An update on emerging drugs for Hodgkin lymphoma.

Review

An update on emerging drugs for Hodgkin lymphoma

Expert Opin. Emerging Drugs Downloaded from informahealthcare.com by Karolinska Institutet University Library on 11/17/14 For personal use only.

Bastian von Tresckow & Volker Diehl† †

University of Cologne, Internal Medicine I, Cologne, Germany

1.

Background

2.

Medical need and existing treatment

3.

Market review

4.

Current research goals

5.

Scientific rationale

6.

Competitive environment

7.

Potential development issues

8.

Conclusion

9.

Expert opinion

Introduction: Most patients with Hodgkin lymphoma (HL) are cured with modern combined modality first-line treatments. Even ~ 50% of patients with relapsed/refractory HL can be cured with high-dose chemotherapy (HDCT) and autologous stem cell transplantation. However, chemotherapy and radiotherapy cause significant acute and long-term side effects and patients relapsing after HDCT have a dismal prognosis. New drugs are therefore needed to reduce the toxicity of first-line treatments and to increase the efficacy of relapse treatments. Moreover, new drugs are needed for the treatment of older patients with HL because results with current treatments are disappointing. Areas covered: This article discusses promising new drugs for the treatment of classical HL that have been evaluated in the last years. There is a focus on the antibody drug conjugate brentuximab vedotin and its potential for the future treatment of HL. Moreover, data on the histone deacetylase inhibitors panobinostat and mocetinostat, the mammalian target of rapamycin inhibitor everolimus, the Janus kinase 2 inhibitor SB1518 and the immunomodulatory agent lenalidomide are summarized. Expert opinion: Besides improving the prognosis of relapsed patients, new drugs should be used to replace the most toxic compounds in first-line therapy to reduce acute and long-term toxicities of the treatment. Keywords: brentuximab vedotin, CD30, everolimus, Hodgkin lymphoma, Janus kinase 2, lenalidomide, mocetinostat, panobinostat Expert Opin. Emerging Drugs (2014) 19(2):215-224

1.

Background

Hodgkin lymphoma (HL) is a relatively rare hematologic malignancy with an annual incidence of ~ 2/100,000 in Western countries [1]. Although generally rare, it is one of the most frequent cancers in young adults. The incidence is stable with a slight male excess. The age distribution of HL is bimodal with a peak at the ages of 25 and a second peak arising at the age of 60. Rates vary internationally: estimated 2002 incidence rates ranged from 2.3 and 1.9 per 100,000 males and females in more developed regions, to 1.0 and 0.5 per 100,000 males and females in less developed regions [2]. The histological hallmark of classical HL is the presence of large, malignant ‘Hodgkin--Reed-Sternberg’ (HRS) cells that are surrounded by a nonmalignant microenvironment of lymphocytes, macrophages, mast cells, fibroblast and other reactive cells [3]. Virtually, all HRS cells abundantly express the CD30 antigen, which is therefore routinely determined by the pathologist if HL is suspected. In addition to classical HL, 5% of patients with HL present with a different histology and clinical course and are classified as nodular lymphocyte predominant HL [4]. This review focuses on classical HL only. HL is one of the cancers with the highest chance of cure. Standard treatment of adult HL consists of classical chemotherapy with either ABVD (adriamycin [= doxorubicin], bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin [= vincristine], procarbazine and 10.1517/14728214.2014.912277 © 2014 Informa UK, Ltd. ISSN 1472-8214, e-ISSN 1744-7623 All rights reserved: reproduction in whole or in part not permitted

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prednisone). Chemotherapy is often followed by radiotherapy in a combined modality setting, but current therapeutic trials aim at the omission of radiotherapy in selected patients based on positron emission tomography. Even at relapse, a significant proportion of patients can be cured with high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). However, this therapy is not suitable for older patients or patients with significant comorbidity and new effective drugs with a favorable side effect profile are thus needed. The US FDA has approved no new agent for the treatment of HL for almost 30 years. In 2011, the antiCD30 antibody drug conjugate (ADC) brentuximab vedotin was approved for relapsed and refractory HL in patients after HDCT-failure or in patients with at least two prior lines of therapy. Current trials evaluate brentuximab vedotin in firstand second-line therapies in combination with standard chemotherapy as well as in maintenance therapy. Other nonchemotherapeutic drugs such as everolimus and panobinostat were recently evaluated in Phase II trials in patients with relapsed/refractory HL. 2.

therapeutic approaches are warranted. New drugs should aim to inhibit specific receptor interactions on the surface of the tumor cells and driving pathways in the malignant HL cells to avoid unspecific side effects known from chemotherapy or antibody-drug conjugates. 3.

