Hodgkin lymphoma is derived primarily from B-cell lineage which consists of two subtypes, cHL and nodular lymphocyte predominant Hodgkin lymphoma. HL is a rare type of lymphoma and represents approximately 10% of the lymphomas in the UnitedStates with cHL accounting for nearly 95% of all HL cases (1), which is divided into nodular sclerosis, mixed cellularity, lymphocyte deplete variant, and lymphocyte rich variant (2). Reed-Sternberg cells are the pathognomonic malignant cell associated with cHL and drives continuous cell proliferation via NF-kB transcription factor expression (3, 4). cHL has a bimodal age distribution with a first peak around the age of 20-30 years and the second peak around the age 50-70 years which is more often associated with Epstein-Barr virus, and can occasionally occur in patients aged ≥75 years (5, 6). While cHL is considered highly curable with combination chemotherapy with or without the addition of radiotherapy (7), there are a small proportion of patients who do not respond or relapse after treatment with these therapies, and often high dose chemotherapy (HDC) and AHSCT can be curative in the 2^nd line setting (8–11).

For a select group of patients who have disease relapse after AHSCT or disease that is not chemo sensitive, allogeneic HSCT can provide a curative therapeutic option and the use of lower doses of chemo- or radiotherapy (reduced intensity conditioning, RIC) has significantly reduced toxicity while maintaining good outcomes (12–16). Prior to transplant, the goal of reducing disease burden is achieved with salvage chemotherapy, radiotherapy, or targeted agents (such as brentuximab vedotin or checkpoint inhibitors) and more frequently with a combination of chemotherapy agents or chemotherapy and immunotherapy. There are no randomized trials that directly compare salvage chemotherapy for relapsed HL. Response rates for salvage regimens in various phase II studies ranged from 60 to 85 percent (17). In this review, we will discuss the available novel therapeutic options and their efficacy and safety in the frontline and relapsed setting.

The therapeutic approach to cHL depends on stage at presentation, clinical prognostic factors and comorbidities. Staging is assessed by the Ann Arbor staging system (18). Treatment for early-stage (I-IIA) HL initially consisted of extended field radiation as the standard therapy. In the modern era, due to high relapse rates and significant long-term complications, extended field radiation therapy is no longer used (19). The current standard treatment for early-stage disease is either combination chemotherapy and involved-field radiation therapy (IFRT) or combination chemotherapy alone. The most widely used first-line chemotherapy regimen for cHL is a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) (20). Moreover, Meyer et al. randomized 405 patients with early-stage disease to ABVD alone or subtotal nodal radiation therapy, with or without ABVD therapy (21). Patients who received subtotal nodal radiation therapy had a poorer overall survival (OS) (87% vs 94%), and on long term follow-up, higher rates of death from causes other than HL. A subsequent study randomized 1395 patients with unfavorable disease (large mediastinal masses, extra nodal disease, high erythrocytes sedimentation rate or ≥3 nodal sites) to ABVD for four cycles or standard doses of BEACOPP (bleomycin-etoposide-doxorubicin-cyclophosphamide-vincristine-procarbazine-prednisone) for four cycles, plus either 20 or 30 Gy IFRT (22). Treatment with ABVD plus 30 Gy was superior compared with 20 Gy, however, similar outcomes were seen between 20 and 30 Gy when used with BEACOPP. The German Hodgkin Study Group (GHSG) HD14 trial analyzed 1528 patients to ABVD for four cycles or escalated doses of BEACOPP for two cycles followed by ABVD for two cycles (2 + 2). All patients received 30 Gy IFRT. Freedom from treatment failure was superior with 2 + 2 regimen with a difference of 7.2% at 5 years, however, more acute toxicities were associated with this regimen (23). Based on multiple trials, early-stage favorable disease is generally treated with two cycles of ABVD followed by 20 Gy IFRT (24).

