[Effect of bortezomib on the efficiency of hematopoietic stem cell mobilization in patients with multiple myeloma].

AIM: To study the results of mobilizing and collecting autologous hematopoietic stem cells (HSC) in patients with multiple myeloma (MM) receiving bortezomib as part of induction therapy regimens. MATERIALS AND METHODS: In June 2001 to April 2010, the Department of Bone Marrow Transplantation, Hematology Research Center, Ministry of Health and Social Development of Russia, mobilized autologous HSC in 93 patients with MM, by using cyclophosphan (CF) and granulocyte colony-stimulating factor. The analysis covered 73 patients who received VAD and/or bortezomib-containing courses as induction therapy. Group 1 comprised 30 patients whose induction therapy was performed as 3-4 courses of VAD. Group 2 included 19 patients who had 2-4 courses of PAD or 4-8 courses of bortezomib + dexamethasone in addition to 1-3 courses of VAD. Group 3 combined 24 patients who used 6-8 courses of bortezomib + dexamethasone or 3-4 courses of PAD + 4-6 courses of bortezomib + dexamethasone. RESULTS: In Group 1 patients whose induction therapy was performed as 3-4 courses of VAD, baseline peripheral blood CD34+ cell counts were 3,575 +/- 631 in 1 ml, which was statistically significantly higher than those in Group 2 patients who had bortezomib-containing courses in addition to VAD courses. In Group 2 patients, premobilization CD34+ cell counts were 2,164 +/- 516 in 1 ml. The lowest blood CD34+ cell levels (1,586 -/+ 405 in 1 ml) were observed in Group 3 patients in whom bortezomib was used as first-line therapy. In Group 1 patients, the maximum peripheral blood counts of CD34+ cells were 322,287 +/- 73,994 in 1 ml, which was significantly higher than their maximum level in Groups 2 (231,624 +/- 39,708 in 1 ml) and 3 (161,007 +/- 44,266 in 1 ml) patients. The efficiency of mobilization proved to be high; more than 4.0.10(6)/kg of CD34+ cells were collected in all the patients with bortezomib-containing induction therapy, which allowed two autologous HSC transplantations to be carried out. CONCLUSION: Adding bortezomib at the stage of induction has no significant impact on the results of HSC mobilization and collection. By taking into account the possibility of achieving a complete or very good partial response in 40-60% of the patients using the bortezomib-containing regimens as first-line therapy, bortezomib should be considered as an essential drug as part of induction therapy.

[Therapy of acute massive blood loss in a hemophilic patient: case report].

A case is reported of management of massive intraoperative blood loss in a male patient with severe hemophilia. Extirpation of hip pseudotumor with one-stage osteosynthesis with an intramedullary joint-pin in a 43 year old male patient was accompanied with 7.5 l blood loss. The infusion-transfusion therapy (ITT) contained transfusion media about 1/3 of the total volume, fresh-frozen plasma and erythrocyte-containing media were used 1:1. Infusion solutions consisted of balanced polyelectrolytic solutions, hydroxyethylated starches 130/0.4, hyperchaes. Intraoperative normovolemic hemodilution and reinfusion of wound blood were made (CellSaver). ITT target markers were standard hemodynamics control tests. Hemostasis monitoring was conducted with thromboelastography. Complex ITT based on modern principles of clinical transfusiology provided a complete and safe compensation of massive intraoperative blood loss in a patient with severe hemophilia.

[Optimization of mobilization regimes of blood hemopoietic stem cells in patients with multiple myeloma].

