Treatment of cutaneous T cell lymphoma with acombination of low-dose interferon alfa-2band retinoidsRobert M. Knobler, MD,a Franz Trautinger, MD,a Thaddeus Radaszkiewicz, MD,bEva M. Kokoschka, MD,a and Michael Micksche, MDc Vienna, Austria

In a pilot study the therapeutic effect and side effect profile oflow-dose interferon alfa-2b incombination with a retinoid for. the treatment ofcutaneous T cell lymphoma were evaluated.Seven patients (four women, three men) with histologically confirmed cutaneous T celllym­phoma were included. Four patients had received therapy previously. The treatment sched­ule consisted of2 million U ofinterferonalfa-2b administered subcutaneously three times perweek and oral 13-cis-retinoic acid, 1mg/kg/day, with subsequent dose reduction in case ofresponse. The combination therapy produced two complete and two partial remissions. Re­sponses were maintained by continuous therapy for up to 15 months even after dose reduc­tion of both agents by 50%. Side effects were negligible and did not result in discontinuationof treatment in any patient. (J AM ACAD DERMATOL 1991;24:247-52.)

Cutaneous T cell lymphoma (CTCL) is a lym­phoproliferative disease (low-grade non-Hodgkin'slymphoma) characterized by a clonal proliferationofT lymphocytes mainly ofthe helper/inducer type;these have a predilection for the epidermis and pap­illary dermis in the early stages of the disease.Involvement of lymph nodes, peripheral blood, andvisceral organs is the predominant feature of laterstages of CTCL. I

Standard therapies for CTCL include local andsystemic measures. Topical nitrogen mustard, pho­tochemotherapy with PUVA, and total body elec­tron-beam irradiation have been used to treat skinlesions. Systemic therapy in more advanced stages ofthe disease with chemotherapeutic agents alone or incombination (i.e., vincristine, cyclophosphamide,doxorubicin, deoxycoformycin) has resulted in re­sponse rates of less than 25% regardless of the agentusOO.2-8

Within the past 5 years biologic response modi­fiers have been introduced for the treatment ofCTCL. Previous studies have shown that in selectedcases retinoids and interferon are active in influenc­ing the course of this disease.9-18

From the Department of Dermatology II,n the Institute of Pathology,band the Institute ofApplied and Experimental Oncology,CUniversityof Vienna.

Reprint requests: Robert M. Knobler, MD, II. Dept. of Dermatology,University of Vienna, Alserstrasse 4, A-1090 Vienna, Austria.

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PhaseIIstudies in CTCLhave demonstrated thatretinoid therapy has resulted in impressive butshort-lived therapeutic responses. For example, in aphase II study of 25 patients, a response rate of44%-eomplete remission (CR) and partial remis­sion (PR)-was achieved.II Isotretinoin (1 mg/kg/day) produced response rates similar to those of ahigher dose (e.g., 3 mg/kg) with significantly re­duced toxicity,lO, 11 For this reason a dose of 1 mg!kg of 13-cis-retinoic acid was used. in this trial.

With the development of recombinant DNAtechniques interferons are now produced with a pu­rity of more than 95%. Interferon-a (IFN-a) par­ticularly is an active agent for the treatment of avariety of malignant and virus-related diseases. 19

In CTCL, IFN-a therapy has resulted in aresponse rate of more than 40% within phase I andII studies. However, in several patients, especiallythose who were receiving high doses of IFN-0:, ther­apy had to be discontinued because of severe sideeffects. IS

In the present pilot study we have investigated thetherapeutic effect and toxicity profile of low-doseIFN alfa-2b in combination with 13-cis-retinoic acidfor the treatment of CTCL.

METHODPatients

Seven patients (four women, three men; mean age 58.3years, range 44 to 70 years) were included~ All patientshad histologically confirmed CTCL (Table I). Patients

247

248 Knobler et aJ.

.... ..,:0- .. ., -,,__

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Fig. 1. CTCL: patient 1 before treatment. A, Dense dermal infiltrate and marked epider­motropism. Arrowheads indicatedermoepiderrnaljunction. (Hematoxylin-eosinstain; X 175.)B, Total tumor infiltrate positive for CD4. (Peroxidase stain; X175.)

Table I. Patients and treatment response

Therapy

Total doseDuration of

Patient Age IFN-a I Retinoid treatmentNo. Sex (yr) Stage" Previous therapy (IU [Xl()6)) (mg [Xl()3)) (mo) Response

1234567

FFFFMMM

60675663497043

IA/TINoMoIlBjT3NoMoIlBjT3NoMoIlBjT3N1Mo

IVAjT2N3MoIVBjT2N3M,IVBjT3N3M1

RadiationChemotherapy, radiationMultipletChemotherapy

276228204

72230

7272

20.217.215.76.7

13.56.76.7

2014138

1133

CR+CR+MR+PR+PR+PD:j:PD:j:

CR. Complete remission; MR, minor response; PD. patient diseased; PR, partial remission.*Staging according to 1978 National Cancer Institute classification.trncluding local and systemic chemotherapy, steroids, and radiation.~Therapy was terminated because of further disease progression.

with erythroderma or Sezary syndrome were not in­cluded.