Market review

In August 2011, brentuximab vedotin, an anti-CD30 ADC, was the first pharmacotherapy for the treatment of patients with HL approved by the FDA since ~ 30 years. Brentuximab vedotin was developed and is marketed in the US by Seattle Genetics, Inc. (Bothell, WA, USA). The licensee for marketing in Europe and the rest of the world, Takeda Pharmaceutical Company Limited (Takeda, Osaka, Japan), obtained European market approval by the European Medicines Agency for brentuximab vedotin in October 2012. In January 2014, Takeda has received approval of brentuximab vedotin from the Japanese Ministry of Health, Labour and Welfare for the treatment of patients with CD30-positive relapsed or refractory HL.

Medical need and existing treatment 4.

At first diagnosis, > 80% of HL patients can be cured [5-7]. Although highly effective, current combined modality treatment regimens for first diagnosed HL patients can induce severe, life-threatening treatment-related side effects, which include organ toxicity and secondary malignancies. Thus, the treatment approaches must be carefully balanced between optimal disease control and the risk of long-term sequelae [8]. In a small proportion of patients, the disease is primary refractory to the treatment or will subsequently relapse. HDCT followed by ASCT has become the standard therapy for patients with refractory or relapsed HL and leads to long-term cure in ~ 50% of patients [9]. Despite these advances, patients relapsing after ASCT have a dismal prognosis and treatment is generally regarded as palliative [10,11]. Similarly, treatment of patients who cannot undergo HDCT with ASCT due to age and/or comorbidities has very limited curative potential [12]. Due to demographic changes, the group of older patients with HL is currently becoming more and more important. With the arrival of the anti-CD30 antibody-drug conjugate brentuximab vedotin [13] a new effective treatment with high response rates is available for patients with recurrence after ASCT as well as for patients who are not eligible for ASCT. However, most patients still relapse after this therapy and the median progression-free survival (PFS) in a large Phase II trial with brentuximab vedotin in relapsed HL patients was only 5.6 months [14]. Dose-reduced allogeneic transplant (RICallo) is a potentially curative option in this patient group; however, this treatment so far shows limited efficacy and causes significant side effects in a large proportion of patients [15]. Thus, patients relapsing after or not eligible for ASCT still represent an area of highly unmet medical need and new 216

Current research goals

The standard first-line treatment of HL consists of conventional chemotherapy followed by radiotherapy since decades. These non-targeted therapies induce significant acute and long-term toxicities. Our goal must be to reduce these toxicities while maintaining the high cure rates by replacing chemo- and radiotherapy by more target-directed agents. The situation in relapsed/refractory HL is different: there is still an unmet need because cure rates approximate 50% and have thus to be improved. This goal might be achieved by combining the current HDCT and ASCT therapies with new, targeted agents. Moreover, targeted therapies with tolerable side-effect profiles are needed in patients not suitable for HDCT and ASCT, especially older patients or in countries where thus far HDCT/SCT is not yet available in sufficient quantities (e.g., parts of Asia, Africa and South America). Finally, patients with relapse after HDCT and ASCT still have a dismal prognosis and even with the new drug brentuximab vedotin durable responses are rarely achieved. Thus, new strategies are needed to achieve long-term remissions or even cures in these patients. 5.

