first-line therapy, as monotherapy, or in combination with other drugs. 6However, data on patients with relapsed disease after alloHCT are limited, as most clinical trials have excluded this subset of patients from enrollment.Here, we report clinical data from four patients with CLL (Table 1) who were successfully treated with venetoclax for haematologica 2019; 104:e224 CASE REPORTS Table 1.Patients' characteristics.

We are grateful to Taylor et al. for their comments on our results to programmed cell death protein 1 (PD1) expression in sequential biopsies of classical Hodgkin lymphoma (cHL) patients with progressive disease under anti-PD1 treatment. Furthermore, we appreciate sharing their results to PD1and PD ligand 1 (PDL1) expression in biopsies of a case series of cHL patients with relapse post conventional chemotherapy. In their case series, Taylor et al. found no evidence of a shift in PD1 or PDL1 expression at relapse after chemotherapy in paired lymph node biopsies. These results are in line with the analyses of Schnitter et al. who examined PD1 expression in 16 and PDL1 expression in 13 paired biopsies at initial diagnosis and after first-line chemotherapy (Schnitter et al., manuscript in preparation). Both analyses thus support our hypothesis that the increase of PD1 T cells in Hodgkin/Reed-Sternberg cell (HRSC) vicinity is associated with anti-PD1 treatment and is not a general feature of relapsing disease. In 4 of 9 analyzed patients (patient 2, 7, 8 and 9) with progressive disease of cHL, under anti-PD1 treatment, we could document a notable increase of PD1 T cells in HRSC vicinity. Additional analyses are required to further characterize the described PD1 T cells in HRSC vicinity. As already discussed by Taylor et al., PD1 expression is a widespread marker of T-cell activation, but might also indicate the presence of follicular helper T cells as well as the development of exhausted, hyperactivated T cells as possible mechanism of resistance to anti-PD1 treatment. Appropriate T-cell activation as the reason for documented increase of PD1 T cells seems rather unlikely since all most recent biopsies were taken in relapse on anti-PD1 treatment. The latter hypothesis is supported by the observation that in 2 patients with progressive disease under anti-PD1 treatment and documented increase of PD1 positive T cells (patients 7 and 8), a disease stabilization could be achieved by doubling the dose of the anti-PD1 antibody. However, as already mentioned by Taylor et al., the interpretation of our results in patient 8 is even more complicated since the histology of the most current relapse changed to a lymphocyte-rich (LR) subtype of cHL, and LR cHL in fact differs from other subtypes of cHL in respect to PD1-positive cells within the tumor specimen. A direct contact (rosette) of HRSC to PD1 strongly positive T cells has been described as a characteristic feature of nodular lymphocyte predominant HL (nLPHL) and of LR cHL. The diagnosis of nLPHL could be excluded in the most current tumor biopsy of patient 8 as well as in the subsequent case series. Taylor et al. reported a significantly higher PD1 expression in their LR cHL cases compared to nodular sclerosis or mixed cellularity cHL cases. In order to further evaluate rosetting of HRSC by PD1 positive T cells as well as PD1 and PDL1 expression in LR cHL, we have analyzed 10 specimens of LR cHL obtained at diagnosis before any treatment by immunohistochemistry as previously described and by fluorescence multistaining. Furthermore, we analyzed the PDL1 gene copy