[Sorafenib - induced thyroiditis in patient with a relapse of acute myelomonocytic leukemia with FLT3-ITD mutation].

Sorafenib has been used in acute myeloid leukemias with FLT3-ITD mutation improving the outcomes. However the high incidence of treatment - emergent adverse event may be associated with treatment using sorafenib with cytotoxic chemotherapy. We have reported a case of severe thyroiditis in patient with a relapse of acute myelomonocytic leukemia.

[Prognostic value of 1q21 amplification in multiple myeloma]. / Prognosticheskoe znachenie amplifikatsii 1q21 pri mnozhestvennoi mielome.

AIM: To determine the prevalence of amp1q21 and its relationship to the clinical manifestations of multiple myeloma (MM). SUBJECTS AND METHODS: In December 2009 to March 2016, a total 134 patients aged 30 to 81 years (median 57 years) underwent a pretreatment FISH-study of bone marrow (BM) with centromeric and locus-specific DNA probes to identify amp1q21, t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), trisomies of chromosomes 5, 9, 15, del13q14, del17p13/TP53, and t(8q24)/cMYC. Induction therapy with bortezomib-containing cycles was performed. Autologous stem cell transplantation was carried out in 48 patients. The median follow-up of patients was 19.3 months (3.2-77.4 months). Disease progression was diagnosed in 69 (51.5%) patients; 12 patients also underwent FISH study during disease progression. RESULTS: At the onset of MM, amp1q21 was detected in 53 (39.6%) patients. The overall 5-year survival rate in patients with amp1q21 was almost 2 times lower than that in those without amp1q21 (43.5 and 79.4%, respectively; p=0.07). The overall 5-year survival rate in patients with one extra copy of 1q21 (only 3 copies) was 67.3%, that in those with 2 or more extra copies of 1q21 (only 4-7 copies) was 20.9% (p=0.0016). Nine (75%) of the 12 patients examined during disease progression were found to have amp1q21: 2 cases were detected in the period of progression to have amp1q21 in its absence at disease onset; 7 cases had amp1q21 both at MM onset and progression; however, the number of copies of 1q21 was unchanged. CONCLUSION: Аmp1q21 is one of the most common chromosomal abnormalities in patients with new-onset MM and may appear in the course of disease progression. The presence of аmp1q21 is an important prognostic factor and must have to be included in the diagnostic study both at disease onset and progression.

[Myeloproliferative masks of multiple myeloma: A review of literature and clinical case reports]. / Mieloproliferativnye «maski¼ mnozhestvennoi mielomy (obzor literatury i opisanie klinicheskikh nabliudenii).

Concurrences of multiple myeloma with myeloproliferative diseases or secondary myeloid leukemoid reactions are rather rare. The paper describes 3 cases of multiple myeloma: the first case concurrent with neutrophilic leukocytosis; the second case with secondary erythropoetin-dependent erythrocytosis, and the third case with chronic myeloid leukemia. In such cases, an accurate diagnosis requires molecular testing, besides routine clinical and laboratory studies. The paper discusses therapeutic strategy in cases of a concurrence of 2 competing tumors of the blood system: to treat them simultaneously or the most aggressive tumor now, as well as a relationship between multiple myeloma and chronic myeloid leukemia, other myeloproliferative disorders, and secondary myeloid leukemoid reactions.

[POEMS-syndrome: a literature review and case reports].

POEMS-syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin Changes) is a rare nosological form occurred in patients with paraproteinemic hemoblastosis. Chronic progressive sensory-motor polyneuropathy is a key syndrome of the disease and it is a common reason for referral to neurologist. The paper presents data about POEMS-syndrome and own case reports with the analysis of disease features and results of examination.

[Multiple myeloma predominantly involving the spleen].

Extramedullary disease is an uncommon manifestation in multiple myeloma (MM) and can be observed at onset or develop at disease progression or relapse. Splenic involvement is very rare. The paper describes a 52-year-old female patient with MM who in 1990 was diagnosed with monoclonal gammopathy of undetermined significance with IgGkappa secretion and a considerably enlarged spