Italian Expert Panel Consensus Statement on the Optimal Use of PD-1 Blockade Therapy in Classical Hodgkin Lymphoma

LEUKEMIA & LYMPHOMA https://doi.org/10.1080/10428194.2018.1519808

ORIGINAL ARTICLE: CLINICAL Italian expert panel consensus statement on the optimal use of PD-1 blockade therapy in classical Hodgkin lymphoma

Pier Luigi Zinzania, Armando Santorob, Arturo Chitic, Secondo Lastoriad, Antonio Pintoe, Lugi Rigaccif, Giovanni Barosig, Martina Pennisih and Paolo Corradinih aInstitute of Hematology L. e A. Seragnoli, University of Bologna, Bologna, Italy; bDepartment of Oncology and Hematology, IRCCS Humanitas Cancer Center, Milan, Italy; cNuclear Medicine Department, Humanitas Research Hospital and Humanitas University, Milan, Italy; dNuclear Medicine Unit, Department of Hematology and Developmental Therapeutics, Istituto Nazionale Tumori, Fondazione Pascale, IRCCS, Naples, Italy; eHematology-Oncology and Stem Cell Transplantation Unit, Department of Hematology and Developmental Therapeutics, Istituto Nazionale Tumori, Fondazione Pascale, IRCCS, Naples, Italy; fDepartment of Hematology, University of Florence, Florence, Italy; gCenter for the Study of Myelofibrosis, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; hDivision of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, Italy

ABSTRACT ARTICLE HISTORY Programmed death 1 (PD-1) blocking antibodies now represent a major advance in the treat- Received 4 April 2018 ment of patients with classical Hodgkin lymphoma (cHL) who relapse after autologous stem cell Revised 7 August 2018 transplantation (ASCT) and pre- and/or post-ASCT brentuximab vedotin or after at least three Accepted 25 August 2018 lines of therapy. However, uncertainties still remain on the optimal use of these agents in refrac- KEYWORDS tory Hodgkin disease. A panel of experts was convened to produce a consensus document Hodgkin lymphoma; aimed at providing practice recommendations for the optimal use of PD-1 blocking antibodies checkpoint inhibitors; in cHL, especially on pretreatment selection and evaluation of cHL patients’ response and treat- practice guidelines ment length, management of PD-1 blockade therapy–treated patients, evaluation and management of toxicity. Our hope is that these recommendations might help hematologists to improve optimal management of patients with pretreated cHL.

Introduction however, several uncertainties still remain on the optimal use of these drugs. As a matter of fact, practi- Recently, the programed death 1 (PD-1) blocking anti- tioners are cautioned about response evaluation, bodies nivolumab and pembrolizumab were shown to optimal length of treatment, possibility to continue have substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory treatment beyond progression until clinical benefit is (r/r) classical Hodgkin lymphoma (cHL). Based on two maintained, management of immune-mediated single-arm multicenter trials in adults with cHL [1,2] adverse effects as well as indications in pediatric nivolumab has been approved by the European patients. Moreover, whether and when allogeneic Medicines Agency (EMA) and the Food and Drug hematopoietic stem cell transplantation (allo-HSCT) Administration (FDA) for patients who failed both should be performed in the era of PD-1 pathway autologous stem cell transplant (ASCT) and pre- and/ blockade is also matter of concern due to the or post-transplantation brentuximab vedotin (BV) [3,4]. increased risk of graft versus host disease (GVHD) and Based on one phase Ib and one phase II study, pem- immune-mediated toxicities. brolizumab was approved by EMA as monotherapy for The aim of this project is to provide practical guid- adult patients with r/r cHL who have failed ASCT and ance to help clinicians to maximize efficacy and safety BV or who are transplant-ineligible and have failed BV. through an appropriate use of PD-1 blockade. Recently, pembrolizumab was approved by FDA for adults and pediatric patients with r/r cHL after three Design and methods or more prior lines of therapy [4]. As of today, nivolumab and pembrolizumab repre- A panel of experts (hereafter called the Panel) was sent a major breakthrough in the treatment of r/r cHL; selected for their expertise in research and clinical

