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New drugs and targeted treatments in Hodgkin’s lymphoma

Cancer Treatment Reviews, 3, 40, pages 457 - 464

Abstract

New drugs are being developed in recent years that may change the handling of relapsed and refractory Hodgkin’s lymphoma patients. Brentuximab vedotin treatment has already been approved by the FDA; and other drugs are promising, such as histone deacetylase inhibitors, bendamustine, lenalidomide and m-TOR inhibitors.

Keywords: Target treatments, Hodgkin’s lymphoma, Brentuximab vedotin, Deacetylase inhibitors, Bendamustine, Lenalidomide, m-TOR inhibitors.

Introduction

Hodgkin’s lymphoma (HL) is the paradigm of a curable disease. Its treatment has pioneered the development of modern chemotherapy, becoming an example and success story of medical oncology [1] .

George P. Canellos wondered how new drugs could be incorporated into the treatment of this disease and whether they could increase HL patients’ survival and cure. In the end, as is always the case for any well-trained oncologist, the real test of the evidence must rest on prospective, randomized studies, such as when, so many years ago now, the treatment of Hodgkin’s disease changed [2] and [3].

HL derives from the B-cells of the germinal center and is characterized by the presence of large bi- or multi-nucleated cells with prominent nucleoli (Reed-Sternberg cells). Its immunohistochemistry is CD15-positive and CD30-positive. The malignant fraction of the entire component comprises 1–10% of the entire tumor volume [4] .

In this chapter we will review the new drugs that have had prospective studies run on them and that in recent years, since the previous edition of this manual, have become firm candidates for improving the prognoses, and perhaps cure, of our relapsed patients. Prognoses are especially poor in those patients with progressive disease or relapse during the year after intensification with high doses of chemotherapy and subsequent autologous stem-cell transplant: their mean expected survival is no greater than twelve months [5] .

Discussion

SGN-35 or brentuximab vedotin

SGN-35 or brentuximab vedotin is an antibody (Ab) conjugated with an antimitotic microtubule inhibitor approved for patients with relapsed HL after autologous transplant or after more than two treatment regimes and who are not candidates for chemotherapy intensification and subsequent autologous transplant. It has also been approved for treating patients with anaplastic large-cell lymphoma (ALCL) who relapse after a line of chemotherapy treatment.

CD 30 is expressed in Reed–Sternberg cells and on the surface of ALCL cells and to a variable extent in other kinds of lymphoma [6] . CD30 is not usually detected in normal tissue outside the immune system [1] except in a small fraction of B, T or eosinophils, which makes it an ideal target for treatment with monoclonal antibodies (moAb). A soluble kind of CD30 has been found in the serum of patients with HL and other tumors that express CD30, as well as in inflammation situations characterized by strong activation of B or T cells [7] . CD30 is a membrane glycoprotein that belongs to the TNF family, which comprises 29 members including Fas and TNFR1. The signaling of the CD30 pathway is tied to NF-κB. CD30 over-expression may cause NF-κB activation, independently of its ligand. CD30 may also have a role in the maintenance of the memory T CD4 lymphocytes and in the co-stimulation of interleukine-4 and CD28 during the activation of T cells [8] . Nevertheless, the pertinence of CD30 to the pathogenesis of lymphoma remains unclear, even though it has been an extensively investigated therapy target ( Fig. 1 ).

gr1

Fig. 1 Mechanism of action of brentuximab vedotin. ADC (antibody–drug conjugate); MMAE (monomethyl auristatin E).

Preclinical studies

The action of two moAb as anti-tumor drugs against CD30 has been evaluated: SNG-30 and SNG-35. SNG-30 is a chimerical anti-CD30 moAb, synthesized with one murine and one human part. It is an IgG1 immunoglobulin. In vitro studies on cell lines from HL and in mouse models have shown that it has high anti-tumor activity [9] . However, despite these results, there is a dichotomy between preclinical findings and those obtained in subsequent clinical trials with unconjugated moAb alone.

Clinical studies of SNG-30 and 35 in Hodgkin’s lymphoma

SNG-30 was evaluated in a phase-II clinical trial [10] in patients with HL and ALCL. Treatment was tolerated well, but there was no response in HL patients, whereas there was in 7 of the 41 ALCL patients: in 2 (5%) response was complete and in 5, partial (12%).