Scientific rationale

Before the advent of brentuximab vedotin, no effective monoclonal antibody existed for the treatment of HL. Although the malignant HRS cells of HL abundantly express the CD30 antigen and anti-CD30 antibodies showed effective tumor cell killing in vitro [16], naked anti-CD30 antibodies failed to induce convincing responses in clinical trials [17]. The anti-CD30 ADC brentuximab vedotin was, therefore, developed. Brentuximab vedotin selectively binds to

Expert Opin. Emerging Drugs (2014) 19(2)



Table 1. Competitive environment. Compound

Company

Brentuximab vedotin

Seattle genetics

Everolimus

Novartis

Lenalidomide

Celgene

Mocetinostat

MethylGene (now Mirati Therapeutics) SBIO

Pacritinib (SB1518)

Panobinostat

Novartis

Chemical name

Immunoglobulin G1, anti-(human CD30 (antigen)) (human-mouse monoclonal cAC10 k1-chain), disulfide with human-mouse monoclonal cAC10 g-chain, dimer, complex with (S)-N-((3R,4S,5S)-1-((S)2-((1R,2R)-3-(((1S,2R)1-hydroxy-1-phenylpropan2-yl)amino)-1-methoxy2-methyl-3-oxopropyl) pyrrolidin-1-yl)-3-methoxy5-methyl-1-oxoheptan-4-yl)N,3-dimethyl-2-((S)-3-methyl2-(methylamino)butanamido) butanamide Rapamycin, 42-O(2-hydroxyethyl)- [CAS]

2,6-Piperidinedione, 3-4-amino-1,3-dihydro1-oxo-2H-isoindol-2-yl N-(2-Aminophenyl)4-({[4-(pyridin-3-yl)pyrimidin2-yl]amino}methyl)benzamide 11-(2-Pyrrolidin-1-ylethoxy)14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6). 1(8,12))heptacosa-1(25), 2(26),3,5,8,10,12 (27),16,21,23-decaene (2E)-N-hydroxy3-[4-({[2-(2-methyl-1H-indol3-yl)ethyl]amino}methyl) phenyl]prop-2-enamide

Indication

Development stage

Mechanism of action

HL, NHL

Approved for HL and NHL

Anti-CD30 ADC

Solid tumors, transplant rejection, HL, NHL

Approved for solid tumors and transplant rejection Approved for MDS, NHL and MM

mTOR inhibitor

Immunomodulatory drug

AML, Solid tumors, CLL, MDS, NHL, HL

Phase II

HDAC-inhibitor

AML, myeloproliferative disorders, HL, NHL

Phase III

JAK2-inhibitor FLT-3 kinase inhibitor

AML, CML, breast cancer, prostate cancer, MM, idiopathic myelofibrosis, HL, NHL

Phase III, approval for multiple myeloma expected in 2014

HDAC inhibitor

MDS, NHL, MM, CLL

ADC: Antibody drug conjugate; AML: Acute myelogenous leukemia; CLL: Chronic lymphatic leukemia; FLT-3: Fms-related tyrosine kinase 3; HDAC: Histone deacetylase; HL: Hodgkin lymphoma; JAK2: Janus kinase 2; MDS: Myelodysplastic syndrome; MM: Multiple myeloma; mTOR: Mammalian target of rapamycin; NHL: Non-Hodgkin lymphoma.

CD30 and is internalized by the malignant cell. This leads to targeted release of the antimicrotubule agent monomethyl auristatin E (MMAE, Table 1 and Figure 1). Another strategy for drug development in HL is to evaluate small molecule inhibitors with more or less defined target molecules known to play a pathogenetic role in HL. Mammalian target of rapamycin (mTOR) inhibitors, histone deacetylase (HDAC) inhibitors and Janus kinase (JAK) inhibitors are currently being evaluated in Phase I/II clinical trials in HL (Table 1). These small molecule inhibitors are expected to be reasonably effective and have a more favorable side-effect profile than conventional chemo- or radiotherapy and might overcome chemotherapy resistance.

6.

Competitive environment

Brentuximab vedotin In a Phase II multi-center trial of single-agent brentuximab vedotin in patients with recurrence after ASCT, patients obtained an overall response rate (ORR) of 75% with mainly partial remissions (PRs) and complete remissions (CRs) amounting up to a rate of 34% [14]. Of note, 71% of patients in the trial had disease refractory to prior treatments. This demonstrates the high activity of brentuximab vedotin even in chemorefractory HL. Importantly, the median PFS for patients who achieved a CR and did not receive an allogeneic transplant was 21.7 months indicating that a subset of 6.1


217


Brentuximab vedotin (SGN-35)

Brentuximab vedotin antibody drug conjugate (ADC) Monomethyl auristatin E (MMAE), potent anti-microtubule agent


