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DERMATOVENEREOLOGY
INVENTION
Patent of the Russian Federation RU2182481

METHOD FOR TREATMENT OF MALIGNANT LYMPHOMA SKIN

METHOD FOR TREATMENT OF MALIGNANT LYMPHOMA SKIN

The name of the inventor: Kungurov NV; Kokhan M.M .; Kuklin IA; Bazarny VV; Belykh OA
The name of the patent holder: Ural Scientific Research Institute of Dermatovenereology and Immunopathology
Address for correspondence: 620076, Yekaterinburg, ul. Shcherbakova, 8, URNIIDViI, Patent Department
Date of commencement of the patent: 1999.08.02

The invention relates to medicine, viz., Dermatology, and relates to a method for treating malignant skin lymphoma in a hospital setting. It is proposed to assign patients with malignant skin lymphoma cytostatic natulana and corticosteroid hormone prednisolone in an adaptive dose. Natulan treatment per os begins with 50 mg / day on the first day, from the second day the dose is increased by 50 mg / day to a daily dose of 250 mg. Continuation of treatment is carried out at 250 mg / day for 10-15 days before the onset of clinical stabilization of the process. Then the dose is reduced by 50 mg / day until complete withdrawal. The course dose of natulana is 4.5-5 g. In addition, prescribe in an adaptive dose of prednisolone per os PO 10-20 mg / day with a decrease of 5 mg in 5-7 days. The method allows to increase the treatment while reducing the risk of immunological complications from the chemotherapy.

DESCRIPTION OF THE INVENTION

The invention relates to medicine, viz., Dermatology, and can be used to treat malignant skin lymphoma.

One of the types of chronic, severe skin pathology is malignant skin lymphomas (ZLK), which belong to the general group of human lymphoproliferative diseases, to the type of non-Hodgkin's lymphomas (NA Probatova, NN Tupitsin, EV Fleishman. Criteria for the revision of the European American classification of lymphoid tumors (T-cell lymphomas, Hodgkin's disease) / / Archives of Pathology, 1998, - 4, - P.61-70). In accordance with the accepted classifications (REAL, 1994, WHO, 1996, EORTC, 1997), ZLKs are divided into T- and B-cell immuno-variants, where T-cell malignant skin lymphomas (T-ZLK) account for 65-80% of all lymphomas of the skin. Among the T-CLC, the most common nosological form is mushroomed mycosis (the classical three-stage Alibera-Bazen form and the erythrodermic Allopo-Bienier form) (Skin and Venereal Diseases: A Guide for Doctors .-- T.3 / Edited by Yu. K. Skripkina. - Rodionov AN, Barbinov VV, Kazakov DV Histological diagnosis of skin lymphomas // Journal of Dermatovenereology and Cosmetology .- 1997. - 1. - P.5-14. Yastrebov VV, Raznatovsky IM Lymphomas of the skin .- 2000. - P.3-74).

While for polychemotherapy of systemic (nodal) lymphomas, there are a significant number of standardized protocols regulating the dose and regimen for the administration of pathogenetically significant cytotoxic drugs and glucocorticosteroids, while at the same time there are no similar protocols adapted for the treatment of ZLK (Basic drugs for cancer chemotherapy // WHO Bulletin - 1994. - T.72, 5. - C.3-8). The current situation makes it urgent to search for new drugs and develop scientifically sound recommendations for their use.

Methods of treating ZLK using corticosteroid hormones in a daily dosage of 30-60 mg (in terms of prednisolone) are known, as well as cytostatics of various pharmacological groups: plant origin, synthetic, alkylating, antimetabolites and antitumor antibiotics. The listed preparations are not highly selective and do not allow achieving complete remission of the disease, which leads to the need to prescribe repeated courses of treatment. To improve the efficiency and optimize the therapy with cytotoxic patients, ZLK patients have developed numerous combined (including several drugs) polychemotherapy regimens. The most common programs were COR (cyclophosphamide 400 mg intramuscularly, intravenously every day from 1 to 5 days, vincristine 1.4 mg intravenously on day 1, prednisolone 60 mg orally daily from 1 to 5 days, 6, 7, 8 day 40 mg, 20 mg and 10 mg / day) and CHOP (cyclophosphamide 750 mg intravenously or intramuscularly on day 1, adriablastin 50 mg intravenously on day 1, vincristine 1.4 mg intravenously on day 1, prednisolone 60-100 mg orally Daily from 1 to 5 days). After achieving remission, another 3 repeated chemotherapy courses are performed (Skin and Venereal Diseases: A Guide for Physicians.-3 / Edited by Yu.K. Skripkina .- 1996.-P.100-105; Treatment of Skin Diseases: A Guide for Physicians / Under the editorship of AL Mashkileyson - 1990. - P. 483-490). At the same time, the use of intensive regimens of chemotherapy, especially for low-grade and intermediate-stage lymphoproliferative diseases (LLP), to which ZLK belong, is fraught with numerous complications, often does not lead to an improvement in objective indicators of treatment effectiveness. In this situation, it is necessary to evaluate the toxicity of therapy in comparison with the favorable course of the disease and to strive for the use of a minimally sufficient cytotoxic effect. (Zhuravlev VS The degree of malignancy of lymphomas and the adequacy of cytostatic treatment // Therapeutic Archives - 1994. - 7. - P.39-43; G Burg, RG et al., Current Problems in Dermatology, 1997, Vol. 5, No. 5, R.187-189).

