clinical options in relapsed or refractory hodgkin lymphoma: an updated review

7/25/2019 Clinical Options in Relapsed or Refractory Hodgkin Lymphoma: An Updated Review.

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Review ArticleClinical Options in Relapsed or Refractory Hodgkin Lymphoma:

An Updated Review

Roberta Fedele,1 Massimo Martino,1 Anna Grazia Recchia,2 Giuseppe Irrera,1

Massimo Gentile,3 and Fortunato Morabito2,3

Hematology and Stem Cell ransplant Unit, Azienda Ospedaliera BMM, Reggio Calabria, ItalyBiotechnology Research Unit, Azienda Sanitaria Provinciale di Cosenza, Aprigliano, Italy

Hematology Unit, Azienda Ospedaliera di Cosenza, Cosenza, ItalyCorrespondence should be addressed to Roberta Fedele; [email protected]

Received July ; Accepted October

Academic Editor: Daniel Olive

Copyright Roberta Fedele et al. Tis is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hodgkin lymphoma(HL) is a potentially curable lymphoma, andmodern therapy is expected to successully cure more than % othe patients. Second-line salvage high-dose chemotherapy and autologous stem cell transplantation (auto-SC) have an establishedrole in the management o reractory and relapsed HL, leading to long-lasting responses in approximately % o relapsed patientsand a minority o reractory patients. Patients progressing afer intensive treatments, such as auto-SC, have a very poor outcome.

Allogeneic SC represents the only strategy with a curative potential or these patients; however, its role is controversial. Based onrecent knowledge o HL pathology, biology, and immunology, antibody-drug conjugates targeting CD, small molecule inhibitorso cell signaling, andantibodies that inhibit immune checkpoints are currently explored. Tis review will discuss the clinical resultsregarding auto-SC and allo-SC as well as the current role o emerging new treatment strategies.

1. Introduction

Hodgkin lymphoma (HL) is a potentially curable lymphomawith distinct histology, biological behavior, and clinical char-acteristics. Tomas Hodgkin rst described the disorder in. In the th century, with the realization that the diseaseconsisted o a lymphoid malignancy, it was renamed HL. It

is a relatively rare disease and accounts or approximately% o all malignant lymphomas, with about , estimatednew cases and , estimated deaths per year in the UnitedStates []. Te treatment o HL has evolved over the pastthree decades, andmoderntherapy is expected to successullycure over % o patients []. Second-line salvage high-dose chemotherapy (HDC) and autologous stem cell trans-plantation (auto-SC) have become the standard care orreractory/relapsed HL, leading to long-lasting responses inapproximately % o relapsed patients and in a minorityo reractory patients []. Disease recurrence or progressionafer auto-SC is associated with very poor prognosis []and patients have an estimated average survival o less than

years []. However, because HL is a rare cancer that is highlycurable, the development o new drugs or the treatment oHL has been very slow []. With growing knowledge o HLpathology, biology, and immunology, several therapeutic tar-gets have been identied and are currently under preclinicaland clinical investigation []. Te aim o drug developmentin HL is not only to cure patients, but also to go urther and

decrease the toxic effects o therapy.In this review, we summarize the most recent updates on

the management o patients with relapsed or reractory HLand the role o novel therapeutic approaches. We also discussthe role o consolidation strategies such as HDC and auto-SC and reduced-intensity (RIC) allogeneic stem cell trans-plantation (allo-SC).

2. Autologous Stem Cell Transplantation

According to retrospective and prospective as well as ran-domized studies, HDC ollowed by auto-SC can rescue %to % o relapsed/reractory HL patients [].

Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2015, Article ID 968212, 11 pageshttp://dx.doi.org/10.1155/2015/968212


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Journal o Immunology Research

In the BNLI trial [], relapsed patients were treatedwith conventional dose mini-BEAM (carmustine, etoposide,cytarabine, and melphalan) or high-dose BEAM with auto-SC. Both event-ree survival (EFS) and progression-reesur-

vival (PFS) showed signicant differences in avor o BEAMplus transplant ( = 0.025 and = 0.005, resp.). Inthe GHSG

trial [], patients who relapsed afer chemotherapy wererandomly givenour courses o mini-BEAM+dexamethasone(dexa-mini-BEAM) or two courses o dexa-mini-BEAMollowed by BEAM and auto-SC. Freedom rom treatmentailure (FFF) in years was signicantly better or patientsgiven BEAM and auto-SC (%) than or those on dexa-mini-BEAM (%; = 0.019). Overall survival (OS) opatients given either treatment did not differ signicantly.Recently, the GHSG group [] evaluated the impact osequential HDC beore myeloablative therapy. Patients withhistologically conrmed, relapsed HL were treated with twocycles o dexamethasone, cytarabine, and cisplatin, and thosewithout disease progression were then randomly dividedbetween standard and experimental treatment arms. In thestandard arm, patients received myeloablative therapy withBEAM ollowed by auto-SC. In the experimental arm,patients received sequential cyclophosphamide, methotrex-ate, and etoposide in high doses beore BEAM. Mortalitywas similar in both arms (% and %). With a medianobservation time o months, there was no signicantdifference in terms o FFF ( = 0.56) and OS ( = 0.82)between arms. FFF in years was % and OS was %.Results demonstrated that sequential HDC did not improveoutcome and was associated with more adverse events andtoxicity. Based on the data presented, the authors concludedthat two cycles o intensied conventional chemotherapy(DHAP) ollowed by HDC (BEAM) and auto-SC are aneffective and sae treatment strategy orpatientswith relapsedHL.

On the basis o this study, BEAM is considered thegold standard conditioning regimen or auto-SC. However,due to drug constraints o carmustine, this drug is ofenreplaced by a variety o agents, including otemustine [],bendamustine [], and thiotepa [].

Sweetenham et al. [] published a retrospective analysiso patients with HL who did not undergo remission aferinduction therapy and results were reported to the EuropeanGroup or Bone Marrow ransplantation (EBM). Te -year actuarial OS and PFS rates were % and %, respec-tively, and results were very similar to those reported rom

single-institution series and rom the Autologous Blood andMarrow ransplant Registry (ABMR) []. Te ABMRseries includes patients with HL who have never achievedremission. Te denition o ailure to achieve remissiondiffers rom that in the EBM series, in that it includesonly those patients who had a documented disease progres-sion or tissue conrmation o persistent disease in residualradiographic abnormalities. With a median ollow-up o months rom the date o auto-SC, the -year actuarial PFSand OS rates in this series were % and %, respectively.Te GELAMO CooperativeGroup [] presented the resultso patients treated with an auto-SC or reractory HL.One-year transplant-related mortality (RM) was %. Te

response rate in months afer auto-SC was %. Actuarial-year time to treatment ailure (F) and OS were % and%, respectively. Te presence o B symptoms at auto-SCwas the only adverse prognostic actor signicantly inuenc-ing F. Te presence o B symptoms at diagnosis, MOPP-like regimens as rst-line therapy, bulky disease at auto-SC,

and two or more lines o therapy beore auto-SC adverselyinuenced OS.andem auto-SC or HL has been evaluated in a small

number o studies [] and in the most recent guidelinesrom the American Society orBlood andMarrow ransplan-tation it is not recommended, although urther studies maybe warranted in high-risk patients [].

3. Allogeneic Stem Cell Transplantation

Although there is relatively limited accessible data regardingthe best approach or patients who relapse afer an auto-SC, the available inormation supports the benet o allo-

SC versus standard therapy []. Evidence o a grafversus HL (GVHL) effect comes rom the demonstrationthat the development o graf versus host disease (GVHD)afer allo-SC is associated with a lower relapse rate [, ].Moreover, the most direct evidence or a graf versus malig-nancy effect comes rom the disease responses to donorlymphocyte inusions (DLIs). Peggs et al. [] assessed theimpact o DLI on relapse incidence when administered ormixed chimerism and the utility o DLI as salvage therapywhen given or relapse in consecutive patients withmultiple relapsed or reractory HL, who underwent allo-SCthat incorporatedin vivo -cell depletion. Te results demon-strated the potential or allogeneic immunotherapy with DLIsboth to reduce relapse risk and to induce durable antitumorresponses.