CONTACT Paolo Corradini [email protected] Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Via Giacomo Venezian 1, Milan, 20133, Italy ß 2018 Informa UK Limited, trading as Taylor & Francis Group

http://guide.medlive.cn/ 2 P. L. ZINZANI ET AL. practice in adult HL. A clinician with expertise in clin- History of current noninfectious pneumonitis requir- ical epidemiology (GB) assured methodological con- ing steroids should also be considered a criterion for sistency throughout the process. treatment exclusion. During a kickoff meeting, the Panel agreed on the In general, all trials with PD-1 blockade drugs major concerns in the use of PD-1 blockade by gener- exclude patients with HIV, HCV, HBV positivity. ating and rank-ordering clinical key-questions using However, HBV or HCV positivity has not been consid- the criterion of clinical relevance, i.e. impact on the ered an exclusion criterion in trials with nivolumab in management of patients and risk of inappropriateness, hepatocellular carcinoma (HCC) where no safety sig- through a Delphi process [5]. The candidate key- nals were observed in patients with HCC and HBV or questions that ranked highest originated the set of HCV positivity [8]. issues of the document. Moreover, the Panel examined the current state of knowledge regarding nivolumab and pembrolizumab therapy in cHL. Thereafter, each Pre-treatment work-up panelist drafted statements addressing the key-questions, and then scored his agreement with the other Monitoring of disease status prior to PD-1 blockade is statements and provided suggestions for rephrasing. accomplished by Computed Tomography scan (CT) 18F For exploiting this phase of the process, the Panel was and/or FDG-Positron Emission Tomography (PET) convened and two consensus meetings were held. [9,10]. It should be acknowledged that, because of the Based on the nominal group technique, participants absence of soft tissue component, detection of bone were first asked to comment in round-robin fashion marrow involvement might not be measurable or on their preliminary votes and then propose a new imperceptible on CT [11]. vote [6]. In cHL, tumor cells overexpress PD-L1 and PD-L2 proteins due to acquired genetic alterations involving the 9p24.1/PD-L1/PD-L2 gene locus. Given the most Results universal (>98% of cases) expression of PD-L1 by Pre-treatment evaluation tumor cells in cHL, most of the panel members agreed Patient selection that, differently from solid neoplasms, pre-treatment testing for PD-L1 expression by immunohistochemistry As reported in trials on solid tumors, PD-1 blockade is unnecessary in clinical practice [12–14]. should not be started in patients with a diagnosis of active autoimmune disease, receiving systemic full dose corticosteroids or any other form of immunosup- Recommendations pressive therapy. However, this clinical evidence derives from retrospective series and case reports. In a Beside staging exams like CT and PET scan, no other group of 52 advanced melanoma patients with preex- pre-treatment specific tests are required, neither to isting autoimmune disorders, treatment with nivolu- assess indication of treatment nor to predict toxicity. mab induced 30% autoimmune flares with no death General contraindications to PD-1 blockade therapy from toxicities [7]. Moveover, rheumatoid disorders are those reported in registration clinical trials, i.e. HIV seemed to exacerbate more likely than other auto- positivity, pregnancy, history of pneumonitis, or active immune diseases (as neurologic or gastrointestinal autoimmune disease receiving systemic full dose ster- ones). Interestingly, patients who were still under oid therapy or any other form of immunosuppres- immunosuppressive drugs when starting anti-PD1 sive therapy. inhibition had lower response rates compared to The Panel discussed whether recommendations on patients out of treatment. In our opinion, history of specific investigations to refine exclusion criteria autoimmune disease with no active immunosuppres- should be provided (e.g. markers of active auto- sive therapy is not an absolute contraindication at immune disease or of active neoplasia), but no agree- Checkpoint Inhibition. This therapeutic option should ment was attained. be discussed with the patient and the immunologist, The panel recommended that both CT and FDG- balancing the severity of the underlying autoimmune PET scan should be used before starting treatment in disorder (as severe Crohn disease, Guillain-Barre syn- order to facilitate response evaluation. Pre-treatment drome, or others), the risk of life-threatening exacerba- testing for PD-L1 expression in cHL by immunohisto- tions, and the risk of lymphoma progression. chemistry is unnecessary in clinical practice.