The prototype of the invention is a modified scheme of polychemotherapy ZLK widely used in dermatological practice to the present. This scheme includes: prospidin (100 mg / day intramuscularly daily, 3-4 g per course), vincristine (1 mg intravenously once a week, for 4 weeks), prednisolone (30 mg / day inwards for 2 weeks, dose reduction To 0.005 g per day). Thus, the total duration of the course is 30-45 days on average, 5-6 similar courses of chemotherapy are conducted with intervals between courses of 4 weeks (Kalamkaryan AA Principles of modern therapy for malignant skin lymphomas and Kalosha's sarcoma // Herald of Dermatology and Venereology. 1988. - 2. - P.5-9, Kutasevich JN Features of pathogenesis, methods of early diagnosis and rational therapy of fungal mycosis / / Author's dissertation at the Sociological degree of the doctor of medical sciences - 1989; Faradzhev Z. Lymphoproliferative diseases of the skin and Kaloshi's sarcoma // Abstract of dissection at the sociological degree of the doctor of medical sciences - 1990, Lezvinskaya EM et al. Multiple erythematous-plaque and nodal foci on the entire surface of the skin / / Bulletin of Dermatology and Venereology .- 1998. - 5. - P.64-65).

The increase in the clinical efficacy of this scheme due to the intensive and prolonged complex use of two antitumor drugs is associated with the development of side effects and complications, especially during repeated courses of polychemotherapy. The use of a vegetable alkaloid - vincristine - can exert neurotoxic effects and cause paresthesias, motor disorders and focal lesions of the central nervous system. In addition, leukopoiesis can be suppressed (development of severe leukopenia), alopecia, ulcerative stomatitis, development of dyspepsia (weight loss, nausea, pain in the epigastric region), fever, polyuria. The daily intramuscular administration of prospidin in combination with the average therapeutic doses of a corticosteroid hormone, prednisolone, significantly increases the risk of developing infectious complications (pyoderma, abscesses of subcutaneous tissue) from ongoing therapy (Mashkovskiy MD Drugs, part II - 1997. - P.440-463).

Treatment with glucocorticosteroids in doses of 30-40 mg / day (in terms of prednisolone) has a significant negative shifts on the part of cellular, humoral immunity and endocrine system, causes a deepening of immunodeficiency. At the same time, treatment with maintenance (15-20 mg / day) doses of corticosteroids has a moderate immunostimulating effect, induces the formation of receptors on the cells for growth factors, leads to a moderately depressing effect on endocrinological parameters (Korolkova TN et al., Influence of glucocorticoid therapy On immunological and endocrinological indicators in patients with low-grade skin lymphomas // Journal of Dermatovenereology and Cosmetology .- 1997. - 1. - P.25-30).

Known synthetic antitumor drug natulan (procarbazine), belonging to the group of methylhydrazines. The mechanism of action of natulan (H) is to simulate the effects of ionizing radiation due to accumulation of the drug in tumor cells, its self-oxidation and intracellular formation of peroxide and hydroxide radicals, methylation of purines, DNA fragmentation and suppression of the process of dividing tumor cells. The drug is used in malignant diseases of lymphatic tissues: lymphogranulomatosis, lymphosarcoma, reticulosarcoma, chronic lymphocytic leukemia. The drug is effective in cases that are resistant to vinblastine (Mashkovskiy MD Drugs, part II. -1997.-P.460).

Prednisolone - a synthetic analogue of the glucocorticoid-steroid hormone cortisone - has anti-inflammatory, antiallergic, desensitizing, immunosuppressive and antitoxic effects. Immunodepressive effect is realized in suppression of migration of bone marrow and B-cell stem cells, violation of interaction of T and B lymphocytes, inhibition of lymphoid tissue development (Mashkovskiy MD Drugs, part II - 1997. - P.28-30 ).

Natulan as a monochemotherapeutic agent in the treatment of ZLK was not used, its combined use with maintenance doses of glucocorticosteroids will significantly improve the effectiveness of treatment, reduce the incidence of complications from the therapy.

The aim of the invention is to increase the effectiveness of ZLK treatment while reducing the risk of immunological complications from ongoing chemotherapy.