Despite early data showing promisingly low relapse ratesafer allo-SC, the transplantation community was not veryenthusiastic about considering allo-SC or HL patients,because o the exceedingly high nonrelapse mortality (NRM).Registry data [, ] has shown that allo-SC afer myeloab-lative conditioning results in lower relapse rates but signi-icantly higher toxicity than auto-SC. Although the poorresults afer myeloablative conditioning can be explained bythe very poor risk eatures o heavily pretreated patientsincluded in these early trials, high RM has been associatedwith high incidence o GVHD and inections afer transplan-tation. Results o allo-SC can be reasonably optimized with

a better patient selection and the use o targeted and less toxictherapies to achieve an adequate response or patients.

In the last years, the use o RIC has reduced NRMand improved OS [] and the percentage o patients withreractory and relapsed HL treated using this approachhas been growing steadily in Europe []. Robinson et al.[] conducted a retrospective analysis o patients withHL who underwent a RIC allo-SC in order to identiyprognostic actors o outcome. Eighty percent o patients hadundergone a prior auto-SC and % had reractory diseaseat transplant. NRM was associated with chemoreractory dis-ease, poor perormance status, age>, and transplantationbeore . For patients with no risk actors, the -year


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phase I dose escalation trial that enrolled patients withrelapsed or reractory CD+ hematologic malignancies[],objective responses, including CRs, were observed in patients and tumor regression was observed in % o evalu-able patients. Seventy-three percent o patients in that trialhad undergone auto-SC. Brentuximab vedotin (. mg/kg

intravenously every weeks) was subsequently evaluated in apivotal phase study o patients with relapsed/reractoryCD+ HL afer auto-SC []. Objective responses weredocumented in % o patients, with CRs observed in % opatients, as determined by an independent radiology reviewacility. Te estimated -month survival rate was % andthe median PFS was . months. Adverse events associatedwith brentuximab vedotin were typically o grade I/II andwere treated through standard supportive care. Cumulativeperipheral neuropathy, the most meaningul clinical adverseeffect, improved or resolved completely in % o patientsduring the study.

Median OS and PFS were estimated in . months and. months, respectively. Improved outcomes were observedin patients who achieved a CR on brentuximab vedotin,with estimated -year OS and PFS rates o % and %,respectively, in this group o patients []. O the patientswho obtained CR, (%) remain progression-ree afera median o . months (range, . to . months); patients remain progression-ree without a consolidativeallo-SC. Younger age, good perormance status, and lowerdisease burden at baseline were characteristic o patients whoachieved a CR and were avorable prognostic actors or OS.

On the basis o these studies, brentuximab vedotin hasbeen approved or the treatment o adult patients withrelapsed or reractory CD+ HL ollowing auto-SC orollowing at least two prior therapies with auto-SC ormultiagent chemotherapy.

Te randomized, double-blind, placebo-controlled,phase AEHERA study [] demonstrated that brentuximab

vedotin improves PFS when given as early consolidationafer auto-SC in patients with HL with risk actors orrelapse or progression afer transplantation. Te high risko progression afer auto-SC is dened by the presence oprimary reractory HL (ailure to achieve CR), relapsed HLwith an initial remission duration o less than months,or extranodal involvement at the start o pretransplantationsalvage chemotherapy. Compared with historical survivaldata or high-risk patients with HL undergoing auto-SC, the-year OS rate exceeding % in this study is remarkable.

A recent SIE, SIES, GIMO position paper declaresthat there is now evidence or recommending brentuximab

vedotin also in HL patients reractory to salvage chemother-apy who are auto-SCcandidatesand as a consolidation strat-egy afer auto-SC. Te use o brentuximab vedotin in HLafer relapse rom allo-SC or as rst-linetherapy is at presentonly experimental []. Te Expert Panel recommends that,in the approved indications o brentuximab vedotin treat-ment or HL, treatment evaluation must be perormed afer courses, and the subsequent treatment should be determinedaccording to the response. In patients with HL attaining a CR,either an early consolidation program including allo-SC orbrentuximab vedotin therapy continued up to cycles is the

approved indications. It is necessary to perorm clinical trialsto clariy which one o the two strategies is more appropriate.Early allo-SC should strongly be considered in patients withHL attaining a PR. Patients not eligible or transplant shouldbe treated with brentuximab vedotin up to a maximumo cycles. In patients with HL and a stable disease, the

decision to continue brentuximab vedotin should rely ona patient-centered balance between clinical benets andrisks. In patients with HL and a progressive disease, bren-tuximab vedotin therapy should be discontinued and patientsmust be enrolled in clinical trials.

