14 Biologics in Cutaneous Lymphoma

14 Biologics in Cutaneous Lymphoma

M. Beyer, Ch. Assaf, W. Sterry

14.1

Introduction

Primary cutaneous lymphomas (PCL) are defined as clonal proliferations of malignant T or B lymphocytes that present in the skin with no evidence of extracuta- neous disease at the time of diagnosis. They can be dis- tinguished into cutaneous T-cell lymphomas (CTCL), cutaneous B-cell lymphomas (CBCL) and the rare pre- cursor dendritic cell neoplasms. The PCL are now clas- sified in the new WHO-EORTC classification (Willem- ze et al. 2005; Table 14.1).

Primary cutaneous lymphomas are different from lymphomas of nodal origin in regard to clinical picture, course of disease and therapy. As there has been no curative therapy hitherto, treatment should be directed towards improvement of quality of life. Initial aggres- sive therapy, i.e. multi-agent chemotherapy, will in most cases result in only a transient remission and is not able to improve overall survival. Therefore an intensive search for new therapeutically active agents, which are acting specifically on the tumour cells, is ongoing. Immune therapies are of special interest as the tumour cells originate from B or T lymphocytes (Table. 14.2). For these cells a whole variety of surface antigens are well defined and monoclonal antibodies are available. In this chapter we briefly describe the

Table 14.2. Biologics in cuta-

neous lymphoma Name Target Molecular structure Disease

DAB389IL-2 (Ontak) CD25 Fusion protein CTCL

Alemtuzumab (MabCampath) CD52 Monoclonal antibody CTCL

90Y-ibritumomab tiuxetan (Zevalin)

CD20 Monoclonal antibody,

chelator and radionuclide CBCL

Rituximab (Mabthera) CD20 Monoclonal antibody CBCL

Depsipeptide (FR901228) Histone deacetylases Cyclic tetrapeptide CTCL Suberoylanilide hydroxamic

acid Histone deacetylases Hydroxamic acid CTCL

Table 14.1. WHO-EORTC classification of cutaneous lympho- mas with primary cutaneous manifestations

Cutaneous T-cell and NK-cell lymphomas Mycosis fungoides

Mycosis fungoides variants and subtypes ) Folliculotropic MF

) Pagetoid reticulosis ) Granulomatous slack skin S´ezary syndrome

Adult T-cell leukaemia/lymphoma

Primary cutaneous CD30-positive lymphoproliferative dis- orders

) Primary cutaneous anaplastic large cell lymphoma ) Lymphomatoid papulosis

Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type

Primary cutaneous peripheral T-cell lymphoma, unspecified ) Primary cutaneous aggressive epidermotropic CD8-posi-

tive T-cell lymphoma (provisional)

) Cutaneous * / · T-cell lymphoma (provisional)

) Primary cutaneous CD4+ small/medium-sized pleomor- phic T-cell lymphoma (provisional)

Cutaneous B-cell lymphomas

Primary cutaneous marginal zone B-cell lymphoma Primary cutaneous follicle centre lymphoma

Primary cutaneous diffuse large B-cell lymphoma, leg type Primary cutaneous diffuse large B-cell lymphoma, other intravascular large B-cell lymphoma

Precursor hematologic neoplasm CD4+/CD56+ hematodermic neoplasm

clinical picture and course of the most common cuta- neous lymphomas. We also review data on treatment, efficiency and safety of biological agents currently used in the treatment of PCL.

14.2

Cutaneous T-Cell Lymphomas

Cutaneous T-cell lymphomas (CTCL) belong to the extranodal non-Hodgkin’s lymphomas. The incidence is 0.5 – 1/100,000. Mycosis fungoides (MF, Fig. 14.1), the most common, and S´ezary syndrome (SS), a leukaemic variant, are discussed in more detail. Another group of CTCL are the CD30+ lymphoproliferative disorders, nominally anaplastic large cell lymphoma and lympho- matoid papulosis, which are characterized by a relaps- ing course but an overall favourable prognosis. All oth- er entities of CTCL are rare.