number by fluorescence in situ hybridization (Zytovision, Bremerhaven, Germany). As shown in table 1 and illustrated in figure 1, the majority of these LR cHL cases show rosetting PD1-positive T cells. HRSC lack PD-L1 expression and copy number alterations. These findings confirm the observation by Taylor et al. In contrast to the results of Roemer et al. in 2016, even in cases with detectable PDL1 polysomy or copy gain, no relevant PDL1 expression could be detected. More analyses are required to understand whether inverse correlation of PD-L1 on HRSC and PD1 on rosetting T cells is a feature restricted to the LR variant of cHL. However, the documented lack of PDL1 expression on HRSC in this case series of LR cHL and in the analyses of Sakakibara et al. in 2018 stands in marked contrast to our observation that in patient 8 of our case series, 90% of HRSC of the most current tumor biopsy showed a strong PDL1 expression. This case of LR cHL might therefore be regarded as an atypical variant of this subtype which may have developed from mixed cellularity or nodular sclerosis subtype under the influence of immunomodulatory treatment. We are aware of the limitations of our analysis, including the mentioned predominantly descriptive nature of our results, a limited analysis of markers due to scarcity of tissue in relapse, cross-tissue comparison and a heterogenous patient cohort. Taylor et al. listed the comparison of PD1/PDL1 expression across different cHL histological subtypes as an additional limitation of our analysis; we agree that assessment of possible dynamics in

PURPOSE Vitamin D deficiency is described as a modifiable risk factor for the incidence of and mortality in many common cancers; however, data in Hodgkin lymphoma (HL) are lacking. PATIENTS AND METHODS We thus performed a study measuring pretreatment vitamin D levels in prospectively treated patients with HL and correlated this with clinical outcomes. A total of 351 patients from the German Hodgkin Study Group clinical trials (HD7, HD8, and HD9) were included. RESULTS Fifty percent of patients were vitamin D deficient (< 30 nmol/L) before planned chemotherapy. Pretreatment vitamin D deficiency was more common in relapsed/refractory patients than matched relapse-free controls (median baseline vitamin D, 21.4 nmol/L v 35.5 nmol/L; proportion with vitamin D deficiency, 68% v 41%; P < .001). Vitamin D-deficient patients had impaired progression-free survival (10-year difference, 17.6%; 95% CI, 6.9% to 28.4%; hazard ratio, 2.13; 95% CI, 1.84 to 2.48; P < .001) and overall survival (10-year difference, 11.1%; 95% CI, 2.1% to 20.2%; hazard ratio, 1.82; 95% CI, 1.53 to 2.15; P < .001), consistent across trials and treatment groups. We demonstrated that vitamin D status is an independent predictor of outcome and hypothesized that vitamin D status might be important for the chemosensitivity of HL. We subsequently performed experiments supplementing physiologic doses of vitamin D (calcitriol) to cultured HL cell lines and demonstrated increased antiproliferative effects in combination with chemotherapy. In an HL-xenograft animal model, we showed that supplemental vitamin D (dietary supplement, cholecalciferol) improves the chemosensitivity of tumors by reducing the rate of tumor growth compared with vitamin D or chemotherapy alone. CONCLUSION On the basis of our clinical and preclinical findings, we encourage that vitamin D screening and replacement be incorporated into future randomized clinical trials to properly clarify the role of vitamin D replacement therapy in HL.

