[Multicenter cooperation--basis of progression in leukemia treatment].
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Biomedical subjects
Publications and source records attributed to G A Kliasova.
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AIM: To develop an original therapeutic strategy in Ph-positive acute lymphoblastic leukemia (ALL). MATERIAL AND METHODS: In November 2001 Hematological Research Center (HRC) initiated the study of chimeric BCR-ABL gene. During the first stage of the study (November 2001-July 2004), 18 primary ALL patients were recruited in HRC, from July 2004 to January 2005--16 patients in HRC, N.N. Burdenko Central Military Hospital, regional Samara hospital. The diagnosis of Ph-positive ALL was established in detection of translocation t(9;22) by standard cytogenetic test or fluorescent hibridization in situ with double signal (D-FISH), or by polymerase chain reaction with reverse transcription (RT-PCR). In detection of aberration of BCR-ABL gene the patients received stem hemopoietic cells, from June 2004 imatinib was added to chemotherapy in the period of induction and consolidation. RESULTS: Incidence rate of BCR-ABL-positive ALL by standard cytogenetic test and D-FISH makes up 20%, by RT-PCR--25%. Differences in chimeric transcripts detectability by different methods may be explained by different sensitivity of the methods. Complete hematological remissions were achieved in the majority of the patients (6 of 8) irrespective of imatinib administration. Achievement of molecular remission in BCR-ABL-positive ALL occurs also in standard chemotherapy but molecular remissions begin 2-4 months later than clinicohematological ones. CONCLUSION: In using imatinib combination with chemotherapy, molecular remission can be achieved simultaneously with hematological one. Long-term results will be analysed later.
AIM: To characterize infectious complications arising within 30 days after transplantation of autologous hemopoietic blood cells in 42 patients with hematological malignancy (HM); to compare the course of early posttransplantation period with reference to a kind of high-dose conditioning and dose of transplanted CD34+ cells. MATERIAL AND METHODS: Autotransplantation (AT) was conducted as consolidation of a complete or partial remission in 20 patients with multiple myeloma, 14 patients with lymphogranulomatosis and lymphosarcoma, 7 patients with acute leukemia and 1 patient with rabdomyosarcoma. The program of pretransplantation conditioning corresponded to the disease form and included: melphalan, BEAM, busulphane-cyclophosphamide. The number of transplanted CD34+ cells was 1.7-20.1 (median 5.3) x l0(6) cell/kg. The transplantation was followed by selective intestinal decontamination and mycosis prophylaxis. Fever was managed with antibiotics. RESULTS: An early period after AT ran without febrile episodes in 7 (17%) patients. This allowed physicians to avoid systemic antibiotic therapy. The infectious focus was not definitely localized in 35 patients with febrile fever in 77% cases. Clinically and bacteriologically verified infections were detected in 8 (19%) patients: 7 cases of pneumonia and 1 of bacteriemia. None of the patients died of infection early after AT. Not a single case of invasive aspergillesis was registered. CONCLUSION: Incidence and features of infections did not vary with the above diseases and did not depend on the dose of transplanted CD34+ cells. The kind of high-dose conditioning had a significant influence on the time of granulocyte recovery, duration of agranulocytosis, duration of one febrile episode and of antibiotic therapy. The dose of transplanted CD34+ cells also influenced the time of granulocyte recovery and duration of antibiotic therapy.
AIM: To evaluate the results of therapy of invasive pulmonary aspergillesis (IPA) in one medical center from 2000 to 2005. MATERIAL AND METHODS: Diagnosis of IPA was made according to the International criteria. Incidence of verified IPA was 2%, probable--84%, possible--14%. RESULTS: IPA was diagnosed in 50 cases in 49 patients aged 16- 78 years, median 35. Most of the patients consisted of acute leukemia cases (54%). Intensive cytostatic therapy was given in 41% cases. In 54% IPA developed in critical neutropenia, median of duration of which being 29 days (3 to 144 days). 29 patients received glucocorticoid drugs. In diagnosis of IPA Aspergillus spp was isolated in 46% cases (A. fumigatus-59%, A. flavus-29%, A. niger-4%, A-versicolor-4%, in 1 (4%) case identification was not made. Positive antigen Aspergillus was detected in 27 cases. All the patients had pulmonary involvement detected at x-ray or computed tomography. Coincidence of pulmonary lesions seen at x-rays and computer tomograms was only in 30% patients. Cure was achieved in 44%, lethality was 56%. Overall survival in IPA for 90 days was 47%. Amphotericine was effective in 29%. Voriconasol--in 3 of 5 patients, kaspofungin--in 3 of 7. Surgical treatment was given to 4 patients. CONCLUSION: Lethality in IPA for 5 years when basic therapy was amfotericin B reached 56%. Reduction of lethality can be achieved due to early diagnosis of the infection and administration of voriconasol at the initial stage of IPA. It is necessary to conduct multicenter studies to ascertain indications for combined antifungal therapy.