In patients with advanced stage (IIB-IV) disease, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, and prednisone) was initially utilized for patients who progressed after radiation therapy and demonstrated an OS of 48% at 20 years (25). To improve efficacy and minimize toxicity, the ABVD regimen was developed. Multiple randomized studies have compared ABVD to MOPP and ABVD alternating with MOPP, the complete remission rate and freedom from progression was worse for patients receiving MOPP alone (26–29). The ABVD regimen showed superiority with less toxicity and is the most common treatment of choice for patients with advanced HL. The GHSG HD18 trial developed an escalated regimen for advanced-stage disease that consist of dose escalated BEACOPP which has shown higher response rates and progression free survival (PFS) in comparison to ABVD (30). Even though both regimens are associated with late toxic effects, such as secondary malignancies, infertility, cardiovascular disease and lung injury, these sequelae are more common with eBEACOPP (31–33). A randomized comparison of ABVD and BEACOPP of 331 patients with advanced stage HL reported the 7-year rate of freedom from first progression was 85% among patients treated with BEACOPP and 73% among patients treated with ABVD (P=0.004) (34). After completion of planned therapy, the 7-year rate of freedom from a second progression was reported as 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year OS was 89% and 84%, respectively (P=0.39). Notably, severe adverse events were more common in the BEACOPP group than in the ABVD group. Recent trials have used positron emission tomography (PET) scans to identify advanced stage patients who may benefit from intensification or de-escalation of therapy, and the RATHL study is an example of this approach (35). In this study, 1214 patients with advanced HL had an interim PET scan following two cycles of ABVD therapy with those who had a negative scan (Deauville score (DS) 1-3) being randomized to receive ABVD or AVD (without bleomycin) for four more cycles. Patients with a positive PET scan (DS 4 or 5) proceeded to intensification therapy with either four cycles of BEACOPP or three cycles of escalated BEACOPP, followed by a repeat PET scan, if negative, patients received two further cycles of BEACOPP or one cycle of eBEACOPP. In patients with a negative interim PET scan, the 3-year PFS and OS rates in the ABVD group were 85.7% and 97.2% respectively, with similar outcomes in the AVD group with PFS and OS rates of 84.4% and 97.6%, respectively. The AVD group had less pulmonary toxicity. In patients with a positive interim PET scan, intensification of therapy to BEACOPP resulted in 3-year PFS rate of 67.5% and OS rate of 87.8%, suggesting that strategy of response-adapted therapy in HL improves outcomes.

While intensification of therapy to improve efficacy and safety in patients with advanced stage HL has been studied in the past, a more recent approach has been to add novel agents to standard chemotherapy regimens in the frontline setting, include brentuximab vedotin (BV) and PD-1 blocking antibodies. BV is an antibody-drug conjugate targeting CD30 expressed on the cHL cell surface and can be used in combination with standard regimen. The binding of BV to CD30 on the tumor cell membrane triggers a cascade of events which results in apoptotic death of the CD30-expressing cell (36). Checkpoint inhibitors exploit the well-known genetic alterations at 9p24.1 in cHL that leads to the overexpression of the ligands of programmed death-1 (PDL-1), consequently, PD-1 inhibitors have successfully been used to target the PD-1 axis (37–42).

The ECHELON-1 trial assessed the safety and efficacy of A+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) versus ABVD in patients with stage III or IV cHL (43). In this trial, 1334 patients were randomized to receive up to 6 cycles of A+AVD (n=664) or ABVD (n=670). An updated analysis of the trial was presented at the 2022 ASCO annual meeting by the lead author Ansell et al. (44) reported the 6-year PFS of 82.3% with A+AVD and 74.5% with ABVD (hazard ratio [HR] 0.678, 95% CI 0.532-0.863). The 6-year OS rates were 93.9% and 89.4% with A+AVD vs ABVD, respectively, favoring A+AVD over ABVD (HR 0.590, 95% CI 0.396-0.879). Fewer secondary malignancies and more live births were reported with A+AVD. On the basis of these findings, the study recommends A+AVD over ABVD for patients with previously untreated stage III/IV cHL. A relatively recent phase II study of pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 (PD-1) protein evaluated outcomes in newly diagnosed cHL when combined with chemotherapy (45). Thirty patients (n=12 with early unfavorable stage and n=18 with advanced stage) were treated with 3 cycles of pembrolizumab monotherapy followed by doxorubicin, vinblastine, and dacarbazine (AVD) for 4 to 6 cycles. After cycle 3 of pembrolizumab monotherapy, 11 patients (37%) showed complete metabolic response (CMR), and 7 of 28 (25%) patients had >90% reduction in metabolic tumor volume on PET scans. All patients achieved CMR after 2 cycles of AVD and at a median follow-up of 22.5 months, there were no changes in terms of therapy, progressions or deaths. The most common adverse events were grade 1 rash and grade 2 infusion reactions. The result of this study suggests that pembrolizumab monotherapy followed by AVD was both effective and safe in patients with newly diagnosed cHL.