AIM: To determine an optimal cyclophosphamide dose in the mobilization scheme providing adequate collection of CD34+ cells in patients with multiple myeloma (MM), to optimize the time of initiation of granulocytic colony-stimulating factor (G-CSF) administration, to study effects of induction therapy schemes on results of mobilization and collection of CD34+ cells. MATERIAL AND METHODS: Department of hemoblastoses chemotherapy and bone marrow transplantation of the Russian Hematological Center performed mobilization of autologous blood hemopoietic stem cells (BHSC) in 93 MM patients treated in 2001-2010. This was done with cyclophosphamide and G-CSF. The former was used in 59 cases in a dose 6 g/m2, in 34 cases - 4 g/m2. RESULTS: Myelotoxic agranulocytosis after cyclophosphamide administration developed in all the patients and was observed for 3-10 days (median 5 days). Agranulocytosis ran without documented infections in 51 (54.8%) patients, with febril fever - in 42 (45.2%) patients. Cepticemia, pneumonia, necrotic enteropathy, stomatitis, herpetic lesion of the skin were registered in 9, 4, 11, 14 and 6 cases, respectively. Severe thrombocytopenia (< 30 x 10(9)/l) occurred more frequently in administration of 6 g/m2 cyclophosphamide. It was corrected with 2-5 transfusions of thromboconcentrates, only 1 transfusion was needed after the dose 4 g/m2. Collection of CD34+ cells started in leukocyte level over 3.5 x 10(9)/l on mobilization day 12-20 (median day 15). The day of the first leukocytapheresis did not depend on the day of the first introduction of G-CSF. Duration of G-CSF administration was significantly shorter in the start of its use after leukocyte count decrease under 1.0 x 10(9)/l. Conduction of 1 to S (median 2) leukocytapheresis was needed for collection of BHSC. Sufficient for 2 autotransplantations number of BHSC were stored in 90 of 93 patients. Cyclophosphamide administration in a dose 6 g/m2 allowed collection of cells sufficient for one autotransplantation for the first leukapheresis in 52 (88.1) patients. A total number of CD34+ cells over 4 x 10(6) cells/kg were collected in 56 (94.9%) patients. In administration of cyclophosphamide in a dose 4 g/m2 mobilization was effective in all 34 patients. The first leukapheresis provided sufficient for one autotransplantation number of cells in 29 (85.3%) patients. CONCLUSION: Administration of high cyclophosphamide doses in combination with G-CSF is an effective and safe method of BHSC mobilization providing collection of adequate number of CD34+ cells for double autotransplantation in 96.8% patients. Cost effective is the start of G-CSF administration in the fall of leukocytes under 1.0 x 10(9)/l. Cyclophosphamide dose 4 g/m2 provides collection of CD34+ cells number sufficient for two autotransplantations in moderate thrombocytopenia and in less number of substitute transfusions in the absence of serious toxic complications.

[Transplantations of allogenic and autologous hemopoietic stem cells in acute leukemia (results of 20-year experience)].

AIM: To analyse results of transplantation of allogenic and autologous hemopoietic stem cells (allo-THSC and auto-THSC) with myeloablation preconditioning in patients with acute leukemia (AL) performed in 1987-2006. MATERIAL AND METHODS: A total of 71 allogenic and 45 autologous THSC were performed in 116 patients with different AL variants. Conditioning in all allo-THSC included busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). This regimen was used in 29 recipients of auto-HSC. Cyclophosphamide in a dose 120 mg/kg and total radiation of the body in a dose 12 Gy were given to 16 recipients. Overall, relapse-free and event-free survival of patients after THSC were analysed as well as early (first 100 days) and overall lethality. Auto-THSC in 15 patients was for the first time followed by immunomodulating therapy aimed at prevention of AL relapses: in acute myeloid leukemia ATRA in combination with alpha-interferon, in acute lymphoblastic leukemia (ALL)--ronkoleukin, interleukin-2 preparation. RESULTS: Overall survival of AL patients after allo-THSC for the observation period increased from 31 to 58%, early lethality fell from 44 to 4%. Results of allo-THSC conducted in the first complete remission were much better than in patients with other AL stages at the time of THSC. After auto-THSC 5-year survival rose from 22 to 60% while early lethality reduced from 33 to 4%. Administration of immunomodulating therapy after auto-THSC increases 5-year survival from 35 to 80%. CONCLUSION: Outcomes of THSC in AL has improved for the last 20 years. Outcomes of allo-THSC performed in the first complete remission are much higher. Immunomodulating therapy after auto-THSC promoted better results.

[Infectious complications after transplantation of autologous hemopoietic blood cells in patients with hematological malignancies].

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.

[Allogenic bone marrow transplantation in chronic myeloid leukemias]. / Transplantatsiia allogennogo kostnogo mozga pri khronicheskom mieloleikoze.

