A method of treating non-hodgkin's lymphomas

 

(57) Abstract:

The invention relates to medicine, namely to Oncology, and can be used for the treatment of patients with non-Hodgkin's lymphoma II-IV stages of the disease. The essence of the method lies in the fact that out of 250 ml of peripheral venous autologous blood of the patient 150 ml of autologous blood incubated with anti-tumor chemotherapy, the remaining 100 ml incubated with Intron a dose 15106ME, both mixtures in separate vials placed in a thermostat at 37oWith an exposure time of 1 h, and then intravenous drip pour in the mixture of blood with anticancer chemotherapy for 25-30 min and the mixture of blood with Intron a for 2-3 hours, the Procedure was repeated on day 8, a total of 6 courses of treatment. The method allows for the efficient destruction of tumor cells in circulating blood and lesions, reduce the size of the tumor and lymph nodes, to reduce the toxicity of administered drugs to stimulate the immunoreactivity and General nonspecific immunological resistance of the body.

The invention relates to medicine, in particular to drug therapy in Oncology, and can be used in the treatment of patients with non-Hodgkin's lymphoma II-IV stages C is ndali "Treatment of non-Hodgkin lymphoma", Leningrad, 1990, page 1-25) by systemic chemotherapy in the form of short intensive cycles with intervals of 2-4 weeks.

However, the effectiveness of the treatment is insufficient. After complete remission, the treatment continues for 2-3 cycles of consolidation and treatment ceased, and upon the occurrence of partial remission treatment continued until complete remission or relapse. If for 3-4 cycles of treatment decreased tumor nodes retain their dimensions unchanged, treatment complement local radiation therapy.

There is a method of treatment of non-Hodgkin lymphoma with the combination of himiopreparatov: cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) (see "Handbook of Oncology, Moscow, 1996, pp. 479-500). The frequency of remissions induced CHOP, ranges from 80-90% of them full - 40-50%. In patients with non-Hodgkin's lymphoma of high-grade malignancy with a poor prognosis after ascertaining complete remission resulting from the use of schema CHOP relapse-free period can be increased by increasing CHOP-schema, for example, the addition of bleomycin, etoposide and other drugs.

However, the scheme CHOP has certain limitations associated primarily with myelotoxicity, in particular, Keomah. In addition, the frequency of complete remission does not exceed 50-55%, and their duration is very variable. To improve results of treatment of common lymphosarcoma used long multipillar scheme of chemotherapy, but this approach, despite its effectiveness is limited doselimiting toxicity. Intensification mode CHOP with a possible increase in efficiency in all cases requires the combined use with prophylactic and therapeutic purposes colony-stimulating factors (see Protocol "evaluating the effectiveness of Intron a in the induction and maintenance therapy of b-cell non-Hodgkin lymphoma", Moscow, 1999, page 4).

Known "Method of treatment of lymphoma (see patent 2144835 from 27.01.2000, 3 from 27.01.2000), chosen as a prototype, which consists in the fact that autochrome patient in 200 ml of centrifuged for 60 minutes at 1500 rpm, evacuate the upper light of the supernatant portion of the blood plasma and in cell sedimentary part of the blood type antineoplastic chemotherapy consisting of: cyclophosphamide - 650 mg/sq m, vincristine to 1.4 mg/sq m or vinblastine 6 mg/sq m and decisin 125 mg/sq m, incubated at a temperature of 36.5-37oC for 25-30 minutes and drip, vnutrepenialnye.

Despite the clinical efficacy of the method, reduction of toxicity, there is a method of treatment of lymphomas has disadvantages, namely, the slight decrease in the size of the tumor, immune depression.

The aim of the invention is the reduction mielotoksichnosti and doselimiting toxicity, reduction of tumor size and lymph node, stimulation of immunoreactivity.