Another trial with another kind of anti-CD30 (MDX-060) in patients with CD30 refractory or resistant lymphoma also had a poor response rate in HL (6%), whereas this was 29% in ALCL [11] .

Preclinical data suggested that combination of SNG-30 and chemotherapy could strengthen effectiveness. The Cancer and Leukemia Group B set up a phase-II clinical trial combining SNG-30 with gemcitabine, vinorelbine and liposomal doxorubicin. The study had to close prematurely, as 5 out of 30 patients died of pneumonitis, probably because of an immunological component [12] .

SGN-35 is a chimeric moAb, cAC10, also aimed at the CD30 protein, which is conjugated with a powerful antitubulin drug, monomethyl-auristatin E (MMAE), through a plasma-stable ligand (valine–citrulline, vc, peptide), forming the complex cAC10-vc-MMAE.

The mechanism of action of SGN-35 consists of its binding to transmembrane CD30 proteins, present on the surface of tumor cells, its internalization through endocytosis and the release of MMAE through enzyme degradation of the ligand at the level of the lisosomes. Through the degradation of the cAC10-vc-MMAE complex at the level of the lisosomes of the CD30-positive tumor cells, the unaltered cytotoxic antitubulin drug, MMAE, responsible for antitumor action, is released [13] .

Once released, the active drug MMAE binds to tubulin, a component needed for the formation of microtubules, with the resulting interruption of the cell cycle (at the G2/M phase) and consequent apoptosis [14] .

Thus, brentuximab vedotin links the effects of cell cycle arrest and apoptosis with the inhibition of microtubule polymerization. The combination of brentuximab vedotin with chemotherapy agents also shows a synergic anti-tumor action in preclinical models [15] .

The initial phase-I clinical trial with brentuximab vedotin was developed on 45 CD30-positive patients [16] , most of them with relapsed HL, with a dose of 0.1–3.6 mg/kg every 3 weeks, using a habitual dose-escalation design. The final dose considered the maximum dose tolerated was 1.8 mg/kg intravenously every 3 weeks. The treatment was tolerated well and the most commonly seen side-effects were fatigue, fever, diarrhea, nausea, neutropenia and peripheral neuropathy. 17 of the 45 patients with HL experienced an objective response. Another phase-I trial [17] encountered a maximum tolerated dose of 1.2 mg/kg, taken intravenously every week for 3 weeks with a cycle every 4 weeks. With this plan, patients suffered similar side-effects to those above: finally, the former was adopted, with administration every 3 weeks.

The pivotal phase-II clinical development trial [18] recruited 102 relapsed or refractory HL patients after ABMT (Autologous Bone Marrow Transplant), treated with brentuximab vedotin at doses of 1.8 mg/kg administered once every 3 weeks. Patients received an average of 9 cycles and only 8% of doses were put back because of side-effects caused by the treatment.

The most common grade ⩾3 toxicities were hematological, including neutropenia in 20% of cases, anemia in 6% and thrombocytopenia in 8%. Of the most common non-hematological toxicities, peripheral sensorial neuropathy was found in 8% of cases, which was reversible in 50% of the patients affected. This toxicity may be a barrier for future combinations with other neurotoxic drugs, normally used in HL treatment, such as vincristine, vinorelbine or taxanes [19] .

The study’s main aim was to find the objective response rate, which was 75%, with a 34% complete response rate, determined by independent observers, and 41% partial responses. After a mean follow-up of 18.5 months, 99% of patients had the disease under control. Response came quickly, with an average of 12 weeks before reaching complete response. The duration of complete response was 20 months and progression-free survival was 5.6 months (CI 95%, 5–9). Overall survival of the series was 22.4 months (CI 95%, 21.7-ND).

Maximum duration of treatment was not established. In this trial the maximum was 16 cycles, with the mean and median at 9 and 10, respectively. The aim sought, when it is reached and with what toxicity will have to be evaluated.

No comparison has been made between this HL therapy and the following ones discussed below. Nevertheless, in Table 1 we summarize the main features of these drugs in the prospective clinical trials published.

Table 1 Prospective studies with new drugs: efficacy data, survival data and most common toxicities lowast .