5. Bendamustine

Bendamustine is a biunctional alkylating agent with onlypartial cross-resistance to other alkylatingdrugs,makingit anattractive agent or use in the relapsed setting []. Althoughit was developed in the s and used in Germany orboth HL and non-HL, it has been approved or treatment o

chronic lymphatic leukemia and indolent B-cell non-HL []and limited data exist regarding its activity in HL patients.Moskowitz et al. [] perormed a phase II study evaluatingthe efficacy and toxicity o bendamustine in relapsed andreractory HL. Tirty-six patients were enrolled, and patients were potentially eligible or allo-SC. Bendamustine mg/m was administered on days and o each -daycycle or a total o six cycles o treatment. Te dose o ben-damustine was reduced to mg/m or treatment delays> days because o neutropenia or thrombocytopenia. Tedose was urther reduced to mg/m or subsequent delayso> days or neutropenia or thrombocytopenia. Te mostcommon nonhematologic toxicities were atigue (primarilygrade I) and nausea (primarily grade I). Trombocytopeniawas the most common hematologic toxicity, with % opatients experiencing grade III or IV thrombocytopenia. Teoverall response rate (ORR) or the patients was %,demonstrating that bendamustine is a goodoption orheavilytreated patients with relapsed and reractory HL who couldproceed to consolidative SC. Zinzani et al. [] reportedtwo cases o patients relapsed/reractory afer brentuximab

vedotin were successully treated with bendamustine indicat-ing that patients with HL relapsed/reractory to brentuximab

vedotin therapy may be chemosensitive and may obtaina good response to subsequent bendamustine treatment.Zinzani et al. [], afer these case reports, perormed aretrospective study on heavily pretreated patients with

relapsed or reractory HL, who had all received brentuximabvedotin as their last treatment and who showed disease pro-gression, reractory disease, or early relapse, when retreatedwith bendamustine. Te ORR was .%, with o patients (.%) obtaining a CR. In comparison, the ORRpreviously observed with brentuximab vedotin in the samesubset o patients was much lower (.%).

Considering the promising results o brentuximabvedotin and bendamustine as single drugs on patients withrelapsed/reractory HL and their independent mechanismso action with manageable saety proles, a phase I-IIstudy was perormed evaluating the saety and efficacy obrentuximab vedotin in combination with bendamustine


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or the treatment o patients with HL rst relapse [].Brentuximab vedotin . mg/kg on day in combination withbendamustine mg/m on days and o -week-cyclesor up to cycles had a manageable saety prole withpremedication. Te CR rate o the combination was %and ORR %. Te majority o CRs (/ patients) were

documented afer cycles o combination therapy and, inthese patients, stem cell mobilization and collection wereperormed with success. Tese data indicate a promisingapproach or maximizing responses prior SC in relapsed/reractory HL patients afer rontline therapy. Promisingdata were reported by OConnor and colleagues [] on thecombination o brentuximab vedotin and bendamustine inrelapsed/reractory HL and anaplastic large -cell lymphoma.

6. Panobinostat and Mocetinostat

Agents that target acetylases may regulate several onco-genic pathways including cell cycle progression, cell survival,

angiogenesis, and antitumor immunity. Panobinostat andmocetinostat target histone deacetylase (HDAC) and theseagents may be effective in patients with HL by modulatingserum cytokine levels and the expression o PD- on intratu-moral -cells.