Approximately 20-30% of patients with cHL will be refractory to or relapse following frontline treatment (16). Salvage chemotherapy followed by HDC and AHSCT is the standard therapeutic option for patients with r/r cHL that is responsive to chemotherapy. Several studies have proven that HDC followed by AHSCT produce a better long-term disease-free survival and improved outcome than expected with conventional chemotherapy (8, 9, 46, 47). In a randomized trial by Schmitz et al, patients with relapsed Hodgkin’s disease were assigned to two cycles of Dexa-BEAM (dexamethasone and carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and AHSCT in patients with chemosensitive disease. Freedom from treatment failure at 3 years was 55% for BEAM-AHSCT cohort compared with Dexa-BEAM (34%, P=0.019). OS did not differ significantly. Patients with disease progression after AHSCT have a poor prognosis with a median survival of 2.4 years (10, 48, 49). Relapse predictors post-AHSCT include relapse within 12 months of initial treatment, extra nodal disease, bulky disease, active disease at the time of transplant, primary refractory disease, and presence of B symptoms from lymphoma (50, 51).

Anti-PD-1 agents have been used extensively to treat cHL. Camrelizumab, a novel anti-PD-1 immune checkpoint inhibitor has been evaluated in a multicenter, phase II study in 75 patients with r/r cHL with median follow-up of 36.2 months (93). Median PFS was 22.5 months and 36-month OS rate was 82.7% (95% CI 72.0-89.5). The most common toxicity was grade 1 or 2 reactive capillary endothelial proliferation with spontaneous regression. A separate multicenter phase II study evaluated the efficacy and safety of GLS-010 or Fiberesima, an anti-PD-1, in Chinese patients with r/r cHL (94). The 12-month PFS and OS rate were 78% (95% CI 67.5-85.6) and 99% (95% CI 91.9-99.8), respectively. Treatment-related adverse events occurred in 92.9% of participants with grade III in 28.2% and most common were abnormal hepatic function, hyperuricemia and neutropenia. However, there is limited data on the long-term survival outcome of those patients after remission with immune-checkpoint inhibitors.

Treating r/r cHL remains challenging and multiple agents have been explored in this space, and one such agent are histone deacetylation (HDACs) inhibitors which function by blocking post-transcriptional histone modification in regulating gene transcription (95). Vorinostat (SAHA) inhibits STAT6 phosphorylation and transcription in HL cell lines which leads to decreased expression and secretion of Th2-type cytokines and chemokines (TARC and IL-5) and converse increase in Th1-type cytokines/chemokines (IP-10) (96). The Southwest Oncology Group (SWOG) reported on a phase II study of 25 patients with relapsed HL treated with single agent Vorinostat (97). While it was well tolerated, it only produced modest clinical activity, 1 patient (4%) achieving a PR and median PFS was 4.8 months. Mocetinostat (MGCD-0103) is a selective inhibitor of HDAC 1, 2, 3 (class I) and 11 (class IV) isoforms, which causes hyperacetylation of histones, and selectively induce apoptosis and cell cycle blockade in various cancer cell lines in a dose-dependent manner (98). The safety and efficacy of Mocetinostat was evaluated in a phase II study with an overall disease control rate of 34.8% and 25% for the 110-mg and 85-mg cohorts, respectively (99). After at least 2 cycles of therapy, 81% had a decrease in tumor measurements, however, 47% discontinued therapy due to disease progression (57% in the 85-mg cohort and 34% in 110-mg cohort). Panobinostat (LBH 589) is a pan-deacetylase inhibitor targeting epigenetic and non-epigenetic oncogenic pathways (100). Panobinostat was evaluated in a phase II study of 61 patients with r/r HL, and 53 patients completed two or more cycles of therapy and had at least one post-baseline imaging studies. Responses include one CR and 10 PR, with up to 92% decrease in tumor burden. The most common grade 3 and 4 adverse events were thrombocytopenia (77%), anemia (20%) and neutropenia (16%). In a similar study, 129 heavily pretreated patients were treated with Panobinostat with median time to response (TTR) of 2.3 months (71). Tumor reduction occurred in 74%, including 23% PR and 4% CR. Median PFS was 6.1 months and 1-year OS rate was 78%. Other HDAC inhibitors include Entinostat (SNDX-275) and ITF 2357 have shown encouraging clinical activity in r/r HL (101, 102).