Drug No. patients Mean age (range) Mean previous treatments (range) Previous treatments with Overall response rate CI 95% Mean duration of response (months) Progression-free survival (range, months) Grade III–IV toxicity
        ABMT ALO        
Panobinostat [38] 129 32 (18–75) 4 (2–7) 78% 10% 27% 6.7 6.1 (0–17.2) Thrombocytopenia 79%
Anemia 21%
Neutropenia 8%
Pneumonia 8%
Brentuximab [18] 102 31 (15–77) 3.5 (1–13) 100% 75% 6.7 (3.6–14.8) 5.6 (5–9) Neutropenia 20%
Sensory neuropathy 8%
Bendamustine [50] 36 34 (21–75) 4 (1–17) 75% 17% 53% 5 5.2 Thrombocytopenia 20%
Anemia 14%
Neutropenia 8%
Pneumonia 11%
Lenalidomide [56] 38 34 (26–63) 4 (2–9) 87% 19% 6 (4⩾24) 4 (2–6) Neutropenia 47%
Anemia 26%
Thrombocytopenia 18%
Asthenia 8%
High AST 8%

lowast >5% Grade 3 and any grade 4.

The U.S. Food and Drug Administration (FDA) decided on the rapid approval of brentuximab vedotin on August 19, 2011, for relapsed HL patients after progression to two chemotherapy lines with multiple drug regimes who were not candidates for transplant or after previous bone marrow transplant failure. The FDA also approved a clinical trial that combined adriamycin, vinblastine and dacarbazine combined with brentuximab vedotin against ABVD in advanced HL. Bleomycin was withdrawn from the initial combination, as there is a high risk of pulmonary toxicity. The FDA required no in vitro diagnostic validation of CD30, given the presence of positive CD30 in almost 100% HL, except the sub-type with lymphocyte predominance [20] and [21]. It was the first drug approved by the FDA for Hodgkin’s lymphoma treatment since 1977.

One question to pose is what happens with those patients who reach response and for whom an allogenic transplant is an option [22] . In Younes’ pivotal study, 8 patients underwent this procedure and continued alive at the time of publication. Finally, another question is what role this treatment might play in relapse after an allogenic transplant [23] . We know that these patients’ prognosis is very poor, with low response rates with any treatment employed [24] and [25]. In a study aimed at finding the efficacy and safety of brentuximab vedotin in this specific population [26] , 75% of 25 patients with refractory disease immediately before treatment obtained, with a dose of 1.8 mg/kg, i.v. every 3 weeks, a 50% overall response rate, which was complete in 38% and with progression-free survival of 7.8 months. The grade 3 or higher toxicity rates were similar to those seen in Younes’ study, with 24% neutropenia, 20% anemia and 16% thrombocytopenia. Viremia due to CVM was detected in 5 patients, but was only clinically relevant in one of them.

Recently, the preliminary results of an open, multicenter phase-I trial, designed to evaluate the safety of Brentuximab vedotin combined with standard ABVD treatment or treatment modified with AVD (ClinicalTrials.gov NCT01060904 ) became known [27] . Patients received a dose of 0.6, 0.9 or 1.2 mg/kg, depending on the cohort. Fifty one patients had been recruited by the time of presentation. Of the 47 that could be evaluated for response, 96% had objective complete response. The highest grade 3 toxicity seen in the ABVD and AVD cohorts was, respectively, neutropenia (80% vs. 65%), anemia (20% vs. 12%), febrile neutropenia (20% vs. 8%) and pulmonary toxicity (24% vs. 0%). No dose-restricting toxicity was found at 1.2 mg/kg every 2 weeks. Therefore, the recommendation of not including bleomycin with brentuximab vedotin due to pulmonary toxicity was confirmed. The high rate of complete response advises comparison of AVD-brentuximab and ABVD.

Another approach under study, the AETHERA trial, is treatment of HL patients at high risk of post-transplant relapse, comparing placebo vs. brentuximab vedotin every 3 weeks for 12 months or till progression or relapse if this occurs first. The main aim is progression-free survival; secondary aims are overall survival, safety of the treatment and its tolerability [28] .