Based on promising results rom a phase I study thatincluded patients with relapsed HL [], a large pivotalinternational phase II study was initiated. Oral panobinostatwas administered at a dose o mg three times per week,every week, in -day cycles. Dose delays and modicationsor management o adverse events were permitted, butthe lowest dose allowed on study was mg. Efficacy wasevaluated every cycles by imaging studies. Surprisingly,patients were enrolled in less than one year. Te median agewas years (range, ), and the median number o priorchemotherapeutic regimens was (range, ). Importantly,the median time to relapse afer the rst auto-SC was only months, which represents a poor prognostic indicator.Moreover, % o the patients did not respond to their lastprior therapy. welve patients also received prior allo-SC.

In a phase II study, patients with relapsed and rerac-tory HL received mg o panobinostat orally three timesper week []. reatment with panobinostat was effective astumor reductions were seen in % o patients, and ORswere achieved by patients (%). Tirty patients (%)had partial responses to treatment and ve patients (%)had CRs. Te median duration o response was . months,

and the median PFS was . months. Te treatment wasreasonably well tolerated with common drug-related gradeI/II adverse effects as diarrhea, nausea, atigue, vomiting,and anorexia. Common drug-related grade III/IV adverseevents were thrombocytopenia, anemia, and neutropenia.Te thrombocytopenia was manageable and reversible withdose hold and modication.

Considering the synergistic activity o HDAC inhibitorswith other therapies [, ], association studies o HDACinhibitors combined with chemotherapy, monoclonal anti-bodies, and small molecule inhibitors will be evaluated. Aphase I study o panobinostat combined with lenalidomidein relapsed HL is ongoing [].

Te saety and efficacy o mocetinostat were recentlyevaluated in a phase II study in patients with relapsedclassical HL []. Mocetinostat was given orally times perweek ( mg to mg starting doses) or year in the absenceo disease progression or prohibitive toxicity. Initially, patients were enrolled in the mg cohort. Subsequently,

because toxicity-related dose reductions were necessary inthe mg cohort, additional patients were treated witha dose o mg. Te disease control rate was % (eighto patients) in the mg group and % (seven o) in the mg group. Tree o the (%) patients inthe mg group achieved partial remissions. Furthermore,grade III and IV toxicity (mainly atigue, with no signicanthematologic toxicity) was reduced to %. Overall, %o the evaluable patients had some decrease in their tumor sizes.Tese data demonstrate that mocetinostat has a promisingsingle-agent clinical activity with manageable toxicity inpatients with relapsed classical HL.

7. EverolimusTe phosphatidylinositol -kinase/mammalian target orapamycin (PIK/mOR) signaling pathway is one o themost aberrantly activated survival pathways in cancer, mak-ing it an important target or drug development [].Everolimus is an oral antineoplastic agent that targets thispathway, specically the mORcomplex (mORC) that hasbeen shown to be activated in patients with HL. Everolimusnot only may target the signaling pathways within the RScbut may also suppress signaling within the immune inltrateand production o cytokines present in the tumor microenvi-ronment []. Nineteen evaluable patients with relapsed HLwere treated with daily doses o mg everolimus, the ORR

rate was %, and patients achieved PR and CR [].Te median time to disease progression was . months. Temajority o patients had received multiple previous lines otherapy and % o the patients had undergone a previousauto-SC. Grade III adverse events included thrombocytope-nia and anemia. Considering that several signal transductionpathways are critical or the prolieration and survival oneoplastic Hodgkin RSc, including NF-B, JAK-SA, PIK-Ak, and ERK [], a combination o therapeutic approachescapable o targeting RSc along with reactive cells o themicroenvironment might prolong the response duration omOR inhibitors to overcome chemoreractoriness.