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Practice indications of PD-1 blockade in cHL with 1-year PFS and OS of 76 and 89%, respectively. The overall rate of grade 2–4 acute GVHD, grade 4 The approval of nivolumab by FDA on 17 May 2016 acute GVHD, and chronic GVHD at 1 year were 44, 13, and by EMA on 22 November 2016 was based on the and 41%, respectively. In the extended follow-up ana- CheckMate 039 phase 1 study and CheckMate 205 lysis of CheckMate 205 Trial [20], 44 over 243 patients phase 2 study [1,2]. In the CheckMate 039 trial, an proceeded to allo-HSCT after a median time from last objective response rate (ORR) was reported in 87% of nivolumab administration of 49 days. Six-months patients, including 17% complete response (CR) and cumulative incidence of transplant-related mortality 70% partial response (PR). In the CheckMate 205, 53 was 13%, with 4 over 5 deaths from acute GVHD. Six- (66.3%) out of 80 patients achieved an ORR, with 9% month PFS and OS estimates were 82 and 87%, CR. The most common severe adverse events (SAEs) respectively. In both reports, no clear correlation has were pneumonitis, pleural effusion, pyrexia, infusion- related reactions, and rash, recorded in 1–3% been identified between time from anti-PD-1 therapy of patients. to allo-HSCT and onset of GVHD or nonrelapse mortal- The approval of pembrolizumab by FDA on 14 ity (NRM). Further and larger studies are needed to March 2017 was based on Keynote 087 phase 2 study confirm these data and to better clarify the role of [13]; the approval by EMA on 5 May 2017 was also GVHD prophylaxis (ATG, posttransplant cyclophospha- based on Keynote 013 phase 1b study [15]. Efficacy mide, etc). Although the follow-up was limited, these was evaluated in 210 adult patients of the Keynote studies indicate that allo-HSCT after PD-1 therapy is 087 study, with ORR and CR reaching 69 and 22%, feasible, but with an increased risk of toxicity. respectively. In the Keynote-013 study, ORR and CR However, for the more favorable toxicity profile of were 64.5 and 16.1%, respectively. AEs were compar- checkpoint inhibitors, some authors suggest that able to those observed with nivolumab. patients responding to PD-1 blockade should not dis- Pembrolizumab has been approved by the FDA continue to proceed to allo-HSCT [21]. Nevertheless, in also for pediatric cHL patients refractory or relapsed the absence of evidence supporting the superiority of after three or more lines of therapy, regardless of prior one treatment over the other, allo-HSCT should be ASCT. The approval for children was based on the considered a therapeutic option for patients in remis- results extrapolated by adult patients’ trials and on sion, especially in heavily pretreated patients. Specific the Keynote 051 phase 1/2 study (still ongoing) evalu- recommendation on timing of allo-HSCT cannot be ating the safety of pembrolizumab in 40 children with inferred, though a minimum delay of 6 weeks after advanced melanoma or solid PD-L1 positive tumors or the last nivolumab/pembrolizumab administration lymphoma [16]. The safety profile in pediatric patients before proceeding to allo-HSCT is part of the current was similar to that observed in adults. FDA cautioned practice [21]. that children could be at higher risk for AEs like vomit- Most reports [22–34] on PD-1 blockade for relapse ing, hypertransaminasemia, hyponatremia, as well as after allo-HSCT suggest they are effective in this set- immune-mediated adverse reactions. ting. Recently a large multicenter retrospective study The role of allo-HSCT in cHL has become less clear was conducted in 31 lymphoma patients [35], includ- after nivolumab and pembrolizumab became available. ing 29 cHL, 27 of which had 1 salvage treatment One reason is the concern that patients treated with after allo-HSCT and before PD-1 blockade. Median PD-1 blockade are more prone to GVHD. In follow-up was 428 days after the first anti-PD-1 CheckMate 039 and 205 [1,2], the combined safety administration. ORR was 77% (15 CRs and 8 PRs). analysis of the 17 patients who underwent allo-HSCT Overall, at the last follow-up 68% remained alive, after nivolumab showed that 35% died from trans- with 8 deaths (26%) related to GVHD. Seventeen plant complications, mostly from severe GVHD. These (55%) patients developed GVHD (6 acute, 4 overlap data prompted an FDA warning to closely follow and 7 chronic), after a median of 1–2 anti-PD-1 doses patients after allo-HSCT for toxicities including hyper- administration. GVHD was graded 3–4 acute or acute GVHD, steroid-requiring febrile syndrome, severe chronic in 9 patients. Only 2 over 17 patients hepatic veno-occlusive disease (VOD), and immune- achieved CR to GVHD treatment, most requiring 2 mediated adverse reactions [17,18]. systemic therapies. Twelve of the 17 patients had In a retrospective analysis of 39 patients who already experienced GVHD at time of anti-PD-1 underwent allo-HSCT after a median of 62 days follow- administration, 6 of whom had active chronic GVHD. ing anti-PD-1 therapy [19], there were 4 treatment- In three of these GVHD worsened after PD-1 block- related deaths (3 acute GVHD and 1 hepatic VOD) ade. Similarly, in a French series [34], prior history of

