Alternating recombinant and natural alpha-interferon helps to prevent clinical resistance to interferon in cutaneous T-cell lymphoma treatment.

Sir, (WellferonB , Glaxo-Wellcome), natural leukocyte (CilferonB , Janssen-Cilag) and raIFN (Intron-AB , Schering-Plough), 3 It is well known that prolonged administration of recombinant alpha interferon (raIFN) in several viral and malignant disMU intramuscularly, daily or on alternate days depending on the clinical outcome, evaluated as in our former paper (4). eases can be followed by loss of clinical activity of the drug. In the majority of these cases, the occurrence of insensitiveness Etretinate, 50 mg/day orally, is routinely coupled. After more than 3 years of experience, we have observed no loss of clinical to raIFN could depend on the synthesis of biologically active raIFN-neutralizing endogenous antibodies (1), although some effectiveness of IFNs in 7 of the 8 patients we have been treating. argue that a cause-and-effect relation between these facts has not been proven (2). Recently, others have pointed out that Formerly we predicted that alternative use of various kinds of IFNs could prove effective in treating lymphoproliferative even non-neutralizing IFN antibodies could be relevant in affecting alpha interferon efficacy (3). We started using alterndiseases of the skin selectively (4). On the ground of our satisfying pilot results we confirm our belief, and we encourage ate treatment with different interferons (IFNs) in 1994, when we observed our first case of resistance to raIFN in connection other groups to try such alternating protocols on extended series of CTCL patients in order to lay the groundwork for with the treatment of cutaneous T-cell lymphoma (CTCL). These are our pilot reports. controlled studies. Incidentally, we must unfortunately recognize that public health service officials are indifferent to, or even mistrustful of empirical therapeutic attempts, which are CASE REPORTS needed in the specialized management of rare conditions for Case 1 which codified therapy is unavailable or often ineffective. In A 44-year-old man with CTCL (Scandinavian MF group stage II ) Italy the use of natural IFNs is limited by bureaucratic and (4) had been treated with raIFN, 3 MU/day intramuscularly, and administrative restrictions, and special authorisations must be etretinate, 50 mg/day orally, according to the protocol described obtained. elsewhere for a former series of CTCL patients treated with IFN (4). Clinical resistance ensued 98 days after the beginning of the treatment. His condition deteriorated to stage III in a few days. Thus we decided REFERENCES to treat this patient with natural IFNs, as already done by other researchers in chronic myelogenous leukemia patients (5). In a fort1. Kuzel TM, Roenigk HH Jr, Samuelson E. Suppression of antinight the disease regressed to a stationary stage II, which has lasted interferon alpha-2a antibody formation in patients with mycosis for more than 3 years up to now. fungoides by exposure to long wave UV radiation in the A range and methoxsalen. J Natl Cancer Inst 1992; 84: 119–121. Cases 2 to 8 2. Steis RG, Smith JW, Urba WJ. Resistance to recombinant interFearing that other cases of resistance to raIFN could ensue, we feron alfa-2a in hairy-cell leukemia associated with neutralizing prophylactically turned the other patients currently treated with raIFN anti-interferon antibodies. N Engl J Med 1988; 318: 1409–1413. or newly enrolled (7 males; 5 stage II, 1 stage III, 1 stage IVa; mean 3. Rajan GP, Seifert B, Prümmer O, Joller-Jemelka HI, Burg G, age 57; range 42–74; mean disease duration 0.5 years) to alternating Dummer R. Incidence and in vivo relevance of anti-interferon IFNs. Partial remissions (4 cases) or reductions of progressive disease antibodies during treatment of low-grade cutaneous T-cell to a stable one (3 cases) were always obtained and maintained (range lymphomas with interferon-alpha-2a combined with acitretin or 9–32 months), except in the stage III case: he became insensitive to PUVA. Arch Dermatol Res 1996; 288: 534–548. IFNs in 1 month and had to be treated with total body electron beam 4. Altomare GF, Capella GL, Pigatto PD, Finzi AF. Intramuscular irradiation, which was successful. low dose alpha-2b interferon and etretinate for treatment of mycosis fungoides. Int J Dermatol 1993; 32: 138–141. 5. Von Wussow P, Jakschies D, Freund H. Treatment of anti rIFN DISCUSSION alpha 2 antibody positive CML patients with natural interferon When we decided to put the first patient of our series on alpha. J Interferon Res 1989; 9 (Suppl 2): S113 (Abstract). 6. Galton J, Finter N, Nethersell A. Low incidence of neutralizing alternating IFNs, we had considered the fact that the developantibodies in patients treated with human lymphoblastoid interment of antibodies to natural IFNs presented with a lower feron (IFN-alfaN1). J Interferon Res 1989; 9 (Suppl 2): S128 incidence and seemed to induce loss of clinical responsiveness (Abstract). less frequently (6). Moreover, it had already been stated that 7. Dianzani F, Antonelli P, Amicucci P. Low incidence of neutralizing in many instances therapeutic efficacy could be re-established antibody formation to interferon-alfa 2b in human recipients. by resuming treatment with natural alpha-IFN (7). These J Interferon Res 1989; 9 (Suppl 1): S33–36. facts opened up the outlook of administration of various IFN mixtures in rotation to CTCL patients. Our results were quite encouraging; thus we extended the rotation administration of Accepted October 1, 1997. IFNs to all of our CTCL patients currently treated with raIFN, without expecting the clinical onset of resistance to a Gianfranco Altomare, Giovanni Luigi Capella and Elena Frigerio given IFN. The ‘‘rotation protocol’’ we now follow consists Istituto di Dermatologia dell’Università, Ospedale Maggiore IRCCS, Via Pace 9, I-20122 Milan, Italy. of alternating 3-month cycles of natural lymphoblastoid