A special consideration to bear in mind in relation with brentuximab vedotin treatment is the report of 3 cases of progressive multifocal leukoencephalopathy caused by the reactivation of the JC virus, without the direct mechanism of its reactivation being identified. This special alert must be borne in mind, known and suspected if patients appear with symptoms of disturbance in the central nervous system [29] .

Histone deacetylase inhibitors

DNA methylation is one of the best-known epigenetic procedures. The term epigenetic has been defined as “inheritable changes in gene expression that occur with no disturbance of the sequence of DNA nucleotides.” Thus, an epigenetic mechanism can be understood as a complex system to use genetic information selectively, activating and deactivating various functional genes. Epigenetic modifications may imply DNA methylation on cytosine residues and/or changes in chromatin structure caused by alterations in histones, which regulate gene expression [30] .

The post-transcription alterations of the histones that regulate chromatin, and thus gene expression, are many. These alterations, including methylation, acetylation and phosphorylation, among others, are known as “histone code” and affect various biological processes such as the regulation of gene expression or repair of DNA. One of the best-known and most relevant of these alterations is the acetylation/deacetylation of histones carried out by the histone acetyltransferases (HAT) and histone deacetylases (HDAC), respectively. The design of therapeutic strategies aimed at correcting histone code disturbances, mainly through the use of HDAC inhibitors (HDACi), looks like a promising route to improve the handling and prognosis of patients with afflictions involving disturbances in their “epigenetic” patterns and basically in those patterns involved in cancer. In this respect, there has been an important development of these HL drugs [31] , which we develop below.

The HDACi block the deacetylation of histones, resulting in their hyperacetylation, and thus affect the regulation of gene expression. This eventually affects cell homeostasis through complex mechanisms, including cell cycle arrest, apoptosis, and inhibition of angiogenesis and induction of a favorable anti-tumor immune response. To date, 18 different kinds of HDACi have been identified [32] .

Some of these HDACi, among which are vorinostat, panobinostat and romidepsine, are classified as pan-inhibitors of HDAC, as they inhibit class I and II HDAC. ( Fig. 2 ). Of these, panobinostat is especially relevant to HL treatment. It has a similar structure to vorinostat, whose chemical name is N-hidroxi-3-[4-[2-metil-1H-indol-3yl)etil-aminomethyl]phenyl]-2(E)-propenamide. Panobinostat induces cell death in HL lines, with a CI50 between 20 and 40 nM [33] .

gr2

Fig. 2 Classification of histone deacetylase inhibitors.

Panobinostat is available for oral or intravenous use. Its oral formulation, administered three times a week, has been explored in HL. This drug is rapidly absorbed orally and has 50% bioavailability. Acetylation induced by it lasts about 72 h.

Preclinical studies

Preclinical studies of panobinostat show that it is active in various HL cell lines, whether through direct anti-tumor activity by inducing cell cycle arrest or apoptosis, achieved through ChK2, p21, caspase activation and inhibition of the JAK–STAT pathway; or indirectly, by modulating the effects of the micro-environment and the immune response through cytokines [34] .

Another HDAC inhibitor, Entinostat, was also successfully evaluated in HL cell lines [35] .

Similarly, in the studies on HL cell lines, a change was found in their gene expression after vorinostat treatment. In addition, increased sensitivity to cisplatin was found, which suggests it might be a good future treatment option [36] . Vorinostat also induces p21 expression and reduces Bcl-xL levels, causing cell cycle arrest and apoptosis.

In addition, it inhibits STAT6 phosphorylation and, in consequence, the reduction of TARC/CCL17 and interleukine-5, suggesting an anti-proliferation effect of Reed-Sternberg cells, possibly due to its interference with the tumor environment [37] .

There are studies of in vitro combination of these agents with others. For example, the combination of everolimus and panobinostat synergized with anti-proliferation effects on HL cell lines.

Clinical studies with histone deacetylase inhibitors in Hodgkin’s lymphoma

Panobinostat has been evaluated in phase-IA/II clinical trials in patients with various kinds of lymphoma, including HL. In the case of HL, represented initially by 13 patients, the drug achieved 5 partial responses (38%) with good tolerance to the treatment, excepting episodes of thrombocytopenia, nausea and diarrhea. In succeeding congresses, updating of this study has been reported. There are 32 HL patients, who received a lot of treatment, with a mean of 5 prior chemotherapy regimes and 90% subjected to bone marrow transplant. The overall response was 69% determined by PET and 41% when documented by CAT. Dose-restricting toxicity was thrombocytopenia and the biggest dose tolerated was 40 mg, three times a week, or 60 mg three times a week every 2 weeks.