AIM: To investigate spread, species spectrum, quantity of aspergilla spores in the air of a hematological hospital. MATERIAL AND METHODS: Air samples (250 I/min, PU-1B device) were collected in hematological departments monthly. Isolation and identification of mycelial fungi were made on Chapek medium. In detection of Aspergillus spp. culture in the biomaterial, additional samples of the air and wash-out from the surfaces were collected. RESULTS: A 4-year mycological monitoring of the air has found that aspergilla constituted dominating micromycetes both by occurrence (45%) and amount (5.66%). The spectrum of Aspergillus spp. were represented by 17 species. Of them A. fumigatus, A. niger, A. flavus, A. terreus and A. nidulans comprised 31%. Aspergillus spp. concentrations in the wards with laminar ventilation was 1.8 CFU/m3, in plenum-air exhaustion ventilation--2.1 CFU/m3, exchange ventilation--12.2 CFU/m3. Increased amount (31%) and concentration (11.9 CFU/m3) of Aspergillus spp spores in the air occurred in autumn. A. fumigatus (44%), a. flavus (42%), A. niger (8%), A. versicolor (3%), Aspergillus spp (3%) were detected in 33 patients. The rate of detection of Aspergillus isolated from the patients was also the highest in autumn (34%). Aspergillus spores mean concentration in the wards of patients with invasive aspergillesis was 13.1 CFU/m3, in the nearby wards--12.4 CFU/m3. Morphologically identical strains Aspergillus spp. isolated from the patient and environment were obtained in 9 cases. CONCLUSION: Minimal concentration of aspergilla spores was in the wards with laminar air flow furnished with plenum-air exhaustion ventilation. Annual correlation (for 4 years) of seasonal dynamics of the incidence of Aspergillus spp. from patients with invasive aspergillesis and number of spores in the air support suggestion that air is one of the sources of infection in immunocompromised patients. In spite of wide prevalence of Aspergillus spp. in hospital air, morphologically identical strains from the patient and environment are encountered rarely. There may be additional sources of infection and mechanisms of invasive aspergillesis onset in immunocompromised patients. Genotyping of morphologically identical strains was not made.
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AIM: Assessment of high-dose dexamethasone efficacy in combination with standard drugs (adriablastin, vincristin, alpha-asparaginase) in patients with refractory acute lymphoblastic leukemia (ALL). MATERIAL AND METHODS: A pilot multicenter trial with participation of hematological departments of Hematological Research Center (Moscow), municipal hospital N 1 (Krasnoyarsk), municipal hospital N 8 (Yaroslavl), Research Institute of Hematology and Blood Transfusion (Kirov) included 34 patients (10 patients with late recurrences, 24--with primary resistant forms, early and secondary recurrences). RESULTS: In patients with late ALL recurrences a complete remission (CR) was achieved in 70% cases, the median being 10 months. In patients with primary resistant ALL, early and secondary recurrences CR reached 37.5%, the median was 14 months. CONCLUSION: The program HiDexa is highly effective: overall complete remission rate reached 47%, median of complete remission duration was 10 months. Dexamethasone in high doses must be used only intravenously.
AIM: To study prevalence, quantity and species of mycelial fungi in the air of a hematological hospital. MATERIAL AND METHODS: Air samples in the hematological departments were taken monthly by PU-1B device in the volume 250 l/min. Seeding and identification of mycelial fungi were made on the Chapeck medium. RESULTS: Tests for mycelial fungi in the air was 95%. Dominating species were the following: Penicillium spp., Cladosporium spp., Aspergillus spp. The fungal contamination was seasonal. Maximal isolation of Penicillium spp was seen in winter and autumn. Aspergillus spp. is represented with 13 species of which most frequent were A.versicolor, A. niger, A. fumigatus, A. ochraceus, A. flavus. Pathological material from 19 patients contained Aspergillus spp.: A. fumigatus, A. flavus, A. niger. The isolation peak was in autumn-winter and coincided with maximal isolation of fungal spores from the air. The analysis of air samples taken in the wards where patients had Aspergillus spp. in biomaterials showed that concentration of spores Aspergillus spp. was higher than in nearby wards and corridor: 45.6 CFU/M3 vs 18.8 CFU/m3 and 24.7 CFU/M3, respectively. However, morphologically identical strains (patient-air) were recognized only in 4 cases from the nearby wards and corridor. None of the air samples taken in the ward of the patient contained identical species. Minimal amount of the spores of micromycetes was registered in the wards furnished with ventilation with laminar air flow. Most contaminated was the air of 4 bed wards in the old building. CONCLUSION: Mycological monitoring of the air in hematological departments determined the structure of mycelial fungi complexes. Though ambient air in the wards is full of fungi, detection of morphologically identical strains causing invasive mycosis in immunocompromised patients is rare. Further studies are necessary.