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GVHD was reported in all GVHD cases occurred after Response evaluation and disease monitoring anti-PD-1 administration. The authors suggested that Response criteria in patients with HL have been time from allo-HSCT to PD-1 blockade played a role designed for chemotherapy and targeted molecular in the development of GVHD, since median time was agents. With these, the response was defined as tumor significantly shorter in patients who presented PD-1- shrinkage [9] and/or absence of glycolytic metabolism related GVHD compared to GVHD-free patients (8 vs. (Lugano classification) within initial lesions and 28 months). In conclusion, PD-1 blockade in relapsed residual masses [10], as evaluated with CT and FDG- cHL allo-HSCT patients appears to be highly effective PET respectively. but frequently complicated by early severe and The introduction of immune checkpoint inhibitors refractory GVHD. Therefore, this option should be in cHL management has highlighted the need for a carefully evaluated and be conducted only in clinical different approach in response assessment. PD-1 trials. No specific recommendation on the time from blockade in patients with solid tumor may induce allo-HSCT can be provided; however, the panel ‘pseudo-progression’ with imaging patterns suggestive agreed that suitable candidates should be off of progressive disease (increased size and metabolic immunosuppressive treatment since at least 4 weeks activity on CT and FDG-PET, respectively) then fol- with no signs of GVHD. lowed by patterns of response [35–41]. Thus, new criteria for imaging interpretation were recently Recommendations proposed for solid tumors [42] and lymphomas [11]. In 2016, the Lymphoma Response to Immunomodulatory According to FDA and EMA, PD-1 blockade with nivo- therapy Criteria (LyRIC) introduced the term lumab is indicated in adult patients with r/r cHL, previ- ‘Indeterminate Response’ (IR) – instead of ously exposed to BV (either pre- or post-ASCT). The ‘progression’–to be used until a biopsy or subse- recommended dose is 240 mg administered as mono- quent imaging confirms either a pseudo-progression therapy in intravenous infusion over 60 minutes every or a true progression [43](Table 1). 2 weeks. Recently, cHL patients treated with PD-1 blockade According to FDA, PD-1 blockade with pembrolizu- therapy were retrospectively recruited at Gustave mab is indicated in the treatment of adult patients Roussy, Villejuif, France, from 2013 to 2015, to investi- with refractory cHL or relapsed after 3 or more lines of gate the accuracy of 3-month-18FFDG-PET/CT in assess- therapy. EMA indicates treatment for patients with r/r ing response to PD-1 blockade and frequency of new cHL following ASCT and BV, or for those who are not immune patterns of response [43]. Sixteen r/r patients candidates for ASCT (e.g. clinical ineligibility or cases were included, 56% of which achieved an objective in which ASCT is not a treatment option) and have response. 18FFDG-PET/CT detected all responders at failed BV. The recommended dose is 200 mg adminis- 3 months and reclassified best overall response in tered as monotherapy in intravenous infusion over 5 patients compared to CT-scan alone. New patterns 30 minutes every 3 weeks. of response were encountered in 31% of patients. According to the FDA, pembrolizumab use is also The Panel agreed that, based on current know- allowed in pediatric patients with refractory cHL or ledge, CT and FDG-PET cannot be considered accurate relapsed after three or more lines of therapy. In pedi- predictors of response to PD-1 blockade. Moreover, a atric patients, the recommended dose is 2 mg/kg, up critical appraisal of the new response criteria high- to a maximum of 200 mg, administered as monother- lighted that IR evaluation introduces the need for apy in intravenous infusion over 30 minutes every repeated imaging, which is not yet validated as bene- 3 weeks, until disease progression or unacceptable ficial for the patient. toxicity, or up to 24 months in patients without dis- Recommendations ease progression. Since studies in pediatric patients are still ongoing and mature results are not available, The Panel agreed that both the conventional response the Panel agreed that this patient population should criteria proposed by Cheson in 2007 and the newly be treated only under a controlled drug regimen, i.e. proposed criteria are inadequate for response evalu- in registries or clinical trials. ation in this setting. Among all, LyRIC criteria could be The Panel argued that the decision to proceed to a proxy in response evaluation. allo-HSCT for cHL patients responding to anti-PD-1 The Panel recommended that monitoring of blockade should be considered a therapeutic option. response should be accomplished with ceCT, while