Protease-cleavable linker Anti-CD30 monoclonal antibody ADC-CD30 complex traffics to lysosome

ADC binds 1 to CD30 2

4 MMAE 3 is released

MMAE disrupts microtubules

5 → Cell cycle arrest and apoptosis

Figure 1. Brentuximab vedotin: mechanism of action. ADC: Antibody drug conjugate; MMAE: Monomethyl auristatin E.

patients with CR after brentuximab vedotin achieve longterm remissions. These data are superior to what can be achieved with conventional chemotherapy combinations. Overall, brentuximab vedotin was well tolerated; the most common grade 3 or grade 4 adverse events were peripheral sensory neuropathy (8%), fatigue (2%), neutropenia (20%) and diarrhea (1%). In the recently presented 3-year followup of the trial [18], the median overall survival (OS) was 40.5 months (95% CI: 28.7, - [range, 1.8 -- 48.3 months]) and the estimated 3-year survival rate was 54% (95% CI: 44, 64%). At a median of 32.7 months (range, 1.8 -48.3 months) since first dose of brentuximab vedotin, 51 of 102 patients (50%) were alive at the time of last follow-up. At the time of presentation, 14 patients remained in remission per central independent review and were still being followed on study; of the 14 patients, 5 received consolidative RICallo and 9 have had no treatment following brentuximab vedotin. These data suggest that a small proportion of patients might be cured with brentuximab vedotin even after post-ASCT relapse. In view of these promising data, brentuximab vedotin is currently being evaluated in first-line trials for advanced HL. Because the combination of brentuximab vedotin and AVD has been found to be safe and effective [19], an international randomized Phase III study (ECHELON-1-Study) comparing standard ABVD with brentuximab vedotin and AVD in advanced HL is currently enrolling (Figure 2). Similarly, the German Hodgkin Study Group (GHSG) is currently comparing two new BEACOPP variants in a multi-centre Phase II trial for patients with advanced HL (Figure 3). This trial aims at further detoxifying the BEACOPP-escalated 218

(BEACOPPesc) regimen while maintaining the high tumor control rates. To this end, brentuximab vedotin is combined with BEACOPPesc and the most toxic drugs of the BEACOPPesc regimen are either dose reduced, replaced by other drugs or omitted. This results in the two ‘Targeted BEACOPP’ regimens BRECAPP (brentuximab vedotin, etoposide, cyclophosphamide, adriamycin, procarbazine, prednisone) and BRECADD (brentuximab vedotin, etoposide, cyclophosphamide, adriamycin, dacarbazine, dexamethasone). The promising interim results of this trial have recently been presented [20]. Given the high single-agent activity of brentuximab vedotin in relapsed or refractory HL, the new ABVD or BEACOPPesc-based combinations will hopefully further reduce the proportion of patients with relapsing or refractory HL and improve the tolerability of the regimens. Patients with relapsed or refractory HL receive a salvage therapy with conventional chemotherapy before the myeloablative HDCT and ASCT by default and several analyses have shown that response to salvage therapy is predictive for the outcome [9]. Therefore, a multi-centre trial led by Anton Hagenbeek is currently evaluating the combination of DHAP (Dexamethasone, High-dose Ara-C and Cisplatin) standard salvage therapy with brentuximab vedotin. Aim of the trial is to improve the response to salvage therapy and thus the overall cure rate. Another strategy to improve the prognosis of relapsed or refractory HL patients is currently being evaluated in the international multi-centre prospective randomized doubleblind Phase III AETHERA trial. Patients with at least one of three risk factors (refractory HL, early relapse or extranodal involvement at the time of pre-ASCT relapse) received



Study flow sheet Newly diagnosed advanced classical hodgkin lymphoma in patients aged 18 or older


2 × ABVD

2 × AVD + A

Interim staging (PET/CT)

Deauville score: 1–4

Deauville score: 5

Deauville score: 1–4

Deauville score: 5

Continue protocol therapy (4 x ABVD)

Continue protocol therapy (4 x ABVD)

Continue protocol therapy (4 x AVD+A)

Continue protocol therapy (4 x AVD+A)

4 × ABVD

4 × ABVD

2 × AVD + A

2 × AVD + A

Or Initiate alternative therapy (physician’s choice)

Or Initiate alternative therapy (physician’s choice)