The introduction of anti-PD1 (programmed death receptor 1) antibodies provides a new treatment option for relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) patients with excellent response rates in the nivolumab and pembrolizumab pivotal trials. So far, only limited data on long-term disease control and survival with PD1-blockade in r/r cHL exist. To address this important issue, we analyzed 30 patients treated with nivolumab in the CheckMate205 trial in Cologne with the longest observation time reported so far (median follow-up 43 months). Despite a higher percentage of patients with stage IV disease and B symptoms compared to the entire patient population of trial cohorts A to C, similar overall response rates (ORR) and median progression-free survival (PFS) were observed in our cohort. Within the extended follow-up period the majority of patients relapsed while on PD1-blockade, but overall survival (OS) is still excellent. Before application of the immunomodulatory approach of PD1-blockade the outcome of patients with disease recurrence after high-dose chemotherapy and autologous stem cell transplant (ASCT) was poor with a median OS of only 2 years.1 In those patients achieving a remission with salvage treatment consolidating allogeneic stem cell transplantation (aSCT) as potentially curative treatment option might be discussed; in highly-selected patients, 3-year relapse free and overall survival rates of up to 40% and 78% after aSCT have been documented.2 By targeting the PD 1/PD-ligand (PD-L) pathway a promising new therapeutic option for patients in a - so far - palliative setting was assessed.3–5 Based on pooled data of a phase I and II trial (CheckMate 039 and 205) nivolumab received approval by the US Food and Drug administration (FDA) and by the European Medicines Agency (EMA) for r/r cHL patients after ASCT and treatment with brentuximab vedotin (BV) or after at least 3 lines of systemic therapies including ASCT.3,4,6 The recently published follow-up analyses of CheckMate 205 confirmed the initial safety profile and efficacy of nivolumab in r/r cHL with no relevant impact of prior BV treatment. As shown after a median follow up of 18 months, duration of response differed dependent on the depth of response, but even in those patients achieving stable disease (SD) as best response a median PFS of 11 months and a 12-months OS rate of 98% were documented.7 The most current analysis with a minimum follow-up of 31 months reported a median PFS of 15 months and 24-months OS rates of 86% to 90% in the different treatment cohorts.8 A total of 30 r/r cHL patients have been treated at the University Hospital of Cologne within the CheckMate 205 trial: 8 patients in cohort A (BV naïve), 16 in cohort B (BV after ASCT), and 6 in cohort C (BV before and/or after ASCT; Fig. 1). The majority of our patients were enrolled at the beginning of the trial enabling us to report the longest follow-up period thus far with a median of 43 months. Details of the trial design (CA209205; clinicaltrials.gov NCT02181738), eligibility criteria, statistics, the initial assessment of cohort B, the current assessment of cohort A, B, and C of the CheckMate 205 trial have already been reported.4,7 Patient characteristics, outcomes and treatment-related adverse events (AEs) documented between September 2014 and January 2019 were assessed for all patients treated in Cologne and analyzed by means of descriptive statistics. PFS and OS were analyzed according to Kaplan–Meier. PFS was defined as the time from the first day of nivolumab treatment until the date of first progression on PD1-blockade, relapse, or until death from any cause. OS was calculated from the same starting date until death from any cause. If none of the events had occurred, PFS and OS were censored at the date of the last documented follow-up in Cologne. Analyses were done using SAS version 9.4 (SAS Institute, Cary, NC).Figure 1: Trial flowchart of the single-center cohort analysis of patients registered for the CA209205 trial in Cologne. ASCT = autologous stem cell transplantation; BV = brentuximab vedotin; CR = complete response.Patient characteristics of our single-center cohort did not differ relevantly from the entire trial cohorts A to C except for a higher percentage of patients with stage IV disease (73% vs 57%) and B symptoms (60% vs 22%) (supplementary Table 1, Supplemental Digital Content). Based on local radiology assessment, ORR in our cohort was 84% (25/30) with best response being complete response (CR) and partial response (PR) in 8 (27%) and 17 (57%) patients, respectively. SD was documented in 4 (13%) patients and 1 patient (3%) had progressive disease as best response (supplementary Table 2, Supplemental Digital Content). Independent review committee (IRC) response assessment in our patient cohort resulted in an ORR of 70% (21/30) including 4 (13%) CRs and 17 (57%) PRs. According to IRC assessment, SD was documented in 6 (20%) and progressive disease in 3 (10%) patients as best response (supplementary Table 2, Supplemental Digital