For MF the mean age of manifestation is 55 years with a male predominance of 2:1. While the life expec- tancy for patients with limited skin involvement equals that of a healthy control group, the 5-year sur- vival rate for patients with lymph node involvement falls to 20 %.

Despite intense research, the exact pathogenesis of CTCL is still not understood. In immunohistochemis- try the malignant cells are of a CD4+ T-cell memory phenotype, and the loss of certain T-cell markers like CD2, CD3 or CD5 is a common finding. However, in ini- tial stages of the disease it can be impossible to differ- entiate between the clonal T cells and concomitantly infiltrating lymphocytes by microscopy.

Fig. 14.1. Mycosis fungoides, plaque stage

The histological hallmark of early MF is the so- called Pautrier microabscess. These are composed of T cells and Langerhans cells, the epidermal antigen pre- senting cells. Therefore chronic stimulation with a, so far unknown, antigen is thought to result in uncon- trolled proliferation of MF/SS cells. Possible triggers may be antigens, derived from the atypical T cells themselves as well as bacterial superantigens.

The clinical picture of MF is characterized by patches, plaques and tumours, which may occur sepa- rately as well as concomitantly. The latter may have a mushroom-like appearance, which is responsible for the term mycosis fungoides.

As there has been no curative therapy hitherto, the treatment of CTCL is stage adapted. While therapy in early stages without extracutaneous involvement is skin directed, e.g. topical steroids, topical chemothera- py or phototherapy, in more widespread disease a com- bination of topical therapy with systemic agents such as interferon- [ and/or retinoids is advisable. Chemother- apy should be reserved for late stages of MF with viscer- al involvement as it results in selection of therapy-resis- tant tumour cell clones in most cases.

S´ezary syndrome is a CTCL defined by erythroder- ma, a leukaemic phase and lymph node involvement at the time of diagnosis. Additional morphologic features are an often-intense pruritus and palmoplantar hyper- keratosis. In contrast to MF the prognosis for SS is much worse, with a 5-year survival rate of only 24 %.

Therapy with extracorporeal photopheresis (ECP)

alone or in combination with interferon- [ has been

shown to induce complete remission. The ECP is a pro-

cedure during which leukocytes are separated from red

blood cells, and are, after incubation with psoralen,

radiated with UV light. The procedure results in lym-

phocyte apoptosis while monocytes differentiate into

immature dendritic cells (DC). The effect of ECP is pos-

sibly mediated by maturation of DC after ingestion of

apoptotic lymphocytes, resulting in presentation of

tumour cell derived antigen to cytotoxic T cells. There-

by an anti-tumour immune response is generated. An

alternative first line therapy is a combination of PUVA

and interferon- [ . However, in advanced disease only

single or multiagent chemotherapy may be able to, at

least transiently, stop disease progression.

14.2.1

Cutaneous B-Cell Lymphoma

The cutaneous B-cell lymphoma (CBCL) comprises around 25 % of all cutaneous lymphomas. The three most common subtypes are the marginal zone lympho- ma (MZL), the follicle centre cell lymphoma (FCL) and the diffuse large B-cell lymphoma (DLBCL), leg type.

Although there is a high tendency to relapse, MZL and FCL have a very good prognosis with 5-year survival rates of 99 % and 95 %, respectively. The DLBCL, leg type, tends to grow more aggressively and the 5-year survival rate is only 55 %.

The pathogenesis of CBCL is still unknown. A chronic stimulation by an infectious agent has been proposed and DNA sequences of the spirochaete Borre-

occurring in Europe.

The clinical picture of the MZL is characterized by erythematous macules, papules, plaques or nodes, mainly located on the trunk and upper extremities. The histology of MZL shows a nodular to diffuse infiltrate, which is located in the dermis and subcutaneous fat and contains the small- to medium-sized marginal zone cells. Immunohistochemical stainings demon- strate expression of the B-cell marker CD20 and the anti-apoptotic protein bcl-2 on tumour cells. A clonally rearranged immunoglobulin heavy chain can be detected by PCR in most cases.