8. JAK Inhibitors

Te Janus kinase (JAK) and signal transducer and activatoro transcription (SA) pathway is an active mediator ocytokine signaling in the pathogenesis o solid and hema-tologic malignancies. Te seven-member SA amily iscomposed o latent cytoplasmic transcription actors that areactivated by phosphorylation intertwined in a network withactivation that ultimately leads to cell prolieration. Aberrantactivation o the JAK-SA pathway has been demonstratedin patients with large granular lymphocytic leukemia, aplasticanemia, myelodysplastic syndrome, myeloprolierative dis-orders, and HL []. Pacritinib is an inhibitor o JAK


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kinase with preclinical activity in a variety o hematologicalmalignancies[]. TisJAK inhibitorhas beenused in a phaseI clinical trial in patients with relapsed or reractory Hodgkinor non-Hodgkin lymphoma o any type except Burkitt orcentral nervous system lymphoma []. Doses o to mg/day were tested, and treatment was well tolerated,

with mostly grade I/II toxicities. Among the patientsstudy, the ORR was %, including three partial remissions.In the group o patients with HL, however, none o the patients had a partial remission or better. However, at leastve o the patients with HL did benet rom the treatment,with a decrease in the sites o active disease.

9. Rituximab

Rituximab has shown activity in nodular lymphocyte pre-dominant HL. It is active in relapsed/reractory classicalHL regardless o subtype or degree o CD expressionon RS cells. Rationale o using rituximab in classic HLincludes elimination o CD+ reactive B-cells supportingRS cells, hence depriving malignant cells o survival signalsand potentially increasing host immune responses []. In apilot study [], patients with recurrent, classic HL whohad received a minimum o two prior treatment regimens,regardless o whether H/RS cells expressed CD, weretreated with weekly doses o mg/m rituximab toselectively deplete inltrating benign B-cells. Five patients(%) achieved partial or complete remission that lasted or amedian o . months (range, .. months). Remissionswere observed in patients only at lymph node and splenicsites, but not at extranodal sites, and were irrespective oCD expression by H/RS cells. Furthermore, systemic (B)symptoms resolved in six o seven patients afer therapy.Tese data need to be conrmed in clinical trial.

10. Lenalidomide

Lenalidomide is an immunomodulatory agent with severalmechanisms o action, including direct induction o apopto-sis in tumor cells, antiangiogenic effects, and the modulationo immune cells, such as natural killer cells and -cells [].Limited data suggest that lenalidomide has clinical activityin relapsed/reractory HL. Fehniger et al. [] evaluated relapsed HL patients with mg/day o lenalidomide on days o -day cycles; o patients had prior SCs. TeORR to lenalidomide in the evaluable patients was %,

with one CR. Additional six patients had stable disease (SD)lasting> months, resulting in an overall cytostatic responserate(CR+PR+SD > months) o %. reatment continueduntil progressive disease or an unacceptable adverse event.Kuruvilla et al. [] evaluated lenalidomide in patientswith relapsed or reractory HL. wo patients achieved a PR(%), with additional seven patients having SD (%). Temedian time to progressionin that studywas only . months,with a median OS time o . months. Boll and colleaguesused lenalidomide in patients []. Preliminary resultsinvolving the rst patients have been reported. welvepatients (%) had an objective response ( with a PR andone with a CR), with additional eight patients achieving SD.

Further studies must be made to evaluate the actual efficacyand long-lasting effect o lenalidomide.

Lenalidomide was urther evaluated in HL by the GHSGin a rst-line phase I combination trial or older patients [].Te GHSG aimed to improve the ABVD regimen by replacingbleomycin with lenalidomide (AVD-Rev) to improve both

efficacy and tolerability o the regimen. Patients received ourto eight cycles o AVD-Rev (standard-dose AVD on days and o a -day cycle and lenalidomide daily rom days to ) ollowed by radiotherapy. Te daily lenalidomidedose or the rst patient was mg; maximum dose in thisdose escalation trial was mg. wenty-ve patients with amedian age o were enrolled. Sixty-eight had advancedstage disease, and % had B symptoms at diagnosis. Aferdose-limiting toxicity evaluation o patients, a prespeciedstopping criterion was reached and the recommended doseor a phase II trial was mg. At least one grade III/IVtoxicity occurred in all patients who were treated at doselevels and mg, and o those patients had a gradeIV toxicity. Te -year estimates or PFS and OS were and %, respectively. In summary, AVD-Rev displayed highefficacy and a manageable toxicity prole in older patientswith HL and should be urther evaluated in phase II/III trials.In addition, a phase II trial combining lenalidomide andpanobinostat in patients with relapsed or reractory HL iscurrently recruiting.