Clinical staging was based on the extent of skininvolvement, morphology of the lesion, and presence ofextracutaneous disease manifestations according to theTNM (tumor, node, metastasis) classification.2o

The staging procedure included thorough history tak­ing and physical examination, chest roentgenography,liver and spleen scintigraphy, ultrasonography, computed

tomographic scanning (as required), and routine bloodanalysis (hematologic, hepatic, and renal function tests).Quantification of circulating tumor cells and atypicallymphocytes as well as bone marrow biopsies wereperformed in all patients. Evaluation of laboratory andclinical factors was performed at least at 3-month inter­vals. In all patients a portion of the skin biopsy specimenwas snap-frozen in liquid nitrogen. For immunopheno­typing a panel of monoclonal antibodies reacting with T

Volume 24Number 2, Part 1February 1991 Treatment ofCTCL with interferon alfa-2b and retinoids 249

and B lymphocyte-associated surface antigens (BectonDickinson, Mountain View, Calif.) and a sensitive three­step immunoperoxidase technique were used.21 In all pa­tients involvementofT helper/inducer lymphocytes and/or Sezary cells in the cutaneous lesions and other diseasemanifestations were verified (Fig. 1).

Four patients with CTCL had previously receivedtherapy that included local and/or systemic chemother­apy such as chlorambucil, electron beam radiation, andlocal or systemic glucocorticoids. Three patients had notreceived any specific previous treatment. No patienttreated more than 1 year earlier had shown any sponta­neous regression.

Therapy

The treatment schedule consisted of the subcutaneousinjection of 2 X 106 IV IFN alfa-2b (Introna, Schering­Plough Corp., AESCA GmbH, Vienna, Austria) threetimes weekly perilesionally (i.e., in the area adjacent totwo to three marker lesions) and the concurrent daily oraladministration of 13-cis-retinoic acid (Roaccutan, LaRoche, Basel, Switzerland), 1 mg/kg. On completeclearing ofcutaneous lesions, IFN alfa-2b was given sub­cutaneously in an upper arm.

Therapy was given for at least 3 months. In case of re­sponse, therapy was continued at an identical dose levelfor 3 additional months. After this period, in case of acontinuediesponse, 50% of the original dose of retinoidand IFN alfa-2b was given for another 3 months. Afterthis period IFN alfa-2b alone was given as maintenancetherapy.

Assessment of treatment results and toxicity

In all patients evaluable cutaneous lesions were initiallyrecorded by individual measurement with the aid of acaliper and were photodocumented. During therapy allsignificant lesions were monitored at monthly intervals forpossible changes.

A biopsy specimen of a representative lesion wasobtained from each patient before therapy. In case ofre­sponse the affected area was subjected to biopsy again.

Lesions were examined for the presence or absence oflymphocytic infiltrates in the dermis and/or characteris­tic Pautrier's microabscesses within the epidermis. Pa­tients with stage IVA and IVB disease were monitored bynoninvasive techniques for changes in systemic involve­ment (lymph nodes, peripheral blood, spleen, liver, lungs).

Clinical responses were classified as follows: CRsincluded complete resolution of all clinically evaluabledisease for 4 or more weeks. A PR consisted of a morethan 50% decrease of all measurable lesions for at least 4weeks. A minor response (MR) was defined as a decreaseofmore than 25% but less than 50% in measurable lesionsfor at least 4 weeks. Stable disease (SD) was classified asno objective response or absence of progression for at least3 months; progression consisted of an increase of 25% or

Fig. 2. Patient 1. Infiltrates found localized on foreheadand periorbital region before (A) and after (B) treatment.

greater in measurable lesions or appearance of newlesions. Objective and subjective side effects were evalu­ated initially on a twice-weekly and thereafter on a weeklyand/or monthly basis and classified according to theWorld Health Organization (WHO) toxicity criteria.22

RESULTSIn the seven patients with CTCL there were two

eRs (stage IA and IIB), two PRs (stage lIB andIVA), and one MR (stage IIB). The median time toresponse was 3 months. Representative photographsof two patients (Nos. I and' 2) are shown in Figs. 2and 3. These pictures demonstrate CR of lesions inforehead and periorbital region (patient 1; Fig. 2)and on the upper arm (Fig. 3, A and C) and in thegluteal region (Fig. 3, B and D) (patient 2). The re­sponse of lesions was independent of location anddistance to marker lesions. Clinical responses inthese patients (Figs. 2 and 3; Table II) correlatedwith the histopathologic changes in repeated biopsyspecimens as shown by absence of helper T cell in­filtrates.

Response was maintained in all patients by con-

250 Knobler et al.

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Fig. 3. Patient 2. Lesions on left upper arm and left gluteal region before (A and B, respec­tively) and after (C and D, respectively) treatment with low-dose interferon alfa-2b andretinoids.