Lymphocyte-activation gene 3 (LAG-3) is nearly always expressed in the tumor microenvironment of cHL and inhibitors of LAG-3 are now in clinical trials. In vitro studies have shown that anti-PD1 immunotherapy-resistant HL has CD8 lymphocytes depleted in microenvironment and overexpress the LAG-3 on CD4+ helper T lymphocytes (103). Timmerman et al. evaluated the safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, given with pembrolizumab every 3 weeks to 33 patients with r/r cHL refractory to anti-PD-1 therapy (104). At a median follow-up of 16.5 months, ORR for patients receiving favezelimab 800 mg was 31%, CR 7%, PR 24% and 66% of the responders had an anti-PD1-based regimen as most recent line of therapy. For all patients, median PFS and OS were 9-mo and 26-mo respectively, while 12-mo PFS and OS rates were 39% and 91% respectively. The most common adverse events were non-hematologic (hypothyroid, nausea, fatigue, etc). Another interesting target is the T-cell immunoglobulin and ITIM domains (TIGIT), which is an immune checkpoint receptor known to negatively regulate T cell functions and highly co-expressed with PD-1 on both CD4 and CD8 T cells in cancers (105). A study conducted by Annibali et al, 19/34 (56%) HL patients were TIGIT positive and of those, 16 (84%) were also PD-1 positive. Out of 15 TIGIT negative, only 4 (27%) were PD-1 positive, but (100%) were PD-L1 positive. Blockade of TIGIT with vibostolimab (MK-7684) has demonstrated antitumor activity in multiple pre-clinical tumor models. A multicohort, phase II study (106) is currently enrolling patients to evaluate the safety and efficacy of vibostolimab with pembrolizumab in patients with r/r cHL (NCT05005442). Camidanlumab tesirine is an anti-CD25 antibody drug conjugate that has been evaluated in r/r cHL. A recent phase I study explored camidanlumab tesirine in a highly pretreated patient population administered once every 3 weeks (107). Overall response rate was 71.4% and CR 48.6% in cHL cohort at 45 µg/kg camidanlumab tesirine with a median follow-up of 9.2 months. Toxicities were dose limiting with most common being rash, anemia, pyrexia and increased γ-glutamyl transferase. Five of 133 patients (3.8%) developed serious neurologic events of Guillain-Barré syndrome (GBS)/polyradiculopathy considered likely immune-related and at least possibly study-drug related but without correlation to dose. Treatment of relapse and refractory cHL remains an unmet need and further studies are needed to evaluate novel agents. A summary of recently completed or ongoing clinical trials of novel agents is shown in Table 3 .

The standard of care at first relapse after frontline therapy is HDC followed by AHSCT as part of salvage therapy. Patients who are eligible and achieve a complete metabolic response should proceed to AHSCT in second remission as the treatment related mortality is significantly lower when compared to alloHSCT. More recently with the availability of newer agents, the timing of alloHSCT is less clear. The decision considering alloHSCT should be individualized given the risk and potential benefit, however, in a selected group of patients it is potentially curative. We recommend alloHSCT be considered in all patients who have relapse of disease post AHSCT or are ineligible for AHSCT due to insufficient disease response with the caveat that patients must have responding lymphoma prior to proceeding to alloHSCT. The role of alloHSCT in patients with r/r cHL has been controversial due to high transplant-related mortality (TRM) as well as transplant related complications associated with acute and chronic graft-versus host disease (GVHD) (108). However, reduced-intensity conditioning (RIC) alloHSCT has shown a promising result with reduced TRM in patients with r/r cHL. In a clinical trial by Alvarez et al, 40 patients were treated with RIC alloHSCT demonstrated 2-year OS and PFS 48% ± 10% and 32% ± 10%, respectively (109). In chemo sensitive disease, the results were even better, 63% ± 12% and 55% ± 16%, respectively. In a phase II study (HDR-ALLO study), 92 patients with r/r cHL were treated with salvage chemotherapy followed by RIC alloHSCT, PFS rate was 48% at 1 year and 24% at 4 years (110). Patients who were allografted in complete remission, OS rate was 71% at 1 year and 43% at 4 years. The incidence of relapse rate was lower in patients with chronic GVHD. The addition of cyclophosphamide post-transplant showed better outcomes with 3-year OS, PFS, relapse rate and 1-year non-relapse mortality (NRM) rates of 63%, 59%, 21% and 20%, respectively (111). Post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvement in PFS and GRFS.