This goal is achieved by the fact that from the total number of 250 ml of peripheral venous autologous blood of the patient 150 ml of autologous blood incubated with anti-tumor chemotherapy, the remaining 100 ml incubated with drug pharmaceutical firm Schering-plough" Intron a dose of 15 x 106ME, then both mixtures in separate vials placed in a thermostat at a temperature of 37oWith exposure time 1 hour, then intravenous drip pour in patient mix blood with anticancer chemotherapy for 25-30 minutes, and the mixture of blood with Intron a for 2-3 hours with prior sedation, the procedure is repeated on the 8th day, a total of 6 cycles of autohomeomorphism (AGAT).

The invention of "a Method for the treatment of non-Hodgkin lymphoma" is new, because it is unknown the level of medicine in the field of Oncology, l is camping in that autohemotherapy for the first time spend in the composition, in addition to the known anticancer drugs, with drug pharmaceutical firm Schering-plough" Intron-A (recombinant interferon-2b). The essence of the method lies in the fact that from the total number of 250 ml of peripheral venous autologous blood of the patient 150 ml incubated with anti-tumor chemotherapy, the remaining 100 ml incubated with Intron a dose of 15 x 106ME, then both mixtures in separate vials placed in a thermostat at a temperature of 37oWith exposure time 1 hour, then intravenous drip pour in patient mix blood with anticancer chemotherapy for 25-30 minutes and the mixture of blood with Intron a for 2-3 hours, the procedure was repeated on day 8, only 6 courses AGAT.

The invention of "a Method for the treatment of non-Hodgkin lymphoma" involves an inventive step, as for a specialist oncologist it is not obvious from the level of development of medicine in the field of drug treatment of non-Hodgkin lymphoma II-IV stages of the disease.

Known methods of treatment of NHL by systemic chemotherapy, transplantation of autologous hematopoietic tissue in her drug damage, comprehensive treatment is Denia operations, high material costs. The well-known "Method of treating lymphoma" autohemotherapy, despite the reduction of toxic manifestations, accompanied by immunosuppression, lack of resorption of tumors.

Proposed by the authors, "a Method for the treatment of non-Hodgkin lymphoma" differs significantly from the known. When the known method interferon used by subcutaneous injection at 3-9 million ME 3 times a week with very high duration of application, not less than 18 months (see Protocol "evaluating the effectiveness of Intron a in the induction and maintenance therapy of b-cell non-Hodgkin lymphoma", Moscow, 1999, page 4).

In the proposed method, the preparation of a pharmaceutical firm Schering-plough" intron-a is used not subcutaneously or intramuscularly, and intravenously drip, as the most effective way of introduction, especially when you link it with cells or proteins autologous blood, very slowly for 2-3 hours, as proven rapid elimination of interferon when administered intravenously. Introduction the combination of anticancer drugs and Intron a (recombinant interferon-2b) on autologous blood a patient with lymphosarcoma significantly reduces doselimiting toxicity is about Trona with Autocraft in vitro was shown to what are introns And acts as a mitogen and activator of T-cell immunity and may further contribute to the activation of natural killer cells at the system level. So this way the drug acts on the mechanism AutoClean immune and adoptive immunotherapy.

In the study mentioned above is confirmed by the dynamic changes of the parameters of immunological status of patients and some biochemical parameters. In comparison with the control group (autohemotherapy without Intron a) in the group of patients treated with intron-A, there were positive changes primarily in changes in the subpopulation composition of lymphocytes and their functional activity in rbcl. So, the content of lymphocyte-helper cells (CD 4+) increases from 0.32 to 0,h9/l, natural killer (CD 16+) - 0.18 to 0,h9/l; the number of spontaneously transformed cells increases from 0.22 to 0,h9/l, PHA-stimulated lymphocytes from 0.41 to 0,h9/L. These data indicate favorable changes mainly in the T-cell immune protection, which, as you know, plays a leading role in the recognition and killing of tumor cells. In addition, the increase in LPS-stimuline suggests, what in the dynamics AGAT the stimulation and B-cell immunity, which is equally important in ensuring antibody-dependent cellular cytotoxicity.

