Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in children and adults.

Acute and chronic steroid-refractory graft-versus-host disease (srGVHD) is a life-threatening complication of allogeneic stem cell transplantation. There are a number of reports on case series describing efficacy of ruxolitinib in both acute and chronic srGVHD. We conducted a prospective study (NCT02997280) in 75 patients with srGVHD (32 acute, 43 chronic, 41 adults, and 34 children). Patients with chronic GVHD had severe disease in 83% of cases, and acute GVHD patients had grade III-IV disease in 66% of cases. The overall response rate (ORR) was 75% (95% CI 57-89%) in acute GVHD and 81% (95% CI 67-92%) in chronic. Overall survival was 59% (95% CI 49-74%) in acute group and 85% (95% CI 70-93%). The major risk factors for lower survival were grade III-IV gastrointestinal involvement (29% vs 93%, p = 0.0001) in acute form and high disease risk score in chronic (65% vs 90%, p = 0.038). Toxicity was predominantly hematologic with 79% and 44% of grade III-IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR (p = 0.31, p = 0.35), survival (p = 0.44, p = 0.12) and toxicity (p > 0.93). The study demonstrated that ruxolitinib is an effective option in acute and chronic srGVHD and can be used both in adults and children.

[Bone marrow immunophenotyping for the diagnosis of multiple myeloma: practical aspects].

Multiple myeloma is a malignant proliferative disease of plasma cells. Flow cytometric immunophenotyping makes it possible to identify a malignant clone of myeloma cells in the shortest possible time, to determine its phenotype, and differentiate transformed and preserved plasma cells. The article presents an immunophenotyping strategy using three-color monoclonal antibodies (CD35, CD14, CD38, CD138, and CD19) and an algorithm of verification of transformed plasma cells. Particular emphasis is placed on both the practical aspects of performing this assay and on the clinical application of the obtained results.

[Cytomegalovirus infection in bone marrow transplantation]. / Tsitomegalovirusnaia infektsiia v praktike transplantatsii kostnogo mozga.

AIM: To evaluate frequency and clinical features of CMV infection in patients with hematological malignancies (HM) after autologous and allogeneic stem cell transplantation, protective and therapeutic methods, efficiency of CMV hyperimmune immunoglobulin cytotest (Biotest Pharma). MATERIAL AND METHODS: The trial enrolled 22 patients (group 1) with HM and severe aplastic anemia after allogeneic bone marrow transplantation, 58 patients (group 2) with HM after autologous stem cell transplantation. The patients were examined for CMV infection by serologic methods and PCR. RESULTS: The probabilities of CMV infection were greater in group 1 than group 2--10/22(45%) versus 12/58 (21%), p < 0.05. Clinical signs of CMV disease were pneumonitis (27%), hepatitis (32%), gastroenteritis (9%), haemorrhagic cystitis (55%), slow engraftment (59%), prolonged thrombocytopenia (68%), encephalitis (5%). Six (60%) patients with CMV infection after allogeneic and 1(8%) patient with CMV infections after autologous stem cell transplantation were dead. The cytotest after allogeneic transplantation of the bone marrow reduced the risk of CMV infection from 62 to 36%. CONCLUSION: CMV infection influences prognosis both in allogeneic and autologous transplantation of hemopoietic stem cells. Cytotest lowers the risk of CMV development after transplantation of allogeneic bone marrow.

[Immunomodulator Cycloferon in the comprehensive treatment of patients with acute non-lymphoblastic leukemia]. / Immunomoduliator tsikloferon v kompleksnom lechenii bol'nykh ostrimy nelimfoblastichnymi leikozami.

The therapeutic benefit and action of the immunomodulator Cycloferon were evaluated in patients with acute non-lymphoblastic leukemia. When administered in conjunction with chemotherapy during first complete remission, it reduced both early-onset relapse frequency and degree of cytostatic-induced immune deficiency. The drug's action is mediated by changes taking place in cytokine and interferon synthesis.

[Levels of complement components in plasma of onco-hematologic patients with defective hemopoiesis]. / Soderzhanie komponentov komplementa v plazme onkogematologicheskikh bol'nykh pri nedostatochnosti gemopoéza.

Immunochemical assay using monoclonal antibodies was carried out to determine levels of a number of complement components (C3 and its derivatives-C4 and C5) and immunoglobulins (lg) in plasma of patients with onco-hematological diseases involving defective hemopoiesis: leukemia, myelodysplastic syndrome (clonal diseases) or aplastic anemia (delayed clonal disease). The most significant disorders were registered in the concentrations of component C3 and its derivatives. In acute leukemia, the nature and extent of C3 splitting was found to depend on disease while Ig level-on stage. Myelodisplasia usually involved a 2-3-fold decrease in C3 level matched by a rise in the concentrations of its derivatives-C3-like form and C3a fragment. Reduced C3 levels matched by increased ones of Ig were observed in some cases of aplastic anemia. It is suggested that disturbances in complement component level may cause changes in cascade reactions of the complement in onco-hematological patients and thus indirectly influence immune response regulation processes.