Patients with cHL with r/r disease may benefit from alloHSCT, but many lack a matched sibling donor (MSD). A study conducted by Ahmed et al. included 596 adult patients who received a first RIC alloHSCT using either a haplo-PTCy (n=139) or MSD/calcineurin inhibitor (CNI)-based (n=457) approach (112). On multivariate analysis, no significant difference was seen between haplo/PTCy and MSD/CNI-based approaches in terms of OS (HR 1.07, P=0.66) or PFS (HR 0.86, P=0.22). The haplo/PTCy platform was associated with higher risk of grades II to IV acute GVHD (OR 1.73, P=0.007) however, the risk of grades III to IV acute GVHD was not different between the 2 cohorts. The haplo/PTCy cohort had a significant reduction in chronic GVHD risk (HR 0.45, P < 0.001) and a significant reduction in relapse risk (HR 0.74, P= 0.03). A European study retrospectively compared the outcome of patients with HL who received PTCy-based haplo alloHSCT (n=98) vs HLA MSD (n=338) vs HLA-matched unrelated donor (MUD) (n=273) transplantation (113). The median follow-up of survivors was 29 months. Haplo alloHSCT was associated with a lower risk of chronic GVHD (26%) compared with MUD (41%, P=0.04). The 2-year cumulative incidence of relapse progression was 39%, 49%, and 32% in haplo, MSD and MUD, respectively. The two-year OS, PFS were 67% and 43% for haplo, 71% and 38% for MSD, and 62% and 45% for MUD, respectively. The rate of extensive chronic GVHD and relapse-free survival was significantly better for haplo (40%) compared with MSD (28%, P=0.049) and similar to MUD (38%, P=0.59). Based on the results of these studies there is support that haplo/PTCy alloHSCT in cHL results in survival comparable to traditional alloHSCT approaches with potentially better outcomes in terms of GVHD and relapse.

Chimeric antigen receptor (CAR) T-cell against CD-30 is a directed novel cellular therapy where patient’s own immune cells are engineered ex vivo to recognize target cancer antigens. A phase I trial evaluated 18 heavily pretreated patients who received anti-CD30 CAR T-cells (120). This study used multiple combinations of drugs for conditioning. Patients received a conditioning regimen that included 3 forms: (I) FC (fludarabine, 3 daily doses of 25 mg/m² + cyclophosphamide, at a total dose of 30 mg/kg) to deplete endogenous leukocytes; (II) GMC-like chemotherapy (gemcitabine 1 g + mustargen 10 mg + cyclophosphamide, at a total dose of 30 mg/kg) to inhibit the disease progression in a short time and eliminate endogenous leukocytes; and (III) PC (nab-paclitaxel 150 mg/m² + cyclophosphamide 30 mg/kg) to deplete the stromal compartment and eliminate endogenous leukocytes. The individual absolute dose was administrated at the discretion of a physician according to treatment history and bone marrow tolerance. The ORR was 39% (all partial responders) with 28% of patients showing stable disease at two months and a median PFS of 6 months. All patients experienced Grade 1 or 2 febrile syndrome at the time of infusion that resolved without intervention. In another phase I/II trial of anti-CD30 CAR T-cells in r/r cHL, 41 heavily pretreated patients underwent lymphodepletion with varying regimens of bendamustine alone, bendamustine-fludarabine or cyclophosphamide-fludarabine (121). The ORR was 72% with 60% of patients attaining a CR. The one-year PFS and OS rates were 41% and 94%, respectively. Five patients had a CR more than a year out from infusion and more than a third showed durable response. The most common adverse event was cytopenia related to lymphodepletion with a favorable profile in terms of CART related toxicity. Subsequently, a phase II, multi-national trial (CHARIOT NCT04268706) which is ongoing, reported in abstract form on 15 patients with r/r cHL treated with CD30 CART (122). This was a heavily pre-treated patient population with 6 median prior therapies, with a range of 4 to 19. At the time of reporting, 12 patients had received CD30 CART infusion and were evaluable, the ORR at Day 42 was 100% (5/5), CR and PR rates were 80% (4) and 20% (1), respectively. The most common adverse events were hematologic and without significant CART associated toxicity such as cytokine release syndrome or neurotoxicity.