Interesting data were obtained on the dynamics of the changes of biochemical parameters in patients. The average of all studied patients with NHL before treatment reduced the intensity of the H2O2- luminal-dependent chemiluminescence (CHL) of blood plasma, reflecting the level of the most reactive free radicals, was 26% compared with people without pathologies. Patients with the most common forms of lymphosarcoma and especially with involvement of the lymph nodes of the abdominal cavity, the degree of reduction was significantly higher, reaching 51-69%. Patients of the main and control groups when the source is close to the distribution process was not different indicators PI before treatment, however, in the group of patients who had AGAT, consisted of patients with the above-mentioned common NHL and with a significantly lower baseline levels of CHL. In the control group changes of CHL were mixed; on average, but the group value of this indicator after 2 courses of treatment was 2430203 pulse/6 sec, which did not differ significantly from among otrastanie indicator PI; the average increase for the group amounted to 11%. A particularly pronounced increase in the intensity of chemiluminescence was in 2 patients of the group with the most extensive tumor lesion; original very low CHL (76% lower than the donor) after 1-year AGAT more than doubled and was only at 40% below normal.

These changes of CHL was accompanied by the optimization of antioxidant (AO) systems of the body. In both compared groups activity ceruloplasmin (CPU) in plasma was 2 times the normal value. In the dynamics of treatment was unidirectional reduction in the activity of the CPU in the direction of normalization, however, this decrease was more pronounced in the group with AGHT (53% of the level before treatment). Patients in the treatment regimen which was included intron-A, superoxide dismutase activity (SOD) after 2 courses exceeded the corresponding value in the group without Intron And 34%. Catalase activity (CAT) in patients of the main group before treatment was, on average, 48% higher than in donors in the control group - 38%. Studies in the dynamics of treatment, showed that the activity of CAT in the group with Intron And decreased by 10% in the direction of normalization, whereas in the group without Intron And continued SOD/CAT in erythrocytes. Before treatment, this figure was reduced by 39% in the group AGAT and 13% in the group IGHT. After 2 courses of treatment normalization of this aspect was noted in both groups. In the group AGHT with Intron a SOD/CAT was practically equal to that in individuals without oncopathology, in the group IGHT without Intron a was increased, however, the donor level never reached.

Thus, the proposed method is effective not only in the destruction of tumor cells in circulating blood and lesions, but also in the stimulation of immunoreactivity and non-specific immune resistance of the organism, the normalization of antioxidant defense and internal biochemical environment.

Thus, the proposed technical solution Method for the treatment of non-Hodgkin lymphoma" is not evident not evident from the level of development of Oncology in the treatment of lymphomas is not known neither in the world nor in the Russian (CIS) medical literature.

The invention is industrially applicable as it can be used in healthcare of the Russian Federation, research Institute of Oncology, Oncology clinics and other medical institutions for the treatment of cancer patients.

"The method of treatment lehocki what infomasi II-IV stages of the disease. Usually provides mnogocentrowoe treatment.

Just before the introduction of the patient from the cubital vein taken 250 ml of peripheral venous blood. One portion of the blood in a volume of 150 ml incubated with chemotherapy (cyclophosphamide 1000 mg, doxorubicin 50 mg, vincristine 2.0 mg), the other - in the volume of 100 ml with drug pharmaceutical firm Schering-plough" Intron-A (recombinant interferon-2b in a dose of 15 x 106ME. Next, the two portions of the blood in vials placed in a thermostat and incubated for 1 hour at a temperature of 37oC. After incubation during the first 25-30 min intravenous drip pour in autochrome with chemotherapy, then in 2-3 hours - autochrome with Intron A. before the introduction of the Intron And produce prophylactic premedication with Dimedrol, aspirin and paracetamol. Mnogocentrowoe treatment according to our method, is carried out according to the standard scheme is used 6 main courses of autohomeomorphism.