The goal is realized by the appointment of patients with ZLK cytostatics natulana and corticosteroid hormone prednisolone in an adaptive dose.

Patients on the background of symptomatic therapy (antihistamines, external ointment treatment) is prescribed on a percussion basis. Treatment begins with 50 mg / day on the first day, from the second day the dose is increased by 50 mg / day to a daily dose of 250 mg. Continuation of treatment is carried out at 250 mg / day for 10-15 days before the onset of clinical stabilization of the process. Then the dose is reduced by 50 mg / day until complete withdrawal. The curative dose of natulan is 4.5-5 g. Simultaneously with natulane it is prescribed in the adaptive dose of prednisolone per os at 10-20 mg / day for 10-15 days, then reduce the dosage by 5 mg in 5-7 days. Treatment is carried out under the control of the hemogram 1 every 5 days.

When assessing the clinical effectiveness of a new method of treatment of ZLK, the following criteria were taken into account: 1) change in subjective sensations (disappearance or reduction of itching, burning sensation); 2) the dynamics of objective clinical manifestations (color change, decrease in infiltration, peeling, dynamics of lymph node size); 3) general condition (temperature, blood pressure, pulse, clinical blood tests, urine, including biochemical and immunological blood tests).

In Table. 1 we present our own data on the clinical efficacy of the proposed method for treating ZLK. Obviously, the effect of treatment was obtained in all (100%) patients, clinical remission was achieved in 30% of cases, a significant improvement in 70%. The duration of the period of improvement and complete clinical remission in patients treated with the claimed method is on average 10.6 months, which is 2.5 times the duration of clinical remission in these patients after other previously used cytotoxic therapy methods.

In Table. 2 shows the clinical effectiveness of therapy with a new method of treating ZLK in comparison with the data of other authors. The proposed method of treatment by clinical efficacy significantly exceeds the data of Faradzhev ZG and by 37% the data of Kutasevich Ya.F. And allows for a greater percentage of cases to improve the condition of patients.

In Table. 3 shows the data of ZG. Farajeva et al. (1990) and his own data on immune status studies in patients with ZLK in the dynamics of therapy. A comparative analysis of the dynamics of changes in the main indices of the immune response in patients with ZLK during the treatment testifies to the coincidence of the vector orientation along the main (9 of 11) positions according to ZG. Faradzhev and co-authors (1990) and according to our data. According to ZG. Faradzhev and co-authors as a result of treatment develop depression of the T-cell link (an average decrease in the level of T-lymphocytes by 40%) with predominant oppression of helper activity, as the level of T-helpers lowered to treatment after treatment is further reduced, deviating from the normative in 1 , 91 times. The number of natural killers (NK), the population of lymphocytes, which provides control of the lymphoproliferative process, decreased already before the beginning of therapy, after its termination it is depressed 5.5 times. Thus, after treatment in a known way, signs of a moderately pronounced immunodeficiency state with inhibition of T-helpers and NK cells, populations of patho- and sanogenetically significant ones develop.

In the treatment with the new method, there are no signs of an immunodeficiency state, the level of T-helpers decreases less than 30% of the norm and remains within normal mean values, and the number of NK cells is restored to normal, which is predictive for patients with ZLK.

The use of the proposed method of therapy is explained by the following examples:

Example 1 : The patient S., 63 years old. Has arrived with complaints on an intensive constant skin itch, a lesion of a skin, disturbance of a dream. Has a given disease for 1 year. Over the previous 4-5 months, the continuous deterioration of the course of dermatosis is noted. It is registered with a dermatologist at the place of residence, hospital treatment including desensitizing, detoxifying, systemic (prednisolone 30 mg / day) and external corticosteroid therapy, discharged without effect with diagnosis - malignant skin lymphoma, erythrodermic form.

When examining the patient, the integuments in the state of total erythroderma of pink and cyanotic hue, pronounced infiltration, finely scaly exfoliation, excoriation on the skin of the trunk and upper limbs, hyperkeratosis of the palms and soles. Diffuse hair thinning on the head, tenderness and an increase in subcutaneous inguinal lymph nodes (1.5-2 cm in diameter, of a densely elastic consistency during palpation) are noted. At a roentgenography of a thorax and US of organs of an abdominal cavity of the increased lymphonoduses it is not revealed. From the side of the cardiovascular system and the gastrointestinal tract, age-related pathology is diagnosed - IHD, atherosclerotic cardiosclerosis, NK 0-1; Chronic calculous cholecystitis, chronic pancreatitis. The liver is not enlarged in size, the spleen is not palpable. A biopsy of the skin revealed pronounced parakeratosis. In the upper layers of the dermis, a lymphocytic infiltrate, intimately adjacent to the germ layer, exocytosis, and dilatation of the dermis. Histological conclusion: malignant skin lymphoma.