[Current principles of treatment of acute nonlymphoblastic leukemia]. / Sovremennye printsipy lecheniia ostrogo nelimfoblastnogo leikoza.

Present-day chemotherapy warrants complete remissions in 45-70% of patients with acute nonlymphoblastic leukemia. However, therapeutic policy at the stages of remission induction and residual disease remains disputable. The authors studied the role of 3 chemotherapy programs (7 + 3, 7 + 3 + vincristine, C-ROPM) in achievement of remission of acute leukemia and effects of long-term standard regimens of remission maintenance and bone marrow transplantation on long-term relapse-free survival of patients. The addition of vincristine to the program 7 + 3 failed to make remission more frequent and recurrence-free survival longer. C-ROMP program warranted remission in 70% of patients, this proportion being significantly higher than on programs 7 + 3 and 7 + 3 + vincristine. More intensive chemotherapy during remission induction resulted in a rise of 4-year recurrence-free survival from 12 to 44%. Bone marrow transplantation used for treatment intensification in remission increased 4-year recurrence-free survival compared to standard chemotherapy from 44 to 80%.

[Bone marrow transplantation in the treatment of acute leukemias]. / Transplantatsiia kostnogo mozga v lechenii ostrykh leikozov.

The effect of bone marrow transplantation on 4-year leukemia recurrence-free survival of patients with acute myeloid and lymphoblastic leukemia has been studied in 11 and 16 patients, respectively. Autologous and allogeneic bone marrow transplantations during the first complete remission of acute leukemia have improved the survival compared to chemotherapy from 44 to 75% in acute myeloid leukemia and from 35 to 60% in acute lymphoblastic leukemia.

[Immunologic monitoring and immune reconstitution in recipients of allogeneic bone marrow]. / [Immunomonitoring i immunorekonstitutsiia retsipientov allogennogo kostnogo mozga]

The dynamics of different peripheral blood lymphocyte subpopulations (CD3+, CD4+, CD8+, CD22+, DR+, CD25+ and CD16+) and levels of serum cytokines TNFa and IL1 beta were evaluated in 10 patients with allogeneic bone marrow transplantation (BMT). It was established that initially low levels of practically all the lymphoid subsets studied came back to normal in patients with favorable post-BMT course, while, in unfavorable post-BMT course (GVHD or relapse), the levels of said lymphoid subsets remained unchanged or even dropped. Post-BMT increase in serum TN alpha level can be of prognostic value for GVHD development whereas serum IL1 beta level does not correlate with post-BMT course.

[The optimization of the infusion therapy procedure in patients with acute leukemias]. / Optimizatsiia taktiki infuzionnoi terapii u bol'nykh ostrymi leikozami.

In a trial of 202 patients with acute leukemia (AL) the authors studied the effect of volume and quality of infusion therapy (forced diuresis 2.5 l/m, parenteral nutrition, hemocomponent therapy) on early mortality, frequency of complications, complete remission, overall and relapse-free survival. It is shown that the response in remission induction depends on the scope and quality of infusion therapy. Balanced complete infusion therapy led to a complete remission in 75% and 92% of patients with acute nonlymphoblastic and acute lymphoblastic leukemia, respectively, compared to 29 and 50% for infusion-untreated patients. Early lethality was 6 and 0%, 42 and 18%, respectively. Higher efficacy of acute leukemia treatment in adjuvant balanced infusion therapy results from lower toxicity of chemotherapy and possible performance of induction therapy without reduction of drug doses.

[Clinical experience using the cryoprotector "hecmolit" in performing autologous bone marrow transplantation]. / Opyt klinicheskogo primeneniia krioprotektora "gekmolit" pri provedenii autologichnoi transplantatsii kostnogo mozga.

The authors summarize clinical evidence obtained on the efficacy of a new Russian cryoprotector hecmolit in the conduction of autotransplantation of 8 patients with acute leukemia. The markers of the preserved hemopoietic potential of the unfrozen bone marrow were the amount of myelokaryocytes, their viability in the test with vital stain, CFU-GM level. Infusions of the marrow suspension incorporating hecmolit (120-180 ml) produced minimaL side effects. After thawing myelokaryocytes remained in the amount 81.7 +/- 8.2% or 1.6 +/- 0.4 x 10(8) cell / kg, on the average. Estimation of the aggregates in terms of the weight revealed that hemopoietic potential was sufficient for the transplant survival (2.9 +/- 0.7 x 10(3) CFU-GM/kg) though only 50 +/- 10% of CFU-GM remained safe. Hecmolit tolerance was satisfactory. The preparation is thought convenient for bone marrow transplantation practice.