EXAMPLES of a SPECIFIC IMPLEMENTATION method of treatment of non-Hodgkin lymphoma

The method was tested in the treatment of patients with non-Hodgkin's lymphoma II-IV stages of the disease. Specific examples of the application of the method can with the OZ: the diffuse non-Hodgkin's lymphoma defeat paraaortal, paratively, deep iliac lymph nodes and lymph node iliac regions of the anterior abdominal wall on both sides, Art. II A. Histologically, diffuse lymphoblastic lymphosarcoma.

Objectively: on both sides in the iliac regions of the anterior abdominal wall are determined by palpation dense, motionless, painless lymph node conglomerates sizes h cm (right) and h cm (left); there is also moderate hepatosplenomegaly. By ultrasound examination of abdominal cavity and retroperitoneal space in mesogastric paraaortal and pregabalin conglomeration of lymph nodes to 7.5 cm, around which many small to 2.0 cm lymph node on the right and anterior to the iliac vessels lymph nodes up to 2.0 cm in diameter, left - to 3.2 cm, moderate hepatosplenomegaly. In General, the analysis of blood at the time of receipt of the most significant were: hemoglobin - 64 g/l, erythrocytes - 2,6X1012/l, ESR - 75 mm/h, lymphocytes - 17%, monocytes - 11%.

The first course AGAT. Autochrome patient in two portions before infusion were incubated with chemotherapy and Intron a for one hour at t=37oC, then poured in for 20-30 minutes (the portion with chemotherapy) and 2-3 izina, 2.0 mg vincristine and h6ME Intron A. Nausea and vomiting was not. Leukopenia was not observed minimum reduction level of leucocytes - 4,4x109/l). After each injection showed marked fever and hyperthermia to 39oWith lasting on average about 6-7 hours.

As a result of treatment, 2 weeks after the 1st course, clinically the condition is satisfactory, no complaints, palpable lymph node conglomerates of the anterior abdominal wall has been reduced in size to 4x1 cm (right) and 10 × 3 cm (left), is softer and more flexible; remains moderate hepatomegaly, spleen not enlarged. By ultrasound examination of abdominal cavity and retroperitoneal space in mesogastric paraaortal and pregabalin remains single conglomeration of lymph nodes to 4.3 cm in diameter; other groups of abdominal lymph nodes are not visible, moderate hepatomegaly. Dynamics of total blood count was as follows: hemoglobin - 84 g/l, erythrocytes - 3,2x1012/l, ESR - 18 mm/h, lymphocytes - 44%, monocytes - 9%.

For objectifying normalizing steps of the method AGAT on the immune status and the system of antioxidant protection of blood researched data of immunological indexes and neenie - 33%, then 45%; CD 8+ /20 32/; CD 16+ /15th and 21st/; CD 4+/CD 8+ /1.25 and 1.66 EN/; SPONT. /22 20/; PHA /33 38/; Kona /22 31/; LPS /25 and 38/. So clearly manifested immunomodulatory effects AGAT.

The intensity of the H2ABOUT2- lomineishvili chemiluminescence of blood plasma of the patient before treatment was low and was 807 pulse/6 seconds, after the first year increased to 1629 pulse/6 sec. Activity ceruloplasmin plasma source was increased to 181,56 mg/l, after the first year AGAT decreased 1.5 times and amounted to 126,43 mg/L. the Activity of SOD and catalase before treatment was 16.9 srvc.u/mg. b and 3.3 μm/minl, after the first year - 22,04 srvc.u/mg. b and 10,04 μm/minl respectively. These changes indicate a normalization of peroxide metabolism and functioning of the system of antioxidant enzymes.

A patient of Dr. Chuck C. N., 43 year history 3419/L.

DIAGNOSIS: diffuse non-Hodgkin's lymphoma with involvement of the nasopharynx, the box right of the tonsils, soft palate, cervical, axillary lymph nodes, and red bone marrow, Art. IV A. Histologically, diffuse prolymphocytes lymphosarcoma.