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Table 1. Lymphoma response to immunomodulatory therapy criteria (LyRIC). Response Parameters Complete remission (CR) PET-CT score: 1, 2, or 3 with or without a residual mass on 5PS OR CT regress to 1.5 cm in LDi of target nodes/nodal masses Partial remission (PR) PET-CT score 4 or 5 with reduced uptake vs. baseline and residual mass(es) of any size. OR CT 50% decrease in SPD of up to six target measurable nodes and extranodal site Progressive disease (PD) PET-CT score 4 or 5 with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment. OR abnormal individual node/lesion (CT) with LDi >1.5 cm þ increase by 50% from PPD nadir þ increase in LDi or SDi from nadir 0.5 cm for lesions 2 cm 1.0 cm for lesions >2cm Increase in splenic length >50% of the extent of its prior increase beyond baseline (eg, a 15-cm spleen must increase to >16 cm)/increase by 2 cm from baseline, if no prior splenomegaly. New or recurrent splenomegaly New or clear progression of preexisting non-measured lesions Regrowth of previously resolved lesions A new node >1.5 cm in any axis or a new extranodal site >1.0 cm in any axis. A new node <1.0 cm in any axis, must be attributable to lymphoma Assessable disease of any size unequivocally attributable to lymphoma AND/OR New/recurrent bone marrow involvement Immune response (IR): IR: 50% increase in SPD in first 12 weeks IR: <50% increase in SPD with new lesion(s)/50% increase in PPD of a lesion or set of lesions at any time during treatment IR Increase in FDG uptake without a concomitant increase in lesion size meeting criteria for PD Adapted from Cheson et al. [10]. CT: computed tomography; FDG: fluorodeoxyglucose; PET: positron emission tomography; IR: immune response; LDi: longest diameter; PPD: product of the perpendicular diameters; SDi: short diameter; 5PS: 5-point scale. Consider a score of 3 as inadequate response thus to avoid undertreatment. PET 5PS: 1 ¼ no uptake above background; 2 ¼ uptake mediastinum; 3 ¼ uptake > mediastinum but liver; 4 ¼ uptake greater than liver; 5 ¼ uptake markedly higher than liver (2–3 times SUVmax in normal liver) and/or new lesions; X ¼ new areas of uptake unlikely to be related to lymphoma). end of treatment response should be evaluated with disease progression or intolerable toxicity [1]; other tri- ceCT and FDG-PET. als allowed treatment for up to 2 years or longer The Panel also claimed that an evidence-based tim- [2,13]. Some studies were amended to allow cessation ing of response evaluation during therapy is not feas- of therapy in case of a prolonged FDG-PET-negative ible. Results of clinical studies allow recommending CR. The Panel argued that, based on the existing evi- that the first response evaluation should be performed dence, a risk-effectiveness balance of different treat- after 4–6 cycles of treatment, in the absence of clinical ment durations in responding patients is not feasible. signs of progression. The assessment should be Thus, consensus-based recommendations were pro- repeated after 2 or 4 months in case of stable disease duced and the need for new evidence was (SD). After treatment discontinuation, monitoring highlighted. should be performed according to general clinical Experience of PD-1 blockade discontinuation is practice and clinical symptoms. scarce. In a phase I study, two responding patients maintained CR at 40 weeks after treatment suspension. One patient relapsed 43 weeks after nivolumab Clinical management of patients with cHL treated discontinuation, but regained CR when treatment was with PD-1 blockade resumed [44]. The optimal duration of PD-1 blockade treatment is an Based on the results of Checkmate 205 trial [20], uncertain matter. Although the majority of response is patients in SD have a median PFS of 11 months, com- being observed within the first 6 months, responses pared to 15 and 22 months for PR and CR patients, occur rather later than after conventional therapy respectively, and similar 1 year OS rate. Moreover, clin- [1,2,13]. Most trials investigated treatment until ical benefits were observed in patients treated with