Based on the results of the phase-I trial, a phase-II [38] trial was run in patients with relapsed HL. The study included adult patients with progressive HL after ABMT, who then had panobinostat at 40 mg doses three times a week (Monday–Wednesday–Friday) every week with 21-day cycles. The aim of the study was to evaluate the response rate. 129 patients were recruited, with a mean age of 32, a mean of 4 previous treatments and 57% with refractory disease: all had received ABMT and 10%, an allotransplant. Panobinostat reduced the size of the tumor in 74% of patients. The response rate was 27%, which included 4% of complete responses and 23% partial responses, with a 55% rate of stabilization. Mean duration of response was 6.9 months and progression-free survival lasted 6.1 months. The grade 3–4 toxicity seen most commonly was thrombocytopenia, recorded in 79% of patients, but rapidly reversible by interruption or modification of the drug dose. 5% discontinued panobinostat because of thrombocytopenia. Other toxicities seen were diarrhea, although it was only grade 3/4 in 6%, and nausea in 9% in the same toxicity range. 16% of patients discontinued the treatment because of its toxicity.

There are several studies under way with panobinostat as maintenance therapy vs. placebo in HL patients who had had an ABMT.

The above data on the in vitro synergy of this drug with everolimus [39] led to the testing of this combination in a phase-I/II clinical trial on refractory or relapsed HL patients. The initial panobinostat dose was 10 mg, with 5 me everolimus. This was subsequently scaled up to the maximum tolerated dose of 20 mg panobinostat and 10 mg everolimus. At present the phase-II clinical trial with this dose is under way.

Similarly, there are clinical trials of panobinostat in combination with ifosfamide, etoposide and carboplatin chemotherapy.

Vorinostat at 200 mg doses twice a day for 1–14 days in 21-day cycles was evaluated by the “Southwest Oncology Group” in patients with relapsed HL. Out of a total of 25 patients, there was partial response in just 4% [40] . The trial was then abandoned because of the poor result. There was good tolerance to vorinostat and the most common side-effects are diarrhea, nausea, fatigue and alopecia.

Mocetinostat is another HDAC inhibitor, which was evaluated in a phase-II clinical trial [41] on patients with relapsed or refractory HL. Treatment lasted for 1 year or until progression or unacceptable toxicity. Of the 51 patients in the study, there was an objective response in 14 (27%), including 2 patients with complete response.

After preclinical studies [42] , entinostat was evaluated in another phase-II clinical trial in patients with relapsed or refractory HL, with the results given as an Abstract [43] . Out of 23 patients that could be evaluated, 65% obtained control of the disease (including complete or partial response and stabilization of the disease) and 35% progressed during treatment. There was grade 3/4 thrombocytopenia in 59%, neutropenia in 28% and anemia in 34%.

Bendamustine

Bendamustine hydrochloride was synthesized in the 1960s by Ozegowski and Krebs, at the Institute for Microbiology and Experimental Therapy, Jena, German Democratic Republic [44] and [45] (IMET 3393 (4-[5-(bis[2-chloroethyl]amino)-1-methyl-2-benzimidazolyl] butyric acid), with the aim of creating a bifunctional anti-cancer agent. It is related chemically with the alkylating agents cyclofosfamide and chlorambucil, but given its origin it had a short clinical development [46], [47], and [48].

Its singularity is that it incorporates a benzimidazole ring, which confers on the molecule properties such as a non-purine analog.

Bendamustine is characterized by its bifunctional action, since it induces apoptosis due to its p53-dependent alkylating activity, with a DNA-damaging effect that is more pronounced and longer-lasting than that of other alkylating agents.

Bendamustine has only partial resistance to other alkylating agents, which makes it an interesting treatment of relapse in patients previously treated with these agents [49] .