Upon physical examination: on the neck right conglomeration of lymph nodes size 20h15 cm, dense, completely stills the Oron single lymph node more than 3 cm in diameter, dense, sedentary. In the oral cavity is visualized large the tumor is irregular in shape with rough surface, originating from the Lodge right of the tonsils, passing on the soft palate, the Palatine arch, pushing back the tongue sharply to the left and partially covers the entrance to the oropharynx. When the rear rinoskopii in the nasopharynx to the right is determined exophytic growing tumor that has spread to parapharyngeal space. Percutere by palpation and marked moderate hepatomegaly. According to the myelogram in punctate bone marrow found atypical cells suspicious prolymphocytes of lymphosarcoma.

The first course AGAT. Total patient received 2000 mg of cyclophosphamide, 80 mg of doxorubicin, 2.0 mg vincristine and h6ME Intron-A. Of adverse reactions were observed moderate fever and hyperthermia to 37.5oC.

As a result of treatment, 2 weeks after the 1st course, clinically marked improvement in General condition. PA neck to the right a large conglomeration of lymph nodes decreased in size up to 10x7 cm, became less dense, shifting to the left lymph nodes regressed to 1 cm in diameter, were moving; in the armpit on both sides lymph is and no bows. When the rear rinoskopii in the nasopharynx to the right, the tumor regressed more than 1/3 of the original size. Percutere and palpation remains moderate hepatomegaly.

Marked shifts when comparing immunograms patient before treatment and after 1-year AGAT. The level of CD 4+ before treatment - 28%, after - 38%; CD 8+ /20 and 19/; CD 16+ /19 25/; CD 4+/CD 8+ /1,4 and 2,0/; SPONT. /14 20/; FGA /36 37/; Kona /23 21/; LPS /42 43/.

The intensity of the H2ABOUT2- lomineishvili chemiluminescence of blood plasma before treatment was 917 pulse/6 seconds, after the first rate increased until 1981 pulse/6 sec. Activity ceruloplasmin plasma source was high - 163,24 mg/l, after the first year AGAT was 109,0 mg/l SOD Activity before treatment was 10.72 services.ed./mg b, after the first year - 15,21 srvc.ed./mg b.

TECHNICAL and ECONOMIC EFFICIENCY of the method of treatment of non-Hodgkin lymphoma is that the method facilitates the efficient destruction of tumor cells in circulating blood and lesions, reduction of tumor size and lymph node, reduces doselimiting toxicity, is for the body mild stress exposure, improves the immediate condition of the patient. Lacope the t immune system, and stimulates immunological reactivity and General nonspecific immunologic resistance of the organism.

A method of treating non-Hodgkin's lymphomas, including autohemotherapy, characterized in that from the total number of 250 ml of peripheral venous autologous blood of the patient 150 ml of autologous blood incubated with anti-tumor chemotherapy, the remaining 100 ml incubated with drug pharmaceutical firm Schering-plough" Intron a dose of 15 x 106ME, both mixtures in separate vials placed in a thermostat at 37oWith an exposure time of 1 h, and then intravenously injected to the patient a mixture of blood with anticancer chemotherapy for 25-30 min and the mixture of blood with Intron a for 2-3 h with prior sedation, the procedure is repeated on the 8th day, a total of 6 courses of treatment.

 

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FIELD: medicine, anesthesiology-resuscitation, infectology, detoxication.

SUBSTANCE: the innovation suggested interrupts infectious-toxic shock, moreover, after that it is necessary to prescribe peroral intake of Reaferon-EC-Lipint at the dosage of 10000 - 15000 U/kg. Then one should sample patient's blood to obtain leukocytes to be washed and diluted in 0.9%-NaCl solution, activated due to incubation with immunophan and intravenously injected for a patient. Then comes peroral intake of Reaferon-EC-Lipint at the dosage of 10000 - 15000 U/kg once daily for 5 d. The innovation enables to decrease the number of complications and lethality due to decreasing immunodeficiency.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

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