http://guide.medlive.cn/ 6 P. L. ZINZANI ET AL. anti-PD-1 beyond disease progression. Indeed, the Evaluation and management of toxicity majority of patients under continuous nivolumab Physicians administering anti-PD-1 inhibitors should treatment demonstrated stable reduction in tumor be aware of their most common side effects – burden, 84% 12-month OS and 17 months median immune-related AEs (irAEs), the more frequent being time to next therapy [45]. These results suggest that pneumonitis, colitis, hepatitis, and hypo- or hyperthy- patients benefit from long-lasting clinical effects of roidism. Immuno-mediated toxicity follows a peculiar anti-PD1 treatment. pattern: cutaneous rash appears after about 4 weeks, As already proven for solid tumors, recent reports diarrhea and colitis after 5–6 weeks, and the onset of have shown improved disease control with chemo- liver toxicity (transaminitis) and hypophysitis is at 6–7 therapy alone or in combination with anti-PD-1 ther- weeks (Table 2). apy in r/r HL patients who had previously Based on solid tumors experience, unexpected demonstrated an unsatisfactory response to anti-PD-1 severe toxicities may occur, such as T-cell-driven myo- treatment alone and previous chemotherapy regi- carditis leading to heart failure or corticosteroid-resist- mens [46,47]. ant colitis [50]. While rash and pruritus remain the most common cutaneous complications, novel derma- Recommendations tologic irAEs continue to emerge as the number of patients treated increases. The recognition of such tox- In patients who achieved CR after PD-1 blockade, both icities is critical to optimal patient management [51]. consolidation with transplant (autologous or allogeneic) or treatment continuation for at least 1 year are Recommendations appropriate strategies. In patients who achieve PR after at least 1 year of Physicians need to be aware of signs, symptoms, and therapy, PD-1 blockade continuation for at least 2 laboratory abnormalities associated with the occur- years or enrollment in a transplant program (auto- or rence of irAEs in order to prevent delays in diagnosis allo-transplant) should be considered. and prompt timely and effective treatment. Available Treatment should be discontinued in patients who data do not currently support neither prophylactic show progressive disease in two consecutive strategies to prevent the occurrence of irAEs nor the evaluations. use of biomarkers allowing prediction or early recogni- In patients with SD, the Panel judged that tion of irAEs. continuation of PD-1 blockade for 2 years is reason- For management, the American Society of Clinical able. Alternatively, patients with SD or confirmed pro- Oncology (ASCO) has recently published detailed gression could be switched to single-agent Clinical Practice Guidelines [52]. chemotherapy. According to ASCO, management of irAEs differs per organ involved. As a general rule, anti-PD-1 therapy should be continued with close monitoring for grade 1 toxicities, except for AEs pertaining to lungs, Biomarkers adrenal glands, kidneys, central nervous system, heart, Amplification and translocation of the 9p24.1 chromo- and some hematologic toxicities, for which the some region, where PD-1 ligands 1 and 2 (PD-L-1, PD- authors suggest treatment suspension. In case of L-2) genes are located, lead to their overexpression in grade 2 toxicities, anti-PD-1 therapy should be tem- cHL [1,48,49]. The Panel discussed the relevance of porarily held with consideration of resuming when PD-L-1/PD-L-2 expression in cHL as a marker for pre- symptoms regress to grade 1 or less. In this case, cor- dicting response to PD-1 blockade. They agreed that ticosteroid treatment may be considered. For grade with such ubiquitous expression of PD-L-1 in cHL, it is 3 toxicities, generally, checkpoint inhibitors suspension unlikely to find a pattern of PD-L-1/PD-L-2 expression and high-dose corticosteroids treatment (prednisone that will carry sufficient power to predict response. 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d) However, recent evidence suggests that genetically is warranted. Steroids tapering should be performed driven PD-L-1 hyperexpression and presence of high over at least 4–6 weeks. Steroid-refractory cases may levels of MHC class II on tumor cells are potential pre- be handled with infliximab or other immunosuppres- dictors of favorable outcome and quality of response sive drugs. Generally, permanent discontinuation of to PD-1 inhibition [12]. anti-PD-1 therapy is strongly recommended with

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Table 2. AntiPD1 Adverse Events [55,56].