11. Anti-PD-1 Antibodies

Te concept that the immune system plays a critical rolein controlling and eradicating cancer and that the immuneresponse, driven by -lymphocytes, is closely regulatedthrough a complicated and delicate balance o inhibitorycheckpoints and activating signals is well established [, ].Programmed death- (PD-) is one o the main immunecheckpoint receptors that, when binding its programmeddeath-ligand- (PD-L), determines the downregulation othe -cell effector unctions, thus contributing to the main-tenance o the tolerance to tumor cells. Te blockade othis pathway by anti-PD- and anti-PD-L antibodies mayprevent this downregulation and allows -cells to maintaintheir antitumor property and ability to mediate the tumorcell death []. Te genes encoding the PD- ligands,PD-L and PD-L, are key targets o chromosome p.amplication, a recurrent genetic abnormality in the nodularsclerosis type o HL. Te p. amplicon also includes

JAK, and gene dose-dependent JAK-SA activity urtherinduces PD- ligand transcription []. Te complementarymechanisms o PD- ligandoverexpression in HL suggest thatthis disease may have genetically determined vulnerabilityto PD- blockade. For these reasons, in a phase I study, extensively pretreated patients with relapsed or reractory HLwere given every weeks mg/kg nivolumab, a ully humanmonoclonal IgG antibody directed against PD- []. Temajority o these patients had previously received an auto-SC, and most had received previous brentuximab vedotin.Drug-related adverse events o any grade were reported in (%) o patients, and grade III drug-related adverseevents were reported in ve (%) patients. O patients,


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: Novel agents evaluated in relapsed/reractory HL patients afer auto-SC.

Author Terapeutic agent(s), study

design Pts.1 Pts.2 Response rate

Median duration oresponse

Younes et al., [] Brentuximab vedotin, phase I ORR = % CR = % . months

Younes et al., [] Brentuximab vedotin, phase II ORR = % CR = % . months or patients

in CRMoskowitz et al., []

Bendamustine, phase II ORR = % CR = % months

Zinzani et al., [] Bendamustine, retrospective ORR = .% CR = % months

LaCasce et al., [] Bendamustine + brentuximab,

phases I-II ORR = % CR = % NR

Younes et al., [] Panobinostat, phase II ORR = % CR = % . months

Younes et al., [] Mocetinostat, phase II ORR = % NR

Johnston et al., [] Everolimus, phase II ORR = % CR = % . months

Younes et al., [] Pacritinib, phase I ORR = % days

Younes et al., [] Rituximab, phase II ORR = % . months

Fehniger et al., [] Lenalidomide, phase II ORR = % monthsKuruvilla et al., []

Lenalidomide, phase II PR = % SD = % Median OS was .

months

Boll et al., [] Lenalidomide phase II NR ORR = % NR

Ansell et al., [] Nivolumab, phase I ORR = % SD = % PFS in weeks was %

Moskowitz et al. []

Pembrolizumab, phase I ORR = % CR = % NR

Pts. 1: total number o patients; Pts. 2: patients who received prior auto-SC; ORR: overall response rate; CR: complete remission; PR: partial remission;SD: stable disease; OS: overall survival; PFS: progression-ree survival; NR: not reported.

our (%) had a CR, (%) had a PR, and three (%) hadSD. In weeks, the rate o PFS was % resulting in a veryhigh proportion o patients achieving an overall response andclinical benet. Te study shows promising results; however,larger trials are needed beore introducing nivolumab in HLtreatment.

A multicenter, open-label, phase Ib clinical trial is ongo-ing evaluating the use o the humanized IgG monoclonalantibody pembrolizumab (ormerly MK-), targeting thePD- receptor, in relapsed or reractory HL patients whoailed brentuximab vedotin treatment, with adequate per-ormance status and organ unction []. Pembrolizumab mg/kg was administered in patients intravenously every

weeks until conrmed tumor progression, excessive toxi-city, or completion o years o therapy. Te drug was welltolerated with no serious adverse events, and only one patientexperienced grade III pain and grade III joint swelling. Temost common drug-related adverse events were grade I/IIrespiratory events (%) and thyroid disorders (%). Treepatients (%) had a CR in weeks. Five additional patients(%) had a PR as the best overall response, or an ORR o%. Four patients (%) experienced progressive disease,although all experienced a decrease in their overall tumorburden. In conclusion, pembrolizumab therapy appears to besae, tolerable, and associated with clinical benet in patientswith heavily pretreated HL.