Clinical studies of bendamustine in Hodgkin’s lymphoma

A phase-II study [50] has just been published of relapsed and refractory patients who are not candidates for autologous transplant or have relapsed after this treatment. The treatment consists of 120 mg/m2 in a 30-min infusion on days 1 and 2 every 28 days, with support of colony-stimulating factors. The study recruited 36 patients, in 34 of which response could be evaluated. They received a mean of 4 prior treatments and 75% of them relapsed after autologous transplant. 50% were refractory to the last chemotherapy received. The overall response rate was 53%, including 12 complete responses (33%) and 7 partial ones (19%). The responses were seen in patients with refractory disease, ABMT and allotransplant (ALO), although no responses were recorded in patients with relapse fewer than three months from the end of the transplant. This is not too surprising, considering that the regimes to condition transplants normally contain high doses of alkylating agents.

The most common ⩾grade 3 toxicities were thrombocytopenia in 20%, anemia in 14% and infection in another 14%. Administration only had to be delayed in 11% of patients.

The mean duration of response was 5 months. The authors thought this short and speculated on the possibility of combining this treatment with other agents that might maintain the response duration. A combination that might be promising is brentuximab vedotin with bendamustine, everolimus, lenalidomide ( NCT01412307 ) or gemcitabine ( NCT01535924 ), which might broaden our therapy possibilities.

In a retrospective study gathering experience with this drug [51] , with the same schedule mentioned above, of 41 patients, 85% had received high doses of chemotherapy and subsequent transplant, with 44% considered refractory. The authors studied the drug’s efficacy in a first evaluation after 2–4 cycles, with a 78% response rate, with 29% complete responses and in another after 6–8 cycles, with the response rate down to 58%, with 31% partial ones.

Mean progression-free survival was 11 months; and overall survival, 21 months. There were no differences in function of the state of refractoriness, whether there had been prior transplant or not.

Other groups [52] presented similar findings at the ASH congress.

Bendamustine, therefore, offers interesting response rates. It would be useful to find the biological factors that identify the patients who are going to respond. We know that bendamustine interacts in the apoptosis pathway on chemo-resistant B cells with mutated TP5 [53] . Equally, action on the microenvironment [54] that possesses bendamustine may be a useful mechanism in HL, given the importance of the microenvironment in this lymphoma [55] .

Lenalidomide [56]

Lenalidomide , a derivate of thalidomide, is thought to be an immunomodulating agent. Various studies have shown promising clinical activity in various kinds of lymphoma at a daily dose of 25 mg for 3 weeks in cycles every 4 weeks.

Lenalidomide’s mechanism of action is to interact with the microenvironment of the tumor: it has anti-angiogenic and immunomodulating properties and induces directly the death of malignant B cells [57] ( Fig. 3 ). The microenvironment has always played an important role in HL survival, with production of cytokines, interleukines and TGFβ. To this are added filtrates of regulatory T-lymphocytes. Some researchers have found worse prognosis when there is greater infiltration of macrophages [58] . All this suggests that an intervention on the microenvironment and the immunological base of HL could have, at least in theory, an effect on the disease, in which case the mechanisms of action of lenalidomide would be ideal for this lymphoma. Other in vitro data have failed to find activity of lenalidomide on these tumor cells [59] .

gr3

Fig. 3 Antitumor effects of lenalidomide.

Clinical experience of lenalidomide in Hodgkin’s lymphoma

HL clinical studies have been developed from these basic findings. We have a phase-II study [56] of relapsed or refractory patients with classic HL, in which the effect of lenalidomide at doses of 25 mg/day for 1–21 days in cycles of 28 days was evaluated. The patients were treated with the drug until progression or unacceptable toxicity. 38 patients were studied, with a mean of 4 previous treatments, with a high percentage of refractory patients (55%) and 87% of them having received high doses previously. The response rate was 19%. The levels of related circulating cytokines such as CCL17 and CCL22 were studied and were associated with the response, as has occurred in the response to other drugs [60] .

Toxicity was manageable, with level 3–4 toxicities: neutropenia (47%), anemia (29%) and thrombopenia (18%).

All this points to a certain efficacy of lenalidomide against HL, which needs to be explored further, and suggests strongly that it is the effect of the microenvironment that determines the response to this drug and that, because of this, the CCL17 and CCL22 levels detectable at the start become non-detectable with treatment. It is worth noting that 82% of HL patients at diagnosis present with high CCL17 and 57%, with high CCL22 vs. controls [61] , which indicates that it could be used as a biomarker of response to treatment.