Frequency Nivolumab [49] Pembrolizumab [50] Very common (>1 in 10 people) diarrhea diarrhea nausea nausea rash, pruritus rash, pruritus fatigue fatigue neutropenia decreased appetite increased AST, ALT, alkaline phosphatase, lipase, amylase, creatinine, hypocalcemia, hyperglycemia, lymphopenia, leucopenia, thrombocytopenia, anemia, hypercalcemia, hyperkaliemia, hypokalemia, hypomagnesaemia, hyponatremia Common (1 in 10 people) upper respiratory tract infection anemia infusion related reactions, hypersensitivity anorexia, dysgeusia hypothyroidism, hyperthyroidism hypothyroidism, hyperthyroidism peripheral neuropathy, headache, dizziness flushing hypertension headache, dizziness pneumonitis, dyspnea, cough pneumonitis, dyspnea, cough colitis, stomatitis, vomiting, abdominal pain, colitis, dry mouth constipation, dry mouth gastritis, constipation, vomiting vitiligo, dry skin, erythema, alopecia erythema, bullous dermatitis, musculoskeletal pain, arthralgia dyschromia, vitiligo pyrexia, edema (including peripheral edema) myalgia, musculoskeletal pain, arthralgia, increased total bilirubin, hypoglycemia, hyper- arthritis, tenosynovitis magnesemia, hypernatremia, weight decreased edema pyrexia, chills, flu-like symptoms increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, creatinine, amylase infusion related reactions (drug hypersensitivity, anaphylactic reaction, hypersensitivity and cytokine release syndrome) Uncommon (1 in 100 people) pneumonia, bronchitis leucopenia (including neutropenia, eosinophilia lymphopenia), eosinophilia, trombocytopenia adrenal insufficiency, hypopituitarism, hypo- hypopituitarism, hypophysitis, adrenal physitis, thyroiditis, diabetes mellitus insufficiency, thyroiditis, type 1diabetes dehydration, metabolic acidosis mellitus (diabetic ketoacidosis); hepatitis hypercalcemia, hypocalcemia, hypokalemia, polyneuropathy, autoimmune neuropathy hyponatremia (including facial and abducens nerve paresis) insomnia; uveitis, blurred vision, dry eye seizures, lethargy, sensitive periph- tachycardia eral neuropathy pleural effusion dry eye, uveitis, photophobia pancreatitis, gastritis myocarditis, pericarditis, pericardial effusion erythema multiforme, psoriasis, ros- hypertension acea, urticaria pancreatitis polymyalgia rheumatica, arthritis hepatitis tubulointerstitial nephritis, renal failure (includ- lichenoid keratosis, psoriasis, alopecia, ing acute kidney injury) dermatitis, dermatitis pain, chest pain acneiform, eczema, hair color changes, papules nephritis Rare (1 in 1000 people) histiocytic necrotizing lymphadenitis (Kikuchi immune thrombocytopenic purpura, lymphadenitis) hemolytic anemia anaphylactic reactions sarcoidosis diabetic ketoacidosis Guillain–Barre syndrome, myasthenic cholestasis syndrome, encephalitis Guillain–Barre syndrome, demyelination, small bowel perforation myasthenic syndrome, encephalitis toxic epidermal necrolysis, Stevens-Johnson arrhythmia (including ventricular arrhythmia), syndrome, erythema nodosum atrial fibrillation, myocarditis vasculitis lung infiltration duodenal ulcer toxic epidermal necrolysis, Stevens–Johnson syndrome Sjogren’s syndrome, myopathy, myositis (including polymyositis), rhabdomyolysis Not known solid organ transplant rejection Vogt–Koyanagi–Harada syndrome AST: aspartate aminotransferase; ALT: alanine aminotransferase.