AIM: To analyse results of treatment of invasive aspergillesis in immunocompromised patients for 2000-2002. MATERIAL AND METHODS: The study was made of patients who, when treated with antibiotics, exhibited foci in the lungs typical for invasive aspergillesis. Aspergillas were detected in the sputum, bronchoalveolar lavage, bronchial wash-ups, aspergilla antigen (galactomannan) was detected in the blood. RESULTS: Invasive aspergillesis was diagnosed in 25 patients. 13 (52%) patients were treated with adjuvant glucocorticoids. 19 (76%) patients had neutropenia. All the patients had fever. Foci in the lungs were in 24 patients. Aspergillas were detected in 15 patients, a positive antigen galactomannan in 7 patients. A. Fumigatus, A flavus, A. Niger occurred in 67, 26.5 and 6.5% patients, respectively. All the patients received amphotericin B (median of the treatment reached 38 days, total dose 880-3500 mg). In 5 patients amphotericin B was replaced for liposomal amphotericin B because of high creatinine. 7 patients continued with itraconasol in a dose 400-600 mg/day. The foci were removed in 3 patients. The cure was achieved in 12 patients, 13 patients, 13 patients died (cause of death--respiratory insufficiency). CONCLUSION: Lethality in invasive aspergillesis in immunocompromised patients remains high--52%. Cultural detection of mycelial fungi was, as a rule, delayed. Early diagnosis of the disease requires monitoring of the aspergilla antigen in the blood and computer tomography of the chest especially in fever persisting in the treatment of wide-spectrum antibiotics.
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AIM: To ascertain the role of lung biopsy in diagnosis of lung lesions in hemoblastosis (HB) patients. MATERIAL AND METHODS: The results of diagnostic biopsies of the lungs obtained from 22 HB patients are presented. Ten patients had no respiratory insufficiency (RI), twelve patients had RI. The biopsy was transbronchial in 1 case, thoracoscopic in 10 and open in 11 cases. RESULTS: In RI-free patients lung biopsy was informative in all the cases. The biopsy provided information which allowed therapy modification resulting in improvement of the patient condition. In RI patients biopsy was informative in 8 of 12 patients. Nonspecific changes in the lungs were identified histologically in 2 of 12 patients. In 2 RI patients lung biopsy confirmed the diagnosis made after examination of the bronchoalveolar lavage. Modification of therapy after the biopsy was conducted in 58.3% HB patients with RI. Improvement was seen in 2 of them. 10 of 12 patients with RI died within 1-2 weeks after biopsy. CONCLUSION: Lung biopsy in HB patients should be obtained only after examination with noninvasive methods and before development of RI as prognosis after lung biopsy in the presence of RI is unfavourable. The histological material should be examined for all expected pathogens.
AIM: To determine clinical effectiveness of high-dose polychemotherapy (PCT) and transplantation of autologous hemopoietic cells (TAHC) in patients with lymphogranulomatosis (LGM). MATERIAL AND METHODS: 27 LGM patients aged 16-42 years who have undergone TAHC after high-dose PCT (BEAM--17 patients or CBV--10 patients). 4 patients given high-dose PCT were in the first-second complete remission (CR), 7 patients--in the first partial remission (PR). Prior to TAHC, 8 patients had one, two and more relapses of LGM, and 8 patients had no remission at all. Bone marrow, hemopoietic blood cells and both were transplanted to 17, 2 and 8 patients, respectively. Mobilization of hemopoietic blood cells and stimulation of hemopoiesis after TAHC were achieved using colony-stimulating factors. RESULTS: The treatment resulted in CR or PR (from 6 to 95 months) in 70.4% of patients. The remission duration varied depending on the disease phase at transplantation. Four patients who underwent TAHC in PR maintained it for 13-95 months (median 47.5 months). Lasting remissions (29-59 months) were achieved in 42.9 and 37.5% of patients who underwent TAHC in the first PR or in recurrent LGM. None of the patients was in remission longer than 2 years after TAHC if high-dose PCT was conducted in advanced tumor process due to resistant LGM or inadequate previous treatment. Infectious complications lethality early after the transplantation reached 7.4%(2 patients). CONCLUSION: High-dose PCT followed by TAHC is effective in LGM if the tumor is chemosensitive.
