Treatment of mycosis fungoides

 

(57) Abstract:

The invention relates to medicine, namely to dermatology, and relates to a method of treatment of mycosis fungoides. To do this, enter the inducer of endogenous interferon, Radostin in the form of intramuscular injections of the drug 8 mg 2 times per week, a rate of 6 injections. Simultaneously with Radostina prescribed prednisolone at a dose of 0.5 mg/kg/day. within 21 days, then reduce dosage to 2.5 mg in 3 days. The treatment leads to the achievement of high clinical efficacy in patients with II and III stage of the process while reducing the risk of complications. 3 table.

The invention relates to medicine, namely to dermatology, and can be used for the treatment of malignant lymphoma of the skin.

One of the types of chronic, severe pathology of the skin is malignant lymphoma of the skin (SLC) related to the total group of lymphoproliferative diseases, the type of non-Hodgkin lymphoma (N.A. Probatova, N. N. Tupitsin, E. C. Fleishman. Basic principles and diagnostic criteria for the revision of the European-American classification of lymphoid neoplasms (T-cell lymphoma, Hodgkin's disease)// Archives of pathology. -1998. No. 4. - S. 61-70). In accordance with the classifications (REAL, 199 and (T-SLK) make up 65-80% of all lymphomas of the skin. Among T-SLK the most common nosological form is mushroom avium (classical three-stage form of Libera of Bazin and erythrodermic form of Allepo-Besnier) (Skin and venereal diseases: Guide for physicians. - So 3/ Ed. by Y. K. Skripkin. - 1996. - N-100-105; Rodionov A. N., Barinov centuries, Kazakov D. C. Histological diagnosis of lymphoma of the skin // Journal of dermatology and cosmetology. -1997. No. 1. - S. 5-14; Hawks centuries, Raznatovic I. M. Lymphoma of the skin. - 2000. - N-3-74).

At the present time for the treatment system (nodal) lymphomas are a significant number of standardized protocols doses and modes of appointment of pathogenetically important drugs (gluco-corticosteroids, cytotoxic drugs, and others), while protocols for the treatment of malignant lymphomas of the skin are absent (essential drugs for cancer chemotherapy//Bulletin of the who. - 1994. - So 72, No. 5. - C. 3-8). This situation makes an urgent search for new drugs for the treatment SLK, especially of mycosis fungoides (GM), and development of scientifically-based schemes and recommendations on their application.

In the literature of recent years special place is occupied by reports of the use of therapies SLK United in enantia interferons, cytokines, retinoids (Heald P. The treatment of cutaneous T-cell lymphoma with a novel retinoid.// Clin. Lymphoma. - 2000. - Vol.1(1). - P. 45-49; Duvic M. Treatment of cutaneous T-cell lymphoma from a dermatologist''s perspective// Clin. Lymphoma. - 2000. - Vol.1(1). - P. 15-20, 2000).

1. It is established that interferon (, and ) have pleotropic effect on lymphocytes: activate macrophages and EC cells, increase the expression of antigens of the major histocompatibility complex on macrophages and target cells, induce re-expression of phenotypic markers in malignant lymphoid cells, which is important for inhibition of tumor process, as well as providing an antitumor effect through the depression in the expression of proto-oncogene C-myc and c-ras, c-fos (gentle N. M., Chekhun C. F. System interleukins and cancer. - K.: DIA, 2000. - 224 S.; Greenway H. T. Interferon - coming of age// Arch. Dermatol. - 1990. - Vol.126. - P. 1080-1082; Baron S., Tyring S. K. The Interferons: machanisms of action and clinical application// JAMA. - 1991. - Vol.266. - P. 1375-1380; Hakansson, A., Gustafsson C., Krysander L., Hakansson L. Effect of IFN-alpha on tumor-infiltrating mononuclear cells and regressive changes in metastatic malignant melanoma// J. of Interferon-Cytokine Res. -1998. - Vol.18(1). - P. 33-39).