[Experience with the use of reaferon (alfa 2-interferon) for treating patients with chronic myeloleukemia]. / Opyt primeneniia reaferona (al'fa 2-interferona) dlia lecheniia bol'nykh khronicheskim mieloleikozom.

The effectiveness of domestic alpha 2-interferon preparation reaferon was studied in vivo and in vitro for eradication of pathological hemopoietic clone in chronic myeloid leukemia. Reaferon administration for 1-30 months produced cytogenetic remission in 7%, hematological remission in 21%, partial hematological remission in 36% of the patients. Reaferon is indicated in chronic myeloid leukemia without splenomegaly. In the disease progression reaferon is uneffective. Mechanism of reaferon therapeutic action comprises three components: a direct antiproliferative effect on hemopoietic precursor cells, activation of cellular immunity, an effect on stem cell microenvironment.

[A comparative analysis of the effect of alpha 2-interferon (reaferon) therapy on the morphofunctional state of the bone marrow in patients with chronic myeloleukemia]. / Sravnitel'yi analiz vliianiia terapii al'fa 2-interferonom (reaferonom) na morfofunktsional'noe sostoianie kostnogo mozga u bol'nykh khroniceskim mieloleikozom.

Marrow trepan biopsy was performed in 11 patients upon diagnosis of chronic myeloid leukemia and in clinicohematological remission of the disease. The patients were treated with alpha 2-interferon (reaferon) versus conventional myelosan (6 and 5 patients, respectively). The biopsies were studied histomorphometrically. In reaferon group the number of megakaryocytes and endosteal stromal cells diminished. This may be due to an indirect action of reaferon on hemopoietic tissue via endosteal cells of the marrow stroma. Reaferon is recommended for myeloid leukemia chronic with a granulocytic-megakaryocytic histological variant of the disease.

[The prognostic role of determining spontaneous leukocyte DNA damage and that occurring during chemotherapy in leukemia patients]. / Prognosticheskaia rol' opredeleniia spontannykh i voznikaiushchikh v protsesse khimioterapii povrezhdenii DNK leikotsitov bol'nykh leikozami.

The authors studied spontaneous DNA damages and the extra plan synthesis of DNA in various leukemias (chronic lympholeukemia, chronic myeloleukemia, acute leukemia) to predict the natural course of leukemias and the efficiency of chemotherapy. The level of genuine DNA breaks, which had been determined by the nic-translation test, was lower in peripheral blood cell DNA in all leukemias than that in the lymphocytes and granulocytes from donors. On the contrary, the levels of alkaline-labile DNA sites and nuclear matrix protein-bound DNA in the mature and maturing leukemia cells are high and decrease with progression of chronic lympholeukemia and chronic myeloleukemia. The extra plan DNA synthesis largely reflects the cellular levels of genuine DNA breaks, and the ultraviolet-induced DNA repair capacity is the highest in the lymphocytes in chronic lympholeukemia and particularly in the blasts in acute leukemia. The efficiency of chemotherapy was predicted during chemotherapy from the intensity of formation of genuine blast cell DNA breaks.

[A method of determining erythrocyte deformability]. / Sposob opredeleniia deformabel'nosti éritrotsitov.

A simple method for determining red cell deformability is suggested, based on red cell packing during centrifugation. This method was used to study red cell deformability in patients with essential hypertension and angina of effort and found it reduced.

[The rheologic aspects of washed donor erythrocytes]. / Reologicheskie aspekty otmytykh donorskikh éritrotsitov.

Washing off donors' red blood cell pack with NaCl isotonic solution results in improvement of red blood cell rheologic properties: their aggregation reduces, deformability increases, osmotic resistance rises. Heparin addition to the washing off solution in a dose of 5 IU/ml prevents development of antiheparin activity in red blood cells after washing off. Application of washed-off red blood cells of donors has advantages as compared to transfusion of the whole blood.

[Hemostasis and T-cell immunity in lung cancer patients]. / Gemostaz i T-kletochnyi immunitet u bol'nykh rakom legkogo.

Complex examination of hemostatic system and T-cell-mediated immunity in 19 cases of stage II-IV lung cancer showed an increased activity of blood coagulation system to be associated with a decrease in OKT3+, OKT11+ and OKT4+ T-lymphocyte subsets levels. A reverse correlation was established between plasma--Willebrand's factor level and those of OKTè+ and OKT8+ lymphocytes whereas a direct one--between blood-platelet aggregate level and that of OKT4+. The data obtained emphasized the need to consider the status of hemostatic system when evaluating the function of cell-mediated immunity.