AIM: To assess the role of allogenic bone marrow (ABM) transplantation in chronic myeloid leukemia (CML). MATERIAL AND METHODS: 44 ABM transplantations were performed in 37 CML patients in the chronic phase and 7 patients in acceleration or blast crisis. RESULTS: A complete molecular remission was achieved in 26 (59%) patients: 67.6% after ABM transplantation in the chronic phase and only 14.3% after myelotransplantation in non-chronic phase. Follow-up was 8-150 months (median--59 months). Early lethality after ABM transplantation in the chronic phase was under 14%. A phase of the disease plays a key role in ABM transplantation. If it is made in a chronic phase, CML recurrence rate is low (in our series it was 14%), efficacy of donor's bone marrow lymphocyte transfusions is high. The second complete molecular remission was achieved in 3 of 4 cases of posttransplantation recurrences. Probability of maintenance of a complete remission after ABM transplantation in a chronic phase was 75%, recurrence-free survival--64%, uneventful survival 55% for 90 months. CONCLUSION: The experience of many years demonstrates high efficacy of ABM transplantation in the treatment of chronic myeloid leukemia. It promotes long-term molecular remission the maintenance of which did not require therapy in 65% patients.

[Quantitative assessment of protein replacement in therapeutic plasmapheresis]. / Kolichestvennaia otsenka belkovogo zameshcheniia pri lechebnom plazmafereze.

AIM: To calculate parameters of replacement in which the amount of total protein (TP) in the circulating blood remains above critical level after removal of 17-75% of circulating plasm volume (CPL). MATERIAL AND METHODS: Therapeutic plasmapheresis (TPA) was made in 96 patients with rheumatoid arthritis, bronchial asthma, systemic lupus erythematosus and other diseases. The plasm was replaced by 0.9% sodium chloride solution, rheopolyglucine and albumin solutions in isovolemic regime. Albumin was given in quantities equivalent to 50-65% of the removed protein. RESULTS: Close correlation was observed between the expected and actual concentrations of total protein in 96 patients who have undergone 206 TPA procedures. In removal of up to 35% CPL protein deficiency is compensated by its mobilization from the deposits and due to protein-synthetizing function of the liver. In removal of 75% and more and in initial hypoproteinemia 50% of the protein should be replaced. CONCLUSION: It is confirmed that rheopolyglucin can be used for plasm replacement in TPA in patients with hyperproteinemia having no contraindications.

[Plasmapheresis in combine therapy of hypercoagulation syndrome in hematogenic thrombophilia]. / Plazmaferez v kompleksnoi terapii giperkoaguliatsionnogo sindroma pri gematogennykh trombofiliiakh.

AIM: To specify indications to plasmapheresis (PA) and to assess its efficiency in patients with hypercoagulatory syndrome in hematogenic thrombophilia (HT). MATERIAL AND METHODS: 18 patients (11 males, 7 females, age 26-50 years) with various forms of HT received standard antiaggregation, anticoagulatory therapy plus therapeutic PA. By PA technique the patients were divided into two groups. RESULTS: A positive trend in clinical, instrumental and laboratory indices was observed in all the patients. CONCLUSION: Therapeutic PA in hypercoagulation syndrome in HT patients leads to fast normalization of the clinical picture and reestablishment of patency of thrombus-affected vessels.

[Osmotic activity of plasma in plasmapheresis in patients with multiple myeloma]. / Osmoticheskaia aktivnost' plazmy pri plazmafereze u bol'nykh mnozhestvennoi mielomoi.

AIM: To control safety and efficiency of therapeutic plasmapheresis (PA) by osmolality, colloido-osmotic pressure (COP), total protein concentration before and after the procedure in patients with paraproteinemic hemoblastosis. MATERIAL AND METHODS: 20 patients with multiple myeloma have undergone 42 PA procedures conducted by two techniques: continuous flow centrifugation on blood fractioners or intermittent centrifugation of blood in plastic containers. The removed plasma volume averaged 1/3 (group 1) or 2/3 of the plasma volume (group 2). The removed protein reached 62-197 g. Isotonic sodium chloride solution and/or reopolyglucin (20-60 g) replaced the removed plasm. Total protein concentration was measured colorimetrically in biuretic reaction, plasma osmolality--cryoscopically and COP--on Knauer osmometer. RESULTS: PA leads to a short decline in osmolality (97.0-99.1%), of total protein concentration (82.8-78.6%) and of COD (79.2% in replacement with saline and 90.2% in replacement with dextran). During recovery after the procedure plasma osmotic activity and protein concentration return to the baseline. CONCLUSION: In elimination of 1/3 of plasma volume and crystalloid infusion, hemodilution promotes release of abnormal proteins from the tissues into the circulation and thereafter removal them from the organism. In removal of 1/2 and more of plasma volume, COP demans correction made by administration of colloids, e.g. solution of low molecular dextran. There is a potential danger of COD lowering several hours after PA due to different speed of dextran elimination and mobilization of protein reserve.