The FCL is characterized by neoplastic proliferation of centrocytes and centroblasts. Patients present with bluish-reddish or reddish-brownish solitary or multi- ple nodes surrounded by papules and plaques or annu- lar erythemas, primarily localized on head and back.

Histologically the lesions are caused by a follicular infiltrate with germinal centres or by a diffuse infiltrate in the dermis and subcutis. In the immunohistochem- istry the cells stain positive for CD20 and in cases with a follicular organization of the infiltrate also for CD10, bcl-6 and CD21.

The typical patient with a DLBCL, leg type, is of old age and presents with brownish- or bluish-erythema- tous nodes, papules or plaques localized on the lower extremities. The histology of the lesions shows a dense nodular or diffuse infiltrate filling the dermis and reaching into the subcutis. Morphologically the neo- plastic cells present as large blastic B lymphocytes with a high mitotic rate. The immunohistochemical expres- sion pattern is defined by CD20, immunoglobulins,

found on the cell surface or in the cytoplasm, and bcl-6.

A monoclonal rearrangement of the immunoglobulin- heavy-chain gene is detectable in the majority of patients.

While standard therapy for indolent CBCL is exci- sion or radiation, diffuse large B-cell lymphoma, leg type, often requires chemotherapy.

14.3

Biologics in the Treatment of CTCL

14.3.1

DAB389-Interleukin-2 (DAB₃₈₉IL-2)

DAB

IL-2 (synonyms: Denileukin Difititox, Ontak) is a recombinant cytotoxic fusion protein composed of the receptor-binding domain of the human interleukin- 2 (IL-2) molecule and a mutated diphtheria toxin (DT) molecule (Williams et al. 1990).

The target structure of DAB

IL-2 is the IL-2 recep- tor (IL-2R). The high affinity IL-2R is formed by associ- ation of CD25 ( [ -chain) with the low affinity IL-2R composed of CD122 and CD132. The heterotrimeric receptor is expressed on activated lymphocytes and monocytes as well as CTCL cells. The complex of DAB

IL-2 bound to the IL-2R is internalized by endo- cytosis. After proteolytic cleavage of the fusion protein the DT fragment becomes active and binds to the elon- gation factor-2. Thereby protein synthesis is inhibited, resulting in cell death by apoptosis.

DAB

IL-2 is administered intravenously in two dif- ferent dosages (9 or 18 μg/kg body weight) once daily on 5 consecutive days every 3 weeks for up to eight cycles. In immunohistochemical studies a high level of CD25 expression (equal to or more than 20 % of lesio- nal T cells) was significantly associated with clinical response. In a phase III trial, 71 CTCL patients were treated. The overall clinical response rate was 30 %, with 10 % showing a complete remission. The median duration of remission lasted for 6.9 months (range from 2.7 to 46.1 months). The quality of life and pruri- tus as assessed by questionnaires improved significant- ly in responders compared to non-responders (Olsen et al. 2001).

Infusion related adverse events were hypotension,

chest or back pain and dyspnoea. Also flu-like symp-

toms like fever, chills and nausea occurred. Few

patients suffered from severe adverse events such as

allergic reactions or a capillary-leak syndrome. Tran-

sient elevations of liver enzymes and hypoalbuminae- mia were observed in serum analysis. Premedication with paracetamol, antihistamines or in severe cases systemic steroids may increase tolerability of DAB

IL- 2 infusions.

Taking these data together, DAB

IL-2 is a generally well-tolerated additional treatment option in patients with CTCL refractory to standard therapy regimens.

The effect of treatment with DAB

IL-2 may be enhanced by bexarotene, a synthetic retinoid that has been shown to increase IL-2R expression in vitro and in vivo. Recently published data have shown comparable efficiency of DAB

IL-2 in B-cell non-Hodgkin’s lym- phoma, but data for treatment of CBCL are still miss- ing.