In clinico-laboratory studies in the hospital of the Ural Institute of Urology, the Institute found deviations from the norm in the basic immunological indicators. In particular, dissymunoglobulinemia, a violation of the ratio of T helper / T suppressor populations, an increase in the level of CD19 (B cells) was detected. In the peripheral blood - leukocytosis, lymphocytopenia, eosinophilia.

Natulan treatment was prescribed from the initial dose of 50 mg / day, followed by an increase of 50 mg / day to a daily dose of 250 mg, followed by full-dose therapy for 15 days with a further reduction in the drug by 50 mg / day until complete withdrawal. The course dose was 4.9 g. Simultaneously with natulan, prednisolone was prescribed per os 20 mg / day for 15 days, followed by a decrease of 5 mg in 5-7 days, antihistamines, external ointment therapy. The treatment was carried out under the control of the hemogram 1 every 5 days.

As a result of ongoing therapy, from the 4th day of treatment, a decrease in the intensity of skin itching, a reduction in flushing and flaking of the skin, a decrease in infiltration, regression of the subcutaneous inguinal lymph nodes, and resolution of erythroderma were observed by the 10-14 day of full-dose natulan therapy. There were no adverse reactions and complications of chemotherapy.

In the re-immunogram after the course of chemotherapy, a significant decrease in the level of IgM was observed, approaching the normal values ​​of the IgG level and the ratio of the T helper / T suppressor populations. In peripheral blood - the normalization of the number of leukocytes, lymphocytes and eosinophils, a decrease in platelet count by 34.3% (relative to the baseline level).

The patient was discharged in a state of clinical improvement, the duration of chemotherapy was 28 days.

Example 2 : Patient K., 59 years old, is under the supervision of the clinic since 1995 with the diagnosis - malignant skin lymphoma, erythrodermic form. Repeatedly passed hospital treatment, including desensitizing, detoxification, systemic (prednisolone 30 mg / day) and external corticosteroid therapy, was discharged with improvement on maintenance therapy with glucocorticosteroids. The skin process acquired resistance to the therapy, frequent exacerbations were combined with short periods of remission.

When clinico-laboratory study in UrNIIDViI in the immunogram was found B-lymphocytosis, dissymunoglobulinemia. In peripheral blood - moderate leukocytosis, eosinophilia.

Natulan treatment according to the above scheme was prescribed, full-dose (250 mg / day) therapy lasted 14 days, the course dose was 4.95 g. Simultaneously with natulan, prednisolone was administered 15 mg / day per os for 14 days, followed by a decrease by 5 Mg in 5-7 days, antihistamines, external ointment therapy. The treatment was carried out under the control of the hemogram 1 every 5 days.

As a result of ongoing therapy, from the 4th to 5th day of treatment, there was a decrease in the intensity of skin itching, from the 10th day, a decrease in flushing and flaking of the skin, a decrease in infiltration, regression of the subcutaneous inguinal lymph nodes, and resolution of erythroderma were observed by the 14th day of full-dose natulan therapy.

Dynamic study of the immunological status revealed a tendency of a decrease in the normal IgM levels and an increase in the IgG level. In peripheral blood - the normalization of the number of leukocytes and eosinophils, a decrease in platelet content by 31.2% (relative to the baseline level).

The duration of the chemotherapy course was 27 days, there were no adverse reactions and complications, the patient was discharged in a state of clinical improvement.

In the proposed method, 10 patients with CLD aged from 47 to 74 years, including 4 women and 6 men, were treated in UrNIIDV. The age of the disease was 3 to 15 years, the diagnoses were verified for the first time in the clinic of UrNIIDViI. Previously, patients were treated with systemic and topical corticosteroids, which prevented complete clinical remission. After the course of chemotherapy, clinical improvement was achieved in 10 out of 10 patients (100%). The duration of remission was from 2 months to 2 years.

Thus, a new, sparing method of ZLK treatment, including the appointment of a single chemotherapy, and the simultaneous administration of an adaptive dose of prednisolone (1.5-2 times lower than the current doses of corticosteroid therapy), is approved, which allows to significantly increase the effectiveness of therapy with a decrease in the risk of immunological complications and a reduction The total duration of treatment up to 25-29 days.

CLAIM

The method of treatment of malignant skin lymphoma, including the use of cytostatics and prednisolone, characterized in that as a cytostat used natulan per os, on the first day of 50 mg / day, from the second day the dose is increased by 50 mg / day to a daily dose of 250 mg, then treatment Is carried out at a dose of 250 mg / day for 10-15 days, after which the dosage is reduced by 50 mg / day until complete withdrawal, and concurrently with natulan, prednisolone is administered per os at 10-20 mg / day with a 5 mg decrease of 5-7 Days.

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Date of publication 01.04.2007гг