Summarizing the results of more than 20 reports on the clinical use of drugs IFN in the treatment of T-SLK, G. Burg in his book "Strategies for Immunointerventions in Dermatology" (Springer-Verlag Berlin Heidelberg. - 1997. - P. 164, P. 322, 324) makes a conclusion about the effectiveness of this group immunomodulatory remission process and only 10% from the complete clinical remission. Experience of application of preparations in the treatment of patients with GM is also represented in the few works of Russian researchers and indicates moderate clinical effectiveness of schemes interferonoterapii in the treatment of patients with GM at various stages of the development process (table 1).

However, the use of officinal preparations in therapeutic doses (30-50 million ME on the course) leads to the development of side effects: prepodobnye clinical symptoms, fever, leukopenia and thrombocytopenia, hepatocellular destruction, significantly affects the quality of life of patients in therapeutic process (Caplan, E. H., Rosen, S. T., Norris D. B. Phase II study of recombinant human interferon for treatment of cutaneous T-cell lymphoma// J. Natl. Cancer Inst. - 1990. - Vol.82. - P. 208-212; Burg G. et al. Cutaneous Lymphomas// Current Probl. Dermatol. - 1997. - Vol.9(5). - P. 137-204; Haley H. R. Durable loss of a malignant T-cell clone in a stage IV cutaneous T-cell lymphoma patient treated with high-dose interferon and photopheresis// J. Am. Acad. Dermatol. - 1999. - Vol.41(5). - P. 880-883).

Thus, immunotherapy T-SLK with the introduction of exogenous interferons, providing comprehensive anti-tumor effect, demonstrates a modest clinical efficacy in combination with a high risk of side effects, and also ookami skin in the dermatological Department of a multidisciplinary medical institutions// journal of dermatol. and venerol. - 2001. No. 4. - S. 33-34).

At the same time, there is an alternative way of interfrontal, devoid of the above disadvantages, the essence of which is the inclusion in the patient's own mechanisms of production of endogenous interferon in biologically adequate amounts with the introduction of its inducers (Ershov, F. I. the interferon System in health and disease. - M.: Medicine, 1996. - 240 S.; Ershov, F. I., Tuzulukov E. B. Inducers of interferon - a new generation of immunomodulators//Bulletin of the Russian Academy of medical Sciences. - 1999. No. 4. - S. 52-56). However, in the treatment of T-SLK a similar approach to the treatment of previously almost never used, and that was the goal of developing new therapies GM (T-cell malignant lymphoma of the skin).

The prototype of the invention is a method of treating T-SLK (GM), which consists in the carrying out of immunotherapy with interferon - A2 at a dose of 3-5 million ME 3 times a week for 2-3 months. In this way were treated 14 patients with T-SLC: 4 with stage 2 and 10 with 3 stage of development of pathological process. Therapy has been effective in 9 of 14 patients (64.3 per cent), from which complete clinical remission was not achieved any of the patients, 7 patients fixed partial remission, 2 patients - minimin I. A. Skin lesions with malignant lymphoproliferative diseases: Dis. Prof. the honey. Sciences. - Saint-Petersburg. - 2001, - 227 C.). At the same time during interferon therapy in patients with T-SLK were marked by poor tolerance of treatment, concomitant formation of undesirable phenomena, such as pronounced chills, pyrexia, anorexia, nausea, weight loss, depression and other (Farajov H., Lymphoproliferative diseases of the skin and Kaposi's sarcoma (pathogenesis and therapy methods): Dis...Prof. the honey. Sciences, M., 1990. - 278 S.; Lamotkin I. A. skin Lesions with malignant lymphoproliferative diseases: Dis...Prof. the honey. Sciences. - Saint - Petersburg - 2001, - 227 S.).

An alternative to the introduction of exogenous interferon are methods of increasing the synthesis of its own interferon activated lymphocytes. Known drug Radostin with polyfunctional immunomodulatory effects and related to the group of inducers of interferon (IFN).