Final restaging (PET/CT)

Follow-up

Figure 2. Flowchart of the ECHELON-I Phase III trial. A: Adriamycin; B: Bleomycin; BR: Brentuximab vedotin; D: Dacarbazine; V: Vinblastine.

brentuximab vedotin or placebo over 16 cycles at 3-week intervals as maintenance after ASCT. The trial has completed enrollment in 2012, and first results are awaited for 2014. Brentuximab vedotin induces long-term remissions in a small proportion of patients only. Lately, two retrospective analyses reported that brentuximab vedotin can provide a bridge to potentially curative RICallo in patients with HL refractory to conventional salvage therapy [21,22]. Best responses were seen after four cycles indicating that allogeneic transplant could be conducted early after the first assessment indicating response to brentuximab vedotin. In view of the moderate PFS achieved with RICallo in HL patients relapsing after ASCT on one hand and the long-term remissions observed in some of the patients achieving CR with brentuximab vedotin on the other hand, it is currently unclear which patients should undergo RICallo. Lastly, combination trials with brentuximab vedotin and chemotherapy (e.g., with bendamustin in adults and with gemcitabine in the pediatric population) in patients with relapsed or refractory HL are currently enrolling and might

lead to further therapeutic options, both as conventional combination therapy and as bridge to allogeneic transplant. HDAC inhibitors HDAC inhibitors are promising new anticancer drugs that regulate a variety of cell functions that are involved in survival, cell-cycle progression, angiogenesis and immunity. HDAC inhibitors have a direct antiproliferative effect on HRS cells, in addition to immune modulatory effects by regulating the expression of key chemokines and cytokines in the microenvironment. Mocetinostat is an oral HDAC inhibitor that was evaluated in an open-label, Phase II trial in patients with relapsed/refractory HL [23]. Mocetinostat was administered three times per week (85 -- 110 mg starting dose) in 4-week cycles, and tumor responses were evaluated every 8 weeks. Fifty-one patients were enrolled (23 in the 110 mg cohort and 28 in the 85 mg cohort). Two patients achieved a CR (110 mg cohort), 12 patients achieved a PR (6 patients in each cohort) and 1 patient achieved durable stable disease (SD, in the 85-mg cohort). The disease control rate was 25% in the 85-mg cohort and 35% in the 110-mg cohort 6.2


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Study flow sheet

Newly diagnosed advanced classical Hodgkin Lymphoma in patients aged 18-60


2 × BrECAPP

2 × BrECADD

Interim Staging (PET/CT) Off study in case of PET-positive new lesions

4 × BrECADD

4 × BrECAPP

Restaging

RT of PET-positive residual lymphoma > 2.5 cm

Follow-up

Restaging & follow-up

Figure 3. Flowchart of the targeted BEACOPP Phase II trial. A: Adriamycin; BR: Brentuximab vedotin; C: Cyclophosphamide; DD: Dacarbazine and dexamethasone; E: Etoposide; PP: Procarbazine and prednisone; RT: Radiotherapy.

in the intent-to-treat population. Most common grade 3 and 4 toxicities were thrombocytopenia (22%), fatigue (16%), neutropenia (14%), pneumonia (12%), anemia (10%) and pericardial effusion (6%). This trial demonstrated that HDAC inhibitors have a therapeutic value in HL. Similarly, panobinostat is an HDAC inhibitor that is orally administered. One hundred and twenty-nine patients with relapsed HL were treated with 40 mg oral panobinostat given 3 days per week in 21-day cycles in a Phase II multi-centre trial [24]. A 27% ORR was observed (5 CRs and 30 PRs). Single-agent activity was evident and with good tolerability, suggesting it could be a candidate for combination regimens. In line with these findings, a Phase I trial combining panobinostat with standard ICE (ifosfamide, carboplatin, etoposide) salvage therapy in relapsed/refractory HL patients is currently enrolling. First promising results have recently been presented [25]: 21 patients were assessed for response and ORR 220

was 86%, with a CR rate of 71%. Treatment was well tolerated, and there was no grade 3/4 non-hematologic toxicity observed. All responding patients (86%) proceeded to HDT and ASCT after this regimen. In conclusion, panobinostat plus ICE seems to be an effective first salvage regimen for recurrent or refractory HL and should be further evaluated. Panobinostat was also evaluated as maintenance therapy for patients at high risk of relapse after HDCT and ASCT in an international multi-centre prospective randomized doubleblind Phase III trial, similar to the AETHERA trial with brentuximab vedotin. However, this trial had to be closed prematurely after the enrollment of 41 patients due to insufficient recruitment. Although efficacy could not be formally evaluated due to the small number of patients in this trial, it is interesting to note that more patients from the placebo arm discontinued from the study due to disease progression (28.6 vs 14.8% panobinostat patients) [26].