[Reestablishment of plasma proteins after plasmapheresis in patients with paraproteinemic hemoblastosis]. / Vosstanovlenie plasmennykh belkov posle plazmafereza u bol'nykh paraproteinemicheskimi gemoblastozami.

AIM: To study the effect of plasmapheresis (PA) on the changes in plasma total protein in the PA intervals in patients with paraproteinemic hemoblastosis (PPH). MATERIALS AND METHODS: 26 PPH patients underwent 80 PA procedures to remove macromolecular pathological proteins and diminish blood viscosity. Before PA the patients were examined hematologically, biochemically. Total protein concentration in plasma was measured before and after PA, in the removed plasma. RESULTS: PA promoted total protein lowering in plasma to 65-85% of the baseline irrespectively of PA technique. After PA the proteins gradually rose. Contents of circulation proteins were found unrelated to the number of PA procedures and averaged 70% of the PA-removed protein. CONCLUSION: The trends in recovery of plasma proteins after PA help to explain therapeutic effect in combination of PA with chemotherapy of paraproteinemic hemoblastoses.

[The monitoring of protein-volemic indices during plasmapheresis in patients with paraproteinemic hemoblastoses]. / Monitoring belkovo-volemicheskikh pokazatelei pri plazmafereze u bol'nykh paraproteinemicheskimi gemoblastozami.

We studied quantitative characteristics of plasma protein before, during and after 133 plasmapheresis (PA) procedures in patients with multiple myeloma and Waldenstrom's macroglobulinemia. A value of removed plasma volume (RPV) was calculated as a part plasma volume (PV) before PA with consideration of quantity and consequence of replacement solution. In the case when we removed 30% of calculated PV we replaced it only with electrolyte solutions. In the case of 50% PV removing, the replacement was a combination of low molecular weight dextran and electrolyte solutions (1:2) or 5% albumin and electrolyte solutions. The results support correlation between a level of total protein and RPV, kind of replacement solutions. We recommend two regression equations for efficient and safety planning RPV and for prediction of protein level after PA. This simple and fast method can be used for prognosis of critic PA parameters, to decrease a risk of side effects and for optimal use of albumin replacement solutions.

[Therapeutic plasmapheresis in immune complex diseases]. / Lechebnyi plazmaferez pri immunokompleksnykh zabolevaniiakh.

We studied the dependence of the plasma protein and volume on the exfusion volume, type and composition of the substitution solution in 140 plasmapheresis procedures given to patients with immune thrombocytopenic purpura and bronchial asthma. The change of blood protein system corresponded to the procedure regime. The procedure does not entail adverse reactions if it removes up to 30% of the plasma circulating volume (replacement with salt solution), 50% of the plasma circulating volume (replacement with dextran solution) or 95% of that with replacement with albumin. We have tested 3 simple mathematic models for postplasmapheresis proteinemia and recommend the regression equation Ct = a0 + a1.Co as the most adequate model.

[The phenomenon of the enhancement of the formation of lymphocytotoxic alloimmune antibodies during the use of plasmapheresis]. / Fenomen usileniia obrazovaniia limfotsitotoksicheskikh alloimmunnykh antitel pri primenenii plazmafereza.

Apheresis was applied in 17 patients with hypoplastic anemia, myelodysplastic syndrome, chronic renal failure and other diseases sensitized to HLA. Apheresis was done for removal of anti-HLA antibodies and prevention of nonhemolytic transfusion reactions. Multiple massive apheresis led to a marked decrease in the antibody level. After the first or second apheresis with removal of 700.0-2000.0 ml of plasma weekly half of the patients showed increasing titres of lymphocytotoxic antibodies.