Radostin domestically - produced interferon inducer "early type", the main active principle of which is double-stranded RNA (DS RNA) killer strains of Saccharomyces cerevisiae. Radostin is a mixture of sodium salts of the active ingredient is East mass of white. The main characteristic of the drug is interferon-inducing activity (alpha-, beta - and gamma - interferons), proven in clinical trials on human volunteers in clinical practice, when the introduction of Radostina resulted in higher titers of interferon in the serum during the first 6 hours in 93% of subjects and was preserved during the day in 60% of patients (Nesterov, F. Biological activity of double strand RNA// Biotechnology. - 1990. No. 4. - S. 7-12; Ershov, F. I., Tuzulukov E. B. Inducers of interferon - a new generation of immunomodulators// Bulletin of the Russian Academy of medical Sciences. - 1999. No. 4. - S. 52-56). It is shown that Radostin not only increases the synthesis of all types of interferon, but also increases in the blood levels of interleukins (IL-1, IL-6) and tumor necrosis factor alpha (Bondar I. A., Radostin in the treatment of diabetes mellitus// J. struct. Dokl. III Grew up. The NAC. fo. “Man and medicine”, - M., 1996. - S. 81). Preclinical trials of the drug showed a reduction in prelevement experimental tumors, the frequency of metastasis and decreased proliferative potential of tumor cells, which is associated with correction of the IFN system (stimulation of its unrealized potential), as well as with the regulatory impact of Radostina on the function of macrophages and T-limpot. 1993. No. 3. - S. 20-23; Barinskiy Of The Imperial Family, Posiva T. A., Lavrukhina L. A., Kosyakov N. P. Antitumor activity of double-stranded inductors of interferon (lariana, Radostina) and reaferona in the experiment// the. Virology. - 1994. - So 39. No. 4. - S. 179-182; Kadagidze H. P. Immunological approaches to the use of cytokines in complex treatment of malignant neoplasms// Questions of Oncohematology. - 1995. - So 41. No. 2. - S. 45-47).

Installed immunomodulating properties of Radostina, including increased antitumor potential of this organism, as recorded in the Register of medicines of the Russian Federation (Revision 1999-2002) and prove the possibility of its use as an adjuvant drug in the treatment of diseases, including proliferative involving disorders of the immune status.

Known pathogenetic use of glucocorticosteroid (GCS) hormones in the treatment of lymphoid neoplasms. Prednisolone is a synthetic analogue of the steroid hormone cortisone, anti-inflammatory, antiallergic, desensitizing, immunosuppressive and anti-toxic effect. Immunosuppressive effect implemented in suppressing migration STV is foigney tissue (Mashkovsky M. D. Drugs, part II. - 1997. - S. 28-30). In the treatment of T-SLK systemic and topical corticosteroids hormones (mainly prednisolone) as monotherapy used in doses 60-30 mg/day, but more applicable to patients with early stages of the development of T-SLK and provides satisfactory clinical effect remission only 43.8% of patients with 3 stage of disease development (Rodionov A. N. Erythrodermic lymphoma of the skin (tutorial). - Leningrad, 1989, 67 S.; Kalemkarian A. A., Berenbaum B. A., Potekaev N. With. Modern problems of clinic, diagnosis, pathogenesis and treatment of malignant lymphomas of the skin and sarcoma Galoshes// Vestnik St.Petersburg University. dermatology and venereology. - 1991. No. 7. - S. 18-26; Litwinska E. M. Cytological diagnosis of malignant lymphomas of the skin, flowing type erythrodermic: Dis... Prof. the honey. Sciences. - M., 1997, 239 C.). Thus, monotherapy with corticosteroids hormones effective in the early stages of the development process (GM stage 1 and 2), a relatively effective in patients with 3-stage disease.

The purpose of the invention is the increased efficiency of treatment of T-SLK while reducing the risk of clinical complications of therapy.

This goal is implemented by the appointment of a sick T-SLK (GM) inducer of endogenous intiem. The method of treatment is used in conditions of specialized dermatology Department with full hospital mode (or in the hospital day stay).

Patients SLC was conducted therapy corticosteroids hormones in the starting dose of 0.5 mg/kg/day in the first 2 weeks of infusion, then oral dose of 0.5 mg/kg/day with subsequent dose reduction to 2.5 mg in 3 days. On the background of corticosteroids therapy was carried out by introduction of Radostina.