6.3

mTOR inhibitors

Everolimus is a derivative of rapamycin, which acts as a signal transduction inhibitor. Its target is mTOR, a key protein kinase regulating cell growth, proliferation and survival. The mTOR pathway activity is modulated by the PI3K/AKT pathway, a pathway known to be dysregulated in numerous human cancers. Everolimus is being investigated as an anticancer agent based on its potential to act directly on the tumor cells by inhibiting tumor cell growth and proliferation and indirectly by inhibiting angiogenesis leading to reduced tumor vascularity. The role of angiogenesis in the maintenance of solid tumor growth is well established, and the mTOR pathway has been implicated in the regulation of tumor production of proangiogenic factors as well as modulation of VEGF receptor signaling in endothelial cells. Everolimus is approved since 2003 in > 60 countries for the prevention of organ rejection in patients with renal and cardiac transplantations. Since 2009, it is approved in relapsed kidney cancer and it is being evaluated in other cancers, including breast cancer. At weekly and daily schedules and at various doses explored, everolimus is generally well tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) associated with everolimus therapy are manageable. Non-infectious pneumonitis has been reported with mTOR inhibitors but is commonly low-grade and reversible. Interestingly, it was shown that everolimus potently suppressed cell-cycle progression in G0/G1 phase of HL cell-line cells and significantly delayed tumor development in mice that had received xenotransplantations. The mechanism of this antiproliferative effect was down-regulation of both the truncated isoform of the transcription factor C/EBP-b and NF-kB activity [27]. NF-kB is one of the key molecules in the pathogenesis of HL. Therefore, everolimus was also tested in clinical trials in HL. In 2010, Johnston et al. reported on the first Phase II trial in relapsed HL. The ORR in 19 heavily pretreated HL patients (84% of the patients had prior HDCT and ASCT) was 47% while the therapy was well-tolerated with the main toxicity being reversible myelosuppression [28]. More recently, a larger multi-centre, open-label, two-step, Phase II trial was presented at the 9th International Symposium on Hodgkin Lymphoma in Cologne [29]. Adults with refractory or relapsed HL after HDCT with ASCT or a gemcitabine-, vinorelbine- or vinblastine-containing regimen received everolimus 10 mg/day until disease progression or unacceptable toxicity. Response was assessed every 12 weeks. Fifty-seven patients were enrolled (57.9% pretreated with ASCT; 66.7% experienced disease progression during previous therapy). The ORR was 42.1%, and median PFS was 9.0 months. At the time of presentation, seven patients remained on treatment (average duration, 2.08 years), including one patient who experienced a PR and had been on therapy for 2.88 years. The most common grade 3/4 adverse events were thrombocytopenia (21.1%) and anemia (12.3%). These encouraging results provide strong evidence for the further evaluation of everolimus in HL and its integration in