12. Conclusions

Auto-SC is the standard o care or reractory/relapsed HL,leading to long-lasting responses in approximately % orelapsed patients and in a minority o reractory patients.Patients progressing afer intensive treatments, such as auto-SC, have a very poor outcome.

In the recent past, particularly effective novel therapieshave been identied to treat these patients (able ). Teseagents have all been tested as single drugs acting on differentpathways implicated in the pathogenesis o HL (able ), andthereore an important uture approach will be to combinethem with each other and with standard chemotherapies.

Up to now, brentuximab vedotin is the only FDAapproved drug or the treatment o relapsed HL. Terehave been attempts to combine brentuximab vedotin ina pretransplant setting, either in sequential mode, that is,brentuximab vedotin as a single agent, ollowed by HDC, orconcurrently (i.e., with bendamustine). Either way, there isan improvement in the overall response rate and completeresponse rate with these treatment strategies, and this mayevolve with time to include brentuximab vedotin as part othe induction in pretransplant regimens.

PD-targeted therapies, pembrolizumab and nivolumab,are becoming very good potential drugs, and most likely bothwill be approved in the near uture.


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: Competitive environment.

Agent Indication Development stage Mechanism o action

Brentuximab vedotin HL, NHL Approved or HL and NHL Anti-CD antibody-drug

conjugate

Bendamustine NHL, MM Approved or NHL Biunctional alkylating agent

Panobinostat AML, CML, breast cancer, prostatecancer, MM, idiopathicmyelobrosis, HL, NHL

Approved or MM HDAC inhibitor

Mocetinostat AML, solid tumors, CLL, MDS,

NHL, HL Phase II HDAC inhibitor

Everolimus Solid tumors, transplant rejection,

HL, NHLApproved or solid tumors and

transplant rejection mOR inhibitor

Pacritinib AML, myeloprolierative disorders,

HL, NHL Phase III JAK-inhibitor

RituximabNHL, CLL, rheumatoid arthritis,

HL, granulomatosis, multiplesclerosis, MM

Approved or NHL, rheumatoidarthritis, granulomatosis, CLL

Anti-CD antibody

Lenalidomide MDS, MM, NHL, HL, CLL Approved or MDS, MM Immunomodulator

Nivolumab Melanoma, lung cancer, renalcancer, HL

Phase I Anti-PD antibody

Pembrolizumab Melanoma, lung cancer, renal

cancer, HL Phase I Anti-PD antibody

HL: Hodgkin lymphoma; NHL: non-Hodgkin lymphoma; MM: multiple myeloma; AML: acute myeloid leukemia; CML: chronic myeloid leukemia; MDS:myelodysplastic syndrome; CLL: chronic lymphatic leukemia.

Although these new therapies have clearly demonstratedefficacy in HL, a molecularly targeted drug achieving long-term responses with good tolerability is still lacking. More-over, the majority o patients are young, and in this scenario

we believe that allo-SC can play an important role inselected patients.

Conflict of Interests

Te authors report no conict o interests or unding sources.

Authors Contribution

Quality control o data and algorithms has been done byRoberta Fedele, Massimo Martino, Anna Grazia Recchia,Massimo Gentile, and Fortunato Morabito. Paper preparationhas been done by Roberta Fedele and Massimo Martino.

Paper editing has been done by Roberta Fedele, MassimoMartino, and Anna Grazia Recchia. Paper review has beendone by Roberta Fedele, Massimo Martino, Anna GraziaRecchia, and Fortunato Morabito. Approval o the submittedand nal versions has been done by Roberta Fedele, MassimoMartino, Anna Grazia Recchia, Massimo Gentile, and Fortu-nato Morabito. Giuseppe Irrera contributed to paper reviewand the approval o the submitted and nal versions.

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