Voorhees and colleagues evaluated factors that were associated with PFS after anti-CD30 CAR T-cells therapy in r/r cHL (123). The tumor burden measured by using Flourine-18 fluorodeoxyglucose (F-FDG) PET imaging or metabolic tumor volume (MTV) showed a direct correlation between MTV and PFS. Patients with higher MTV (>60 ml) before CAR T-cells therapy and lymphodepletion had a lower 1-year PFS (14%) compared to those with a low MTV (58%) and interestingly, patients who responded to bridging therapy with a decrease in MTV had an improved 1-year PFS (40%) compared to those who showed no reduction in tumor burden post bridging therapy (1-year PFS 0%). However, bridging therapy was not associated with a significant difference in PFS neither the persistence of anti-CD30 CAR T-cells. In another study by Voorhees and colleagues, they evaluated the role of checkpoint inhibitors in patients with disease progression following CAR T-cell treatment and found a clinical benefit in all patients including those that had not responded to checkpoint inhibition prior to CAR T-cell therapy, presumably due to reprogramming and reactivating CAR T-cells that persisted after the initial infusion (124).

Other types of cellular therapy have also been explored with encouraging results of an ongoing trial with natural killer (NK) cells derived from umbilical cord blood (CB) and activated with a novel bispecific antibody known as AFM13 (targeting CD16A and CD30) demonstrated safety and efficacy in r/r CD30+ lymphoma (NCT04074746) (125). Patients received two cycles of fludarabine/cyclophosphamide followed by AFM13-precomplexed CB-NK cells (day 0) and 3 weekly intravenous infusion of AFM13. Eighteen patients completed both planned cycles and therapy was well tolerated. The ORR was 89% and at median follow-up of 6 months, PFS/OS across all dose levels were 52% and 81%, respectively. All patients treated at the recommended dose for phase II responded, for an overall response rate of 100% with 62% in complete remission. Expansion of CB-NK cells occurred as early as 3 days post infusion. The preliminary results of this study indicate high tolerability and activity. In summary, randomized clinical trials are needed to assess the long-term safety and efficacy of these novel cellular therapies.

In the frontline setting, patients are treated according to age. For early-stage HL, we generally recommend a combined modality approach with chemotherapy (ABVD and/or eBEACOPP) and radiation, or risk-adapted PET-guided approach. Patients aged <60 years with advanced stage disease and no significant comorbidities, we recommend AAVD. Young women with disease in the thorax who may receive radiation exposure to breast tissue, we recommend chemotherapy alone approaches. In patients aged >60 years, the intensity of therapies is based on comorbidities. In the relapsed setting, chemoimmunotherapeutic or chemotherapy-free approaches can be used. AHSCT is considered the standard treatment for patients with r/r cHL and among those who experience r/r cHL after HDC/AHSCT, single agent and combinations with novel agents including BV and/or PD1 has demonstrated substantial efficacy and favorable toxicity. For a select population of patients, alloHSCT should be considered. Ongoing trials are evaluating the efficacy of CAR T-cells therapy in r/r cHL.

Classical Hodgkin lymphoma is a rare lymphoma, and while the majority of patients will respond to frontline therapy, up to 30% of patients may experience relapsed or refractory disease. The therapeutic approach to each patient depends on clinical prognostic factors, comorbidities and toxicity profile. Undeniably high dose chemotherapy and AHSCT remains the standard consolidation for patients whose disease responds to salvage systemic therapy, however, treatment options have dramatically changed over the years. The integration of novel therapies with standard regimen has achieved higher response rates and durable benefits with tolerable toxicity. Brentuximab vedotin and checkpoint inhibitors have shown survival benefits in patients whose HL has relapsed after AHSCT. More recently, CAR T-cell therapy has demonstrated exceptional response rates and safety, however longer follow up is required to confirm durability of responses. The new era of immune-chemotherapy and targeted agents continues to provide significant clinical benefits, although there is still a subset of patients with refractory disease who do not experience durable long-term responses with current treatment paradigms, and this remains a significant unmet need.

The authors confirm contribution to the paper as follows: study conception and design: SA and FU; data collection: FU, DD, NO, and OO; draft manuscript preparation: all authors.