salvage regimens for relapsed or refractory disease. Therefore, the GHSG is currently evaluating a combination of everolimus with standard DHAP salvage chemotherapy in the Phase I/II HD-R3i trial. The Phase I part of the trial has completed enrollment in early 2014, and first results are awaited. Preclinical experiments demonstrated in vitro synergism between panobinostat and everolimus and led to a Phase I/II study evaluating the safety and efficacy of this novel combination regimen in relapsed lymphoma, including HL. Response rates were promising; however, there was a high rate of thrombocytopenia (grade 3/4 in 64%) that limits further clinical evaluation of this combination [30]. JAK inhibitors A considerable number of cytokine and growth factor receptors utilize the JAKs to transmit extracellular ligand binding into an intracellular response. In humans, JAK3 expression is restricted to hematopoietic cells, whereas the remaining three JAK family members JAK1, JAK2 and TYK2 are ubiquitously expressed. JAKs activate a number of downstream pathways implicated in proliferation and survival, including the signal transducers and activators of transcription (STATs) [31]. Recently, aberrant activation of the JAK/ STAT pathway has been reported to promote proliferation and survival of HL tumor cells [32], making it an appealing target for pathway-directed therapy. In line with these findings, the JAK/STAT inhibitor lestaurtinib has been shown to induce apoptosis and growth inhibition both in HL cell lines and tumors from HL patients [33]. Recently, the clinical activity of the oral JAK2-inhbitor SB1518 (pacritinib) in relapsed or refractory HL has been demonstrated in a Phase I clinical trial [34]. SB1518 is a pyrimidine-based macrocycle small-molecule ATP-competitive inhibitor of JAK2 kinase that potently inhibits wild-type JAK2 as well as the JAK2V617F mutant. Thirty-four patients including 14 patients with classical HL received doses of 100 -- 600 mg/day in the trial; the maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. There were three partial responses (‡ 300 mg/day) and 15 patients with SD, with most responses lasting longer than 2 months. Of 13 SDs, 7 had tumor size reductions of 4 -- 46%, including 4 patients with HL. In conclusion, SB1518 has encouraging activity in relapsed HL, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in HL in the clinical setting. Due to these promising results, both the French Lymphoma Study Association and the GHSG are currently performing a Phase II trial with the oral JAK2-inhibitor ruxolitinib that has been approved for the treatment of certain types of myelofibrosis in 2012. 6.4

Lenalidomide Lenalidomide is an immunomodulatory agent with pleiotropic effects that also has antiangiogenic properties. It was first approved for the treatment of multiple myeloma in 2006. 6.5


221



Lenalidomide was administered in a daily oral dose of 25 mg per day for 3 weeks followed by 1 week of rest in a Phase II multi-centre study in relapsed/refractory HL [35]. Thirty-six patients were enrolled of which seven responded (ORR 19%). The disease control rate including patients achieving SD was 33% and median time-to-treatment failure in responders (CR/PR/SD ‡ 6 months) was 15 months (range, 4 -- 43). Of the patients, 47% developed grade 3 and 4 neutropenia and 18% had grade 3 or 4 thrombocytopenia. Due to these promising results, lenalidomide was also evaluated in a continuous dose resulting in a higher ORR of 30% [36]. Moreover, in a named patient programme for relapsed/refractory HL patients an ORR of 50% with one patient achieving a CR was reported [37]. These data suggest that lenalidomide has single-agent activity in relapsed HL. Consequently, lenalidomide was further evaluated in HL by the GHSG in a first-line Phase I combination trial for older patients [38]. A(B)VD is considered standard of care for HL patients between 60 and 75 years of age; however, both outcome and feasibility are poor, because tolerability of cytotoxic drugs is often markedly decreased. Therefore, the GHSG aimed at improving the ABVD regimen by replacing bleomycin with lenalidomide (AVD-Rev) to improve both efficacy and tolerability of the regimen. Depending on stage and response at interim staging, patients received four to eight cycles of AVD-Rev (standard-dose AVD on day 1 and 15 of a 28-day cycle and lenalidomide daily from day 1 -- 21) followed by radiotherapy. The daily lenalidomide dose for the first patient was 5 mg, maximum dose in this dose-escalation trial was 25 mg. Twenty-five patients with a median age of 67 years were recruited and assigned to dose levels 5 mg (n = 1), 10 mg (n = 1), 15 mg (n = 1), 20 mg (n = 6) and 25 mg (n = 16). Sixty-eight had advanced stage disease, and 80% had B-symptoms at diagnosis. After dose-limiting toxicity evaluation of 20 patients, a prespecified stopping criterion was reached and the recommended dose for a Phase II trial was 25 mg. At least one grade 3/4 toxicity occurred in all 22 patients who were treated at dose levels 20 and 25 mg, and 16 of these patients had a grade 4 toxicity. Of note in these highly vulnerable patients, no treatment-related death occurred. ORRs were 79% for all evaluable patients (19/24) and 86% (18/21) in patients treated with at least 20 mg lenalidomide. After 12 months median observation time, five patients had a disease progression and three patients died. The 1-year estimates for PFS an OS were 69 and 91%, respectively. In summary, AVD-Rev displayed high efficacy and a manageable toxicity profile in older patients with HL and should be further evaluated in Phase II/III trials. In addition, a Phase II trial combining lenalidomide and panobinostat in patients with relapsed or refractory HL is currently recruiting. 7.