AIM: Comparison of effectiveness of induction regimens varying in intensity and maintenance variants in patients with acute myeloid leukemia (AML) included in a randomised multicenter trial. MATERIALS AND METHODS: Clinical trial 1 enrolled 185 AML patients. Vepesid-free induction was used in 85 patients (group 1), induction with vepesid--in 99 patients (group 2). 223 AML patients entered trial 2. Of them 37 patients were treated for 3 years 7 + 3 with daunorubicin in the dose 45 mg/m2 in the induction phase (group 1), 85 and 101 patients received 7 + 3 with daunorubicin for a year in the dose 45 mg/m2 and 60 mg/m2, respectively, (group 2 and 3). RESULTS: For group 1 in trial 1 the remission rate, early lethality, resistance were, respectively, 60, 20 and 20%, respectively. For group 2 in trial 1--66, 22 and 12%, respectively. 5-year recurrence-free survival reached 32 and 37% for group 1 and 2, respectively. For trial 2 relevant figures made up 75.5, 16.2, 8.1% for group 1; 60, 17.6 and 22.4% for group 2; 63, 20.8 and 16% for group 3, respectively. The 3.5-year recurrence-free survival in groups 1, 2 and 3, was 16, 46 and 50%, respectively. For both trials, the differences between the groups were insignificant. CONCLUSION: The results evidence that the treatment can be shorter (not 3 but 1 year or even 6 months), the induction more intensive (the dose of anthracycline antibiotics can be elevated up to 60 mg/m2 without a rise in early lethality).
AIM: Evaluation of trans-retinoic acid (ATRA) in combination with cytostatic drugs in treatment of acute promyelocytic leukemia (APL). MATERIALS AND METHODS: In a multicenter study APL was treated according to protocols APL 01.97 and APL 06.87 in 28 patients (14 males and 14 females, median age 36 years). RESULTS: Administration of ATRA in combination with standard program 7 + 3 (cytosine-arabinoside 100 mg/m2 twice a day v.v. day 1-7, daunorubicin 60 mg/m2 v.v. day 1-3) induced a complete remission in 25 patients (90%). Early lethality was 10% (3 patients died). Resistant APL was not registered. Retinoid syndrome was diagnosed in 15 patients, one patient died. 2-year overall and recurrence-free survival made up 72 and 82%, respectively. CONCLUSION: ATRA combination with cytosine-arabinoside and daunorubicin is a novel treatment of acute promyelocytic leukemia providing a high rate of complete remission and long-term survival.
AIM: To study clinical efficiency of allogenic bone marrow transplantation (ABMT) in patients with acute leukemia (AL) in the first remission and in patients with chronic myeloid leukemia (CML) in chronic phase; to analyse overall and recurrence-free survival in relation to the diagnosis and age. MATERIALS AND METHODS: 26 patients with AL and 24 ones with CML (29 males and 21 females) were subjected to ABMT within 10 last years. Median of age in AL and CML was 24.5 and 25.5 years, median of the time since the diagnosis was 9 and 13 months, respectively. Follow-up since the ABMT made up 67.5 months (31-107) and 38 months (6-108), respectively. Conditioning was made with cyclophosphamide (120 mg/kg) plus total radiation of the body (12 Gy) in 16 patients, myelosan (mileran) in a dose 16 mg/kg plus cyclophosphane (120 mg/kg) in 34 patients. The marrow was taken from HLA-identical sibs, enzygotic twins (5 recipients). Cytogenetic investigations were made in CML. The retention of the transplant was controlled by immunological and molecular tests. RESULTS: Among AL patients 50% are still alive. Probability of 80-month survival reached 55%, 110 months--42%. Probable recurrence-free survival was 78%. All the patients are in a complete clinico-hematological remission. Among CML patients 75% are still alive. Of them 89% had a complete hematological remission, 72% are in a complete hematological and cytogenetic remission. Probable 110 month survival equals 75%, probability to survive without recurrence--52%. Early lethality (100 days) of toxic and infectious complications was as low as 10 and 6%, respectively. Frequency of lethal acute secondary disease was under 8%. CONCLUSION: ABMT made in AL patients during the first complete remission and in CML patients in the chronic phase brings about very good results which are much better than after routine cytostatic chemotherapy.
Meropenem was used in the treatment of 14 infectious complications in 11 patients including 8 with acute myeloid leukemia due to the cytostatic therapy, 1 with chronic myeloid leukemia, 1 with aplastic anemia and 1 with acute intermittent porphyria. At the moment of the meropenem use critical neutropenia (less than 500 granulocytes per 1 ml) in 11 cases (79 per cent) was stated. The drug was administered as intravenous infusions in a dose of 1 g every 8 hours for 4 to 41 days (the median of 11 days). 9 out of the 14 infectious complications were cured (the body temperature normalized and all the inflammation foci were eliminated), among them 6 out of 8 pyocyanic sepsis. Eradication of gram-negative bacteria was observed in 8 out of 10 cultures of the biological materials. No toxic complications or electrolytic disorders due to the drug use were recorded. The drug tolerance was good.
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