Table II. Treatment response

Total dose

IDuration

IFN-a Retinoid of treatmentPatient No. Therapy (lU [XIC)6D (mg) (rno) Response

1 IFN + Ret 276 20,250 20 CR+2 IFN + Ret 228 17,250 14 CR+3 IFN + Ret 204 15,750 13 MR+4 IFN + Ret 72 6,750 8 PR+5 IFN + Ret 230 13,500 11 PR+6 IFN + Ret 72 6,750 3 PD*7 IFN + Ret 72 6,750 3 PD*

Ret, Retinoids; for other abbreviations see Table I.*Therapy has been terminated because of further disease progression.

tinuous therapy even after a 50% dose reduction andfinal maintenance therapy with IFN alfa-2b alone.The therapeutic effect was systemic; distant lesionsresponded as well as marker lesions. So far none ofthe patients has had a relapse within an observationtime of up to 15 months.

In two patients (Nos. 6 and 7; Tables I and II)with stage IVB CTCL who had received extensive

previous therapy, disease progression was not af­fected by this combination therapy. Therapy waswell tolerated and resulted only in WHO grade I andII toxicity. Initially patients had IFN-a-associatedside effects such as flulike symptoms (in all patients)and nausea, vomiting, and other intestinal symptoms(n ;;:; 2). Flulike symptoms could be effectively alle­viated with acetaminophen or paracetamol. After 2

Volume 24Number 2, Part IFebruary 1991 Treatment ofCTCL with interferon alfa-2b and retinoids 251

months of therapy patients developed tachyphylaxisto these symptoms. No signs of hair loss wereobserved. Hematologic and other laboratory find­ings were only transiently influenced by therapy.Leukopenia, grades I and II, was observed in twopatients. No significant decrease in platelet countswas observed. An increase in serum transaminaseand alkaline phosphatase was detected in one pa­tient. Blood cholesterol and triglyceride values wereincreased in all patients but did not exceed WHOgrade I levels. The retinoid-associated side effectswere mild in all patients and were easily controlledby local measures. With the dose reduction regimenused, no long-term retinoid therapy-related toxici­ties were detected. In none of the patients did the in­cidence and severity of side effects require anunplanned dose reduction or discontinuation ofcombined treatment.

DISCUSSION

We have shown that low-dose IFN alfa-2b incombination with a retinoid causes significant im­provement in some patients with CTCL. Increasingevidence exists that IFN-a is active especially inearly stages of CTCL and produces remission ratesof 20% to 40%.12-18 However, the duration ofresponses was only about 3 months despite continu­ous treatment. In the majority ofthese studies IFN­a-related side effects, probably because ofthe use ofhigh-dose regimens (15 to 30 X 106 IE), were con­sidered to be a therapy-limiting factor. In severalcases, therapy had to be interrupted because of sideeffects.

In our investigation of low-dose IFN alfa-2b incombination with l3-cis-retinoic acid, side effectswere negligible and did not result in a need todiscontinue treatment. Furthermore, with continu­ous therapy, generally after 6 months, we were ableto reduce doses by 50%. Mter this reduction andduring subsequent IFN alfa-2b maintenance ther­apy no interruption in the on-going response wasseen.

Systemic retinoid therapy has been used for thetreatment of premalignant and malignant skin le­sions as well as other oncologic and hematologicdiseases.9-11,23 CTCL, particularly in its earlystages,seems to respond frequently and response rates in therange of 40% to 60% have been reported in largerpatient series. However, in several patients responseswere short-lived and the retinoid had to be discon­tinued or reduced because of side effects.9-11

Recently therapy with a retinoid and high doses

of IFN-a has been evaluated in seven patients withCTCL; there was one CR and three PRs. However,in four of these patients therapy had to be discontin­ued after 1 to 2 months because of side effects.24

Although our results are preliminary, they clearlydemonstrate that the combination of low-dose IFNalfa-2b with a standard dose of 13-cis-retinoic acidis an effective dose regimen. The exact mechanismof action of this combination therapy remains un­clear. These agents can modulate the biologic func­tion of normal and malignant cells, both in vitro andin vivo. These biologic response modifiers also have,besides differentiation-inducing activities, modulat­ing and/or enhancing effects on the expression ofcertain cell surface molecules such as histocompat­ibility and tumor-associated antigens, glycoproteins,and activation markers.25, 26 Whether this, togetherwith the known immunomodulating effect of IFN­a and retinoids, results in an enhanced cell-mediatedlysis of malignant target cells in vivo remains a mat­ter of speculation. However, both these agents areable to augment cytotoxic activity of T-cells andnatural killer cells in vitro and in vivo.25, 27 Further­more, an augmentation of both biologic responsemodifiers on macrophage function has beendocumented.26,27 In addition, IFN-a and retinoidshave an antiproliferative effect on a variety oftumorcells in vitro and possibly in vivo.28 Which of thesebiologic response modifying properties contributedto the objective clinical responses observed in ourstudy n~mains to be elucidated.

Because of the high efficacy observed, even aftera short period of treatment, together with a negligi-

. ble incidence of side effects, this combination oflow-dose IFN alfa-2b and a retinoid should be con­sidered in the treatment ofCTCL, particularly in theearly stages.

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