Potential development issues

Current standard combined modality treatments with chemotherapy and radiotherapy are highly effective and cure 222

80 -- 90% of HL patients. To avoid acute and long-term toxicities of these general treatments, more targeted substances with fewer side effects should be introduced in first-line therapy. However, it is crucial to maintain the high cure rates achieved with standard therapy. Therefore, standard therapy regimens cannot be changed completely but must be thoroughly adapted by replacing selected drugs or modalities with new drugs. Especially, drug--drug interactions that might be unknown before first evaluation of a given combination must be carefully monitored. The examples of the unexpected pulmonary toxicity of the combination of brentuximab vedotin and bleomycin in a Phase I trial [19] and the combination of the naked anti-CD30 antibody SGN-30 and gemcitabine, vinorelbine and pegylated liposomal doxorubicin in a Phase II trial [39] teaches us that clinical trials with new combinations should be performed with predefined safety surveillance and stopping rules. Moreover, many of the long-term side effects of conventional therapies appear as late as 20 -30 years after therapy and similar or unknown long-term side effects of targeted substances cannot be completely ruled out. In addition, due to the high cure rate with first-line therapy, relapse rates in HL are low and large relapse trials for the establishment of new substances in the relapsed/ refractory setting can only be performed in cooperative international multi-centre trials. 8.

Conclusion

After decades of classical chemotherapy and radiotherapy, brentuximab vedotin, the first targeted drug for the treatment of HL has been approved. Brentuximab vedotin is approved for patients with refractory/relapsed disease but the full potential of this drug is currently being evaluated in all lines of therapy, from first-line to maintenance after HDCT and ASCT. Moreover, other interesting targeted drugs have shown high efficacy and tolerable side effect profiles in the relapsed/ refractory setting. Some of these drugs are being evaluated in prior lines of therapy and will hopefully increase cure rates while decreasing acute and long-term side effects. 9.

Expert opinion

A plethora of new drugs has been evaluated in HL in the last years but unlike in other hematologic malignancies, only one drug has gained approval. Although brentuximab vedotin and other drugs have clearly demonstrated efficacy in HL, a molecularly targeted drug achieving long-term responses with good tolerability analogical to imatinib in chronic myelogenous leukemia is still lacking. Increased knowledge of the molecular pathogenesis of HL might lead to the development of such a drug in the future. The ultimate goal in HL is to replace chemotherapy and radiotherapy by targeted substances without losing efficacy. Notwithstanding brentuximab vedotin is the most potent single agent for the treatment of




HL; long-term remissions in relapsed/refractory disease can only be achieved in a small proportion of patients. Currently, brentuximab vedotin cannot completely replace chemotherapy or radiotherapy but can rather substitute single substances or allow for dose reductions of chemotherapy and/or radiotherapy in the combined modality setting. If brentuximab vedotin might serve as combination partner for other new drugs to completely replace chemotherapy or radiotherapy has to be elucidated in the future. Due to demographic changes, more older patients will be first diagnosed with HL in the coming years. Less aggressive first-line and relapse therapies with high efficacy are therefore warranted. Combinations of new drugs such as lenalidomide or brentuximab vedotin with established combined modality Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest B von Tresckow has received honoraria from Novartis and honoraria and travel grants from Takeda. V Diehl is the chairman of the Data monitoring Committee of the Aethera trial (Seattle Genetics). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation Bastian von Tresckow1 MD & Volker Diehl†2 MD † Author for correspondence 1 University Hospital of Cologne, Department I of Internal Medicine, Kerpener Str. 62, 50937 Cologne, Germany Tel: +49 221 478 97657; Fax: +49 221 478 98622; E-mail: [email protected] 2 Professor, Emeritus, Honorary Chairman of the German Hodgkin Study Group, University of Cologne, Internal Medicine I, Kerpener Strasse 62, Cologne 50937, Germany Tel: +49 221 4780; Fax: +49 221 478 88188; E-mail: [email protected]

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