14.3.2 Alemtuzumab

Alemtuzumab (Campath-1H, MabCAMPATH) is a humanized monoclonal IgG antibody binding to CD52.

The CD52 antigen is expressed on monocytes, granulo- cytes, B and T lymphocytes and clonally proliferating malignant lymphocytes. CD52 is not expressed on hae- matopoietic stem cells. In vitro experiments suggest that the effect of alemtuzumab is mediated by comple- ment mediated lysis, antibody dependent cellular cyto- toxicity and induction of apoptosis. After administra- tion, alemtuzumab results in depletion of the vast majority of lymphocytes for a prolonged period of time.

In the first trial incorporating patients with advanced therapy, refractory CTCL remission was seen in four out of eight patients, two of them showing com- plete remission. In a consecutive phase II trial conduct- ed by the Swedish lymphoma study group (Lundin et al.

2003), 22 patients with therapy refractory advanced MF/SS were included. Alemtuzumab was administered 3 times weekly at a dosage of 30 mg for a maximum of 12 weeks. All patients received premedication with paracetamol and antihistamines. The administration of steroids in the first week of infusions was optional.

As infectious prophylaxis, cotrimoxazole and acyclovir were given throughout the study.

The overall response rate was 55 %, with 32 % of the patients showing a complete remission. The efficacy was higher in less heavily pre-treated patients and in erythrodermic patients compared to plaque or tumour stage patients. Interestingly, all patients with lymph

node involvement showed complete remission while patients with dermatopathic lymphadenopathy had a stable or progressive disease. A strong reduction of pruritus was observed in responding patients. The median time to relapse was 12 months, ranging from 5 to 32 months.

Side effects in temporal association to the infusion were generally mild reactions like fever, nausea or aller- gic reactions and could be controlled with premedicati- on. In terms of haematological toxicity, grade 4 neutro- penia and thrombopenia occurred but resolved sponta- neously during or after the end of treatment.

Infectious complications in the above-mentioned study were fatal in two cases. One patient died from pulmonary aspergillosis while the other succumbed to

lovirus was detected in 18 % of patients, presenting as fever without pneumonitis. All of these patients could be successfully treated with intravenous ganciclovir.

Another patient developed a generalized herpes sim- plex virus infection, which resolved after foscarnet treatment.

Another potential complication of alemtuzumab is cardiac toxicity. While in one study cardiac abnormali- ties were reported in 50 % of patients, in another trial no such events were recorded.

In conclusion alemtuzumab should be considered as an option in patients with advanced MF/SS disease who did not respond to previous systemic therapies.

Because of the potential severe infectious complica- tions, patients should receive antibiotic and antiviral prophylaxis and should be monitored closely for early signs of infections.

14.3.3 Rituximab

Rituximab (MabThera) is a recombinant chimeric IgG antibody binding to the human CD20 antigen. CD20 is expressed on pre-B cells and mature B lymphocytes, and is expressed on > 90 % of B cells in non-Hodgkin’s lymphoma. CD20 expression is not detectable on hae- matopoietic stem cells, plasma cells, or non-haemato- poietic tissues.

The effect of rituximab is mediated by induction of apoptosis in target cells, antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity.

In the treatment of CBCL rituximab has been used as

a systemic infusion as well as an intralesional injection.

In an applicational observation, Gellrich et al.

reported on ten patients with CBCL (FCL, MZL) (Gell- rich et al. 2005). The dosage was 375 mg/m

body sur- face area once per week, up to 8 weeks. All patients received premedication with hydroxyhydrochloride and indomethacin. Complete remission was observed in seven out of the ten patients, while two of the ten had a partial remission. The mean duration of remission was 23 months. Observed side effects were infusion- related fever, shivering and nausea. Laboratory analysis showed a nearly complete depletion of B cells, leaving other parameters, e.g. creatinine and alkaline phospha- tase, unchanged. During the study two patients suf- fered from bacterial infections; albeit no severe adverse events were recorded.