http://guide.medlive.cn/ 8 P. L. ZINZANI ET AL. grade 4 toxicities, except for endocrinopathies con- identified as the critical areas potentially advancing trolled by hormone replacement. the use of these agents. In conclusion, an assessment with patients and A more detailed understanding of the mechanisms multidisciplinary group about drug resumption, con- of PD-1/PD-L-1 pathway blockade is indispensable in sidering vantages/disadvantages for high-risk disease order to apply this treatment efficiently. Two major and risk of permanent toxicities, is recommended. preconditions are required for effective PD-1 blockade: a capacitated host immune system to act against the tumor and effective tumor antigen presentation and Future perspectives: multiagent therapy including recognition, enabling a specific immune response. All anti-PD-1 inhibition currently available PD-1 blockade trials in cHL included Many trials are currently ongoing to test safety and r/r patients after multiple lines of chemotherapy: thus, efficacy of combining Checkpoint Inhibition to avail- modest response rates could be due to the weakened able effective treatments (bendamustine, radiotherapy, host immune system. Earlier implementation of PD-1 ibrutinib, etc.), and results are awaited. A recent phase blockade in the course of disease, with a potentially I/II study of brentuximab plus nivolumab showed more competent immune system, should be investigated. On the other hand, mutational load and mis- promising, although preliminary, results in 62 r/r match-repair deficiency have been identified as patients, with ORR of 82% and CR rate of 62%. possible biomarkers for PD-1 blockade response, Seventeen patients, who did not achieve CR with explaining why refractory or relapsed disease might brentuximab plus nivolumab, underwent subsequent be associated with a more obvious benefit from treat- chemotherapy with 80% ORR. Forty-two patients ment. Moreover, it is important to underline how the underwent ASCT directly after the combination, with mechanism of action of PD1-blockers in cHL may 80% CR, although follow-up is too short to evaluate rather differ from solid tumors. In this regard, recent survival [53]. Moreover, recent reports have shown studies have highlighted that PD-L1-expressing tumor improved response with the combination of chemo- cells in cHL preferentially interact with PD-1 þ CD4 þ T therapy and anti-PD-1 therapy in patients who previ- cells rather than with PD-1 þ CD8 þ T cells as typical of ously demonstrated an unsatisfactory response to neoplastic cells from most solid tumors [54]. Similarly, – anti-PD-1 treatment alone [46 47]. other immune effectors such as macrophages may Evidence of anti-PD-1 inhibition concurrent with play a relevant role in regulating the response to PD1- other agents is encouraging and ongoing trials results blockade in cHL [54]. In this context, the usual lack of are awaited; however, no specific recommendation can HLA-Class I expression by tumor cells of cHL and the be made about it since safety and efficacy results are potential role of alternative HLA-Class II-mediated anti- too preliminary. Currently, patients can receive these gen recognition/presentation pathways within the cHL combinations only in the context of clinical trials. microenvironment may turn of significant relevance in determining response to PD1-blockade [12,54]. A potential strategy to improve PD-1 blockade is to Discussion combine this approach with other immunological In this article, experts in HL judged whether the body agents or conventional therapeutics. Studies combining of evidence is sufficient to provide recommendations anti-CTLA-4andanti-PD-1antibodiesareunderway,as regarding how to optimize the approved use of nivo- well as those testing their combination with brentuxi- lumab and pembrolizumab in cHL. The lack of mab vedotin. Based on its important regulatory role on randomized clinical trials testing treatment issues that HLA-class II-dependent antigen presentation, co-target- are currently unmet has forced the Panel to use the ing of the checkpoint protein LAG3 and PD1 is going to methods of consensus to shape the recommendations be clinically exploited in a very near future. presented in this work. As a consequence, the gener- ation of this document is mainly based upon the Acknowledgements expertise and knowledge of experts in the field, coor- The authors thank the patients and their families for dinated by the methods of group decision. their support. An effect of this endeavor was to highlight the new knowledge acquisition that might lead to an optimal Potential conflict of interest: Disclosure forms provided use of PD-1 blockade therapy in cHL. Response evalu- by the authors are available with the full text of this article ation, early treatment, and association therapy are online at https://doi.org/10.1080/10428194.2018.1519808.

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