Another experience with Lenalidomide in patients with refractory HL [62] was that of Böll et al., who found in 12 patients, treated outside a clinical trial, 50% responses with relatively low toxicity [63] . Isolated clinical cases have also been reported [64] .

PI3K/m–TOR pathway

The fosfatidilinositol bifosfate-3-kinase (PI3K) family is a group of kinases involved in a variety of cell processes, including cell growth, proliferation, differentiation, motility and survival. PI3K is involved in multiple cell-signaling pathways and activation of many proteins, such as AKT. Mutated PIK3CA (PI3K alpha catalytic sub-unit) is involved in the pathogenesis of a great many tumors, including lung, colon, gliomas, gastric cancer and lymphomas. The constitutive activation of P13K in HL cell lines and primary tumor tissue has been demonstrated.

There are various drugs that interact in this pathway, like rapamycin (mTOR). mTOR activation permits the activation of proteins involved in metabolism, growth, proliferation and tumor angiogenesis ( Fig. 4 ).

gr4

Fig. 4 mTOR signaling pathway.

Clinical experience of mTOR inhibitors in Hodgkin’s lymphoma

A phase-II trial with 10 mg/day everolimus in 19 patients with refractory or relapsed HL, with 84% of them transplanted, gives an overall response rate of 47%, with 8 patients in partial response and one in complete response. Mean time to progression was 7.2 months [65] . In another trial with 37 patients [66] , the same treatment gave a 35% overall response rate. 27% had the disease stabilized and, with this, progression-free survival of 7.2 months. The treatment had the following grade 3–4 toxicities: thrombocytopenia in 38%, tiredness in 43%, neutropenia 8% and anemia 8%.

As in other previously described treatments, cases of spectacular responses to treatment in highly pre-treated patients have been reported [67] .

This leads us to think that everolimus may have a clinically relevant role in relapsed or refractory HL. In addition, data of its possible synergy with other RAF inhibitors exist [68] .

Future treatments

The future is open for other multikinase inhibitors to play a role in the treatment of HL patients. The JAK/STAT pathway is one of the most commonly affected pathways in HL.

Lestaurtinib is a multikinase inhibitor that inhibits the phosphorylation of JAK2, STAT5 and STAT3, causing reduction in Bcl-xL expression [69] and [70], which explains the pro-apoptotic effect of this drug, effect confirmed in both HL-resistant cell lines and lymphatic ganglions of HL patients [71] . Another classic multikinase inhibitor that induces apoptosis in HL lines is BAY 43-9006 (sorafenib), which could play a role in the process through its effect on the microenvironment of lymphoma [72] .

Proteasome inhibitors regulate the homeostasis of cell proteins, disturbing the cell cycle, arresting it and leading to apoptosis. Undoubtedly the most widely studied proteasome inhibitor is bortezomib, which has a high response rate in myeloma [73] or mantle lymphoma, but a scant one in HL as the sole agent [74] and [75]. Maybe its future lies in its conjugation with conventional chemotherapy or other biological agents.

Conclusions

Despite the high curability rates of Hodgkin’s lymphoma, there is still a huge space for improving treatment of refractory or relapsed patients. Many are the drugs in clinical trial and demonstrating benefit, but it is certainly too soon to know whether all these drugs will contribute to improving survival more than the customary treatments we use for these patients. We also need to go deeper into the understanding and handling of toxicity and interactions with other drugs and, finally, how to rationalize their use and make this sustainable in the current economic situation.

Conflict of interest

None.

Acknowledgements

M.S-B. is supported by a Miguel Servet contract from the Fondo de Investigaciones Sanitaria.

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Footnotes

Medical Oncology Service, Onco-hematology Research Unit, Instituto de Investigación Sanitaria Puerta de Hierro, Hospital Universitario Puerta de Hierro-Majadahonda, Spain

lowast Corresponding author. Address: Servicio de Oncología Médica, Unidad de investigación en Onco-hematología, Instituto de Investigación Sanitaria Puerta de Hierro, Hospital Universitario Puerta de Hierro-Majadahonda, Calle Manuel de Falla, 1, Madrid 28222, Spain. Tel.: +34 913445148; fax: +34 913445190.