Content). As already discussed by Armand et al, 2018, the response criteria applied in the CheckMate 205 trial might not properly reflect atypical response patterns observed with immune checkpoint inhibitors.7,9 These atypical response patterns are even more difficult to be quantified in advanced-stage disease including organ or bone marrow involvement and might explain the discrepancies between local and IRC response assessment in our patient cohort.10,11 With a median observation time of 43 months, a median PFS of 18.6 months and 12-, 24- and 48-months PFS estimates of 59.4% [95% CI 41.6%–77.1%], 41.9% [95% CI 23.9%–59.9%] and 24.4% [95% CI 5.1%–43.8%], respectively, were assessed (Fig. 2A).Figure 2: Kaplan–Meier survival plots showing 95% confidence intervals (CI) for (A) progression-free survival (PFS) and (B) overall survival (OS).15/19 patients who developed progressive disease had persistent clinical benefit and therefore continued treatment within the trial beyond documented tumor progression (TBP). TBP resulted in PR in 2, SD in 3 and progressive disease in 10 patients as best response with a median treatment duration beyond progression of 25.1 weeks (range 6–177 weeks) (supplementary Table 3, Supplemental Digital Content). 2/19 patients with progressive disease on nivolumab proceeded to aSCT after achieving remission with salvage chemotherapy and nivolumab combined with radiotherapy, respectively. In 1 patient severe acute graft vs host disease had to be treated. Both patients are still in remission. The 12-, 24- and 48-months OS estimates were 96.7% [95% CI 90.2%–100.0%], 86.3% [95% CI 73.8%–98.8%] and 82.9% [95% CI 69.2%–96.5%], respectively (Fig. 2B). Response rates, median PFS, 12- and 24-months OS in our cohort were similar to results of the overall trial population of cohorts A to C of CheckMate 205 and to the results of Keynote-087, the phase II approval trial with the anti-PD1 antibody pembrolizumab. In accordance with the recently reported update of these trials the majority of patients in our cohort relapsed or developed progressive disease.7,8,12 However, also in line with the available follow-up analyses of cohorts A to C, our single-center analysis indicates that, at least in a subset of patients, further disease control might be achieved by continuing anti-PD1 TBP.7 Of note, nine patients enrolled in our center continued to receive nivolumab as single agent or as part of a multimodal therapy approach after discontinuation of treatment within CheckMate 205 because of disease progression. As of January 2019, 5 of those patients receiving nivolumab as monotherapy beyond progression had SD more than one year after first documentation of progressive disease. Retrospective analyses of Rossi et al, 2018, and of Carreau et al, 2018 suggest that in patients with a former aggressive and chemotherapy-refractory disease who develop relapsed or progressive disease on anti-PD1 treatment, this immunomodulatory treatment approach might result in a more indolent disease at relapse and might re-sensitize it to subsequent chemotherapy.13,14 However, this hypothesis has to be confirmed by evaluation of a larger patient cohort. The current assessment of nivolumab-related AEs in our single-center cohort confirmed the recently reported safety data of the CheckMate 205 trial and are in line with the safety profile reported for PD1-blockade with pembrolizumab.5,7,8,10 Twenty-four patients of our single-center cohort (80%) developed at least 1 drug-related AE. The majority of these AEs was mild or moderate. All infusion- and the majority of autoimmune reactions (irAEs) completely resolved with the appropriate management. In 20 patients the manifestation of an irAE required the application of corticosteroids. Only 1 patient discontinued nivolumab due to a drug-related AE. No relevant treatment-related cytopenia and no treatment-related infections were documented (supplementary Tables 4 and 5, Supplemental Digital Content). In conclusion, with the longest follow-up reported so far, our single-center analysis of patients treated within the CheckMate 205 trial confirms the existing favorable efficacy and safety profile of PD1-blockade in r/r cHL. Neither the response nor the survival rates were impaired by the high proportion of patients with stage IV disease and B symptoms in our cohort. However, our analysis showed that despite a favorable initial response the majority of patients relapse on anti-PD1 monotherapy. A durable response - as indicated by results of small case series - might be achieved by consolidating aSCT. It is not clear yet if the reduced relapse rate after aSCT translates in an improved OS.15 Furthermore, application of current response criteria might not properly reflect clinical benefit as well as overall survival on checkpoint blockade. These questions need to be addressed and mechanisms of resistance to PD1-blockade to be explored in order to optimize checkpoint blockade in r/r cHL. Supplementary Material Supplemental Digital Content

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