In accordance with General recommendations on the application of Radostina the drug was administered I/m 8 mg of the active substance dissolved "ex tempore" in 2.0 ml of water for injection. Radostin appointed since 1 week primary care patients were administered 2 times a week with an interval of 2-3 days, at the rate of 4-6 injections of the drug.

The duration of the basic course of treatment was 30 days, after which continued oral therapy GCS with lower doses.

Positive clinical dynamics, as a rule, began in the first weeks of therapy and was expressed in the reduction of hyperemia and infiltration into the lesions, a decrease in the intensity of itching and burning skin. During the introduction of Radostina and after completion of the course continued regression of symptoms, and 4-6 week treatment status eritrodermii PR is stavley when the regression hyperpigmented areas of the skin.

The proposed method was applied in the treatment of 13 patients with T-TLC, 9 of which were in a state of eritrodermii (classification TNM - stage III development process), 4 patients with GM (stage IIA) with symptoms of partial eritrodermii in age from 39 to 70 years, including 3 women and 10 men. Disease duration ranged from 2.5 to 6 years.

The diagnoses were histologically verified in the clinic of Urnie Shown. Previously patients were treated mainly with the use of systemic and topical corticosteroids, which made it possible to achieve extremely short duration of clinical remission (3-5 months). Anamnestically and clinically the patients of this group differed frequent exacerbations process (from 3 to 6 episodes), the rapid development of eritrodermii accompanied by the occurrence of pyogenic complications on the skin, the presence of comorbidity systems and organs of an inflammatory nature.

Table 2 shows the own data of the clinical effectiveness of the modified method of treating T-SLK Radostina in comparison with the data Lamattina I. A. (2001) treated with interferon - alpha 2.

From table 2 it is seen that the described method of treatment did not lead to the progression of the process no pain is tov after the end of therapy with Radostina was achieved clinical improvement: in 1 patient a minimum, in equal proportions (6 patients - 46,2%) partial and complete remission. Method comparison was significantly less effective: in 14.3% of patients with minimal improvement, and 50% had only partial remission of the disease. In addition, when treating Radostina side effects were observed only in 2 patients (15.4 per cent), they were easily stopped, did not necessitate drug discontinuation.

Clinical efficacy of treatment with the use of Radostina was accompanied by significant changes in the immune status of patients with T-SLK (GM) after treatment (table 3). Treatment Radostina determined a significant increase reduced before treatment the content of interferon - gamma in the serum and even a tendency to excess regulatory indicator, indicating that the pathogenic effects of the drug. Achieve clinical effect after the end of therapy Radostina was also accompanied by a unidirectional increase in populations of CD8+, CD16+ lymphocytes and cells expressing the apoptosis-associated receptor, indicating that reliable activation factors antitumor immunity, determining the possibility of regression of lymphoid neoplasia.

The use of the proposed method TEI rash on the skin of the trunk and limbs, intense constant itching. Sick with this disease for 2 years, notes continuously relapsing course of the disease, despite ongoing therapy (desensitized, detoxification, system (prednisone 20 mg/day, topical corticosteroids). Histology and immunophenotyping sample skin in Arnieboy health Ministry has allowed to establish the diagnosis of Malignant T-cell lymphoma of the skin. Mushroom avium, erythrodermic form (stage III).

On examination, the patient: skin condition eritrodermii, the skin is reddish-bluish tint, expressed infiltration, fine-flaked scaling, excoriation on the skin of the trunk and upper extremities, hyperkeratosis of palms and soles. Associated diseases: ischemic heart disease, atherosclerotic cardiosclerosis, NC 0-I; chronic bronchitis. The liver is not enlarged, the spleen not palpated.