Intralesional administration of rituximab has also been shown to be effective in the treatment of CBCL (Piekarz et al. 2001). In a retrospective study, patients received 10 mg rituximab intralesionally in up to four lesions three times weekly. Cycles were repeated every 4 weeks for up to eight cycles. With this regimen a com- plete remission was observed in six out of seven patients. While in one patient the tumour recurred locally after 27 months, two patients had a recurrence at distant body sites after 12 and 14 months, respective- ly. Side effects were burning sensations at the injection site during and several hours after injections. Interest- ingly, B cells were depleted from the circulation, indi- cating systemic effects of locally applied rituximab.

Intralesional injection of rituximab is especially suit- able for solitary or a small number of lesions as system- ic adverse events have not been observed and the amount of rituximab needed is less than for systemic administration, thus lowering treatment costs.

Currently rituximab is recommended as second line treatment for patients with relapsing or refractory CBCL and is generally well tolerated.

14.3.4

90Y-Ibritumomab Tiuxetan

90

Y-ibritumomab tiuxetan (Zevalin) is a radioimmuno- therapeutic agent composed of a monoclonal murine IgG antibody, which binds to the human CD20 mole- cule, and tiuxetan, a molecule which contains the radionuclide yttrium-90. Yttrium-90 is a q -radiator with a half-life of 64 h and a radiation distance within tissues of 5.3 mm. Binding of the antibody to cells expressing CD20 results in radiation-induced apopto-

sis of target cells and nearby cells (so called “collateral damage”). Whether other antibody-specific mecha- nisms contribute to the therapeutic effect of

Y-ibritu- momab tiuxetan is unclear today. Compared to the chi- meric antibody rituximab described above, ibritumo- mab is cleared faster from the circulation. Therefore duration of exposure to radiation is limited.

Y-Ibritu- momab tiuxetan is approved in Europe for the treat- ment of B-cell non-Hodgkin’s lymphoma.

CD20-positive cells are depleted from the circula- tion by administration of rituximab 1 week and several hours before the one-time infusion of YIT. The admin- istered dosage is 0.4 mCi/kg.

Preliminary results of a prospective study on treat- ment of CBCL showed complete response in eight of nine treated patients while one patient had progressive disease (Duvic et al. 2005). In the follow-up phase, one patient had a relapse after 6 months while seven out of nine patients remained in remission. Reported side effects were a decrease in ECOG status from 0 to 2 or 3 and a weight loss in 33 % of patients. Haematological toxicities (thrombopenia, lymphopenia and anaemia) resolved after 12 weeks.

Adverse events, recorded in studies treating non- Hodgkin’s lymphoma, were infusion-related side effects such as fever, nausea, chills and flu-like-symp- toms. The myelosuppressive effects of

Y-ibritumo- mab tiuxetan are observed 4 – 8 weeks after administra- tion. Of observed grade 4 haematological toxicities, neutropenias were the most common, in 30 % of patients on average, with thrombocytopenia and anae- mia occurring in 10 % and 3 %, respectively. It is note- worthy that neutropenia and thrombocytopenia required active therapy in 60 % of cases. However, most of the cytopenias are only short-lived. As the haemato- logical side effects correlate with the pre-treatment platelet count, the dose has to be reduced if the pre- treatment count is < 150×10

platelets/l.

So far only preliminary data are available regarding

treatment of CBCL with ibritumomab tiuxetan. Remis-

sions have been achieved, but so far duration of remis-

sion remains unclear. Because of the generally benign

prognosis of CBCL,

Y-ibritumomab tiuxetan should

be reserved for CBCL, which are refractory to other

treatments or have systemic involvement.

14.3.5

Histone Deacetylase Inhibitors

The acetylation status of histones is involved in regula- tion of gene transcription. While histone acetylation favours DNA transcription, histone deacetylases keep the DNA in a transcriptional inactive state. Histone deacetylase inhibitors (HDACIs) increase the acetyla- tion status of histones and thereby facilitate the tran- scription of genes involved in cell differentiation, cell cycle arrest and apoptosis.

Currently two substances, namely depsipeptide (FR901228) and suberoylanilide hydroxamic acid (SAHA), from the group of HDACIs are being investi- gated for the treatment of CTCL. Depsipeptide has been given to three patients with CTCL refractory to previ- ous topical or systemic therapies (7). The drug was administered intravenously on days 1 and 5 of a 21-day cycle. Improvement of skin erythema and oedema was reported for two patients with S´ezary syndrome and nearly complete remission for a patient with tumour stage CTCL. Development of multiple subcutaneous abscesses in one patient was reported as an adverse event. Because of these promising results, a phase II trial was initiated.

An oral formulation of SAHA has been tested in a phase II trial with 37 CTCL patients participating (8).

The used dosage was 400 mg once daily. Reported results showed a partial remission in 27 % of patients. A decrease in lymphadenopathy and pruritus was seen in 58 % and 68 %, respectively. Observed adverse events were fatigue, symptoms, nausea, dry mouth, and decreased appetite. Thrombocytopenia (grade 3 or 4) occurred in 18 % of patients.

In conclusion HDACIs showed clinical activity in CTCL patients, which were refractive to previous thera- py. However, before they can be recommended for the treatment of CTCL, the existing results need to be con- firmed by the ongoing studies.

References

Duvic M, Talpur R, Zhang C, Goy A, Richon V, Frankel SR (2005) Phase II trial of oral suberoylanilide hydroxamic acid (SAHA) for cutaneous T-cell lymphoma (CTCL) unrespon- sive to conventional therapy. J Clin Oncol 23(16S):abstract 6571

Gellrich S, Muche JM, Wilks A, Jasch KC, Voit C, Fischer T, Audring H, Sterry W (2005) Systemic eight-cycle anti-CD20 monoclonal antibody (rituximab) therapy in primary cuta- neous B-cell lymphomas – an applicational observation. Br J Dermatol 153(1):167 – 173

Lundin J, Hagberg H, Repp R, Cavallin-Stahl E, Freden S, Juli- usson G, Rosenblad E, Tjonnfjord G, Wiklund T, Osterborg A (2003) Phase II study of alemtuzumab (Campath-1H) in patients with advanced Mycosis fungoides/Sezary syn- drome. Blood 101:4267

Olsen E, Duvic M, Frankel A, Kim Y, Martin A, Vonderheid E, Jegasothy B, Wood G, Gordon M, Heald P, Oseroff A, Pinter- Brown L, Bowen G, Kuzel T, Fivenson D, Foss F, Glode M, Molina A, Knobler E, Stewart S, Cooper K, Stevens S, Craig F, Reuben J, Bacha P, Nichols J (2001) Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 19:376 – 388 Piekarz RL, Robey R, Sandor V, Bakke S, Wilson, Dahmoush L,

Kingma DM, Turner ML, Altemus R, Bates SE (2001) Inhibi- tor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood 98:2865 – 2868

Willemze R, Jaffe ES, Burg G, Cerroni L, Berti E, Swerdlow SH, Ralfkiaer E, Chimenti S, Diaz-Perez JL, Duncan LM, Grange F, Harris NL, Kempf W, Kerl H, Kurrer M, Knobler R, Pimpi- nelli N, Sander C, Santucci M, Sterry W, Vermeer MH, Wechsler J, Whittaker S, Meijer CJ (2005) WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768 – 3785

Williams DP, Snider CE, Strom TB, Murphy JR (1990) Struc- ture/function analysis of interleukin-2-toxin (DAB486-IL-2).

Fragment B sequences required for the delivery of fragment A to the cytosol of target cells. J Biol Chem 265:11885 – 11889