When clinical and laboratory research hospital, Arnieboy were detected abnormalities in basic immunological indicators: disimmunoglobulinemia, Hyper-E-immunoglobulinemia, the violation ratio of populations of T-helper/T-suppressor cells, raising the level of CD19 (b-cells), decreased 1.7 times the content of IFN-gamma in si is the treatment Radostina under the traditional scheme in the form of I/m injection of 8 mg of active substance, dissolved ex tempore" in 2.0 ml of water for injection. Radostin appointed since 1 week primary care patients were administered 2 times a week with an interval of 2-3 days, just spent 6 injections of the drug. At the same time was prescribed prednisone per os 30 mg/day for 21 days, followed by a decline of 2.5 mg in 3 days, antihistamines, outer topical therapy. The treatment was conducted under the supervision of hemogram 1 time in 5 days.

As a result of ongoing therapy after 2 injections of the drug, Radostin (1 week of treatment) showed a significant decrease in the intensity of pruritus and burning; after 4 injections (2 week treatment) was recorded reduction of redness and peeling of the skin, in the same period significantly decreased infiltration of the skin, peeling. Resolution erythrodermic manifestations occurred in week 4 of treatment. Adverse reactions and complications of therapy were noted.

In re the immunological after the course of treatment, there was significant reduction in IgE levels, the approximation to the normal values of IgG and the ratio of populations of T-helper/T-suppressor. In the peripheral blood - normalization of the content of IFN-gamma, lymphocytes and eosinophils. The patient was discharged in a state of complete clinical read observation in the clinic, Arnieboy since 1999, after numerous histological studies in 2001 verified the diagnosis of T-cell malignant lymphoma of the skin. Mushroom avium, ON stage. The patient repeatedly held stationary treatment in the clinic using desensitizing, detoxification of drugs, systemic therapy (prednisolone 30 mg/day up to 14-20 days) and the outer corticosteroid therapy, were discharged with improvement on maintenance therapy glucocorticosteroids. The skin has acquired resistance to therapy, often combined with short periods of remission (2-3 months).

When clinical and laboratory research in Arnieboy in the immunological was detected disimmunoglobulinemia, a moderate increase of IgE, high levels of IL-4. In the peripheral blood - moderate leukocytosis, eosinophilia.

Was prescribed treatment with Radostina under the traditional scheme in the form of I/m injection of 8 mg of the active substance dissolved ex tempore" in 2.0 ml of water for injection. Radostin appointed with 1 weeks total therapy the patient was administered 2 times a week with an interval of 2-3 days, just spent 6 injections of the drug. At the same time was prescribed prednisone per os 35 mg/day for 21 days, with follow what stralem hemogram 1 time in 5 days.

As a result of ongoing therapy after 4 injections of the drug, Radostin (2 week treatment) was a decrease of active hyperemia and infiltration in the area of plaques, reduce itching at the rash. After 6 injections of the drug spotty rash almost regressed, and plaques was significantly reduced in height, completely disappeared itching. Within 3 weeks after the introduction of Radostina dose of prednisolone was slowly decreased until full repeal. At discharge (total duration of hospital stay 43 days) process regressed by 50%, which characterizes the outcome of therapy as partial remission process. Adverse reactions and complications during therapy were noted.

Dynamic study of the immunological status revealed a tendency to decrease IgE in the peripheral blood, decreased leukocytosis, eosinophilia.

Proposed method in Arnieboy treated 13 patients with T-SLK in age from 39 to 70 years, including 3 women and 10 men. Disease duration ranged from 2 to 17 years, diagnoses were histologically verified for the first time in the clinic Arnieboy. Previously, patients were treated with the use of systemic and topical corticosteroids, it was not possible to achieve complete clinical remissive achieved in 12 of 13 patients (92.4 per cent), one patient (7.6%) is the minimum improvement process. The duration of remission ranged from 12 to 19 months.

Thus, tested a new method of treatment of T-SLK (of mycosis fungoides), including appointing inducer of interferon in combination with the medium therapeutic doses of prednisone, which helped to significantly improve the efficiency of care by reducing the risk of complications.

Treatment of mycosis fungoides involving the use of immunotherapy and prednisolone, characterized in that as an inducer of endogenous interferon apply Radostin in the form of intramuscular injection of 8 mg 2 times per week General course of 6 injections and at the same time with Radostina prescribe prednisone per os at a dose of 0.5 mg/kg/day with subsequent dose reduction to 2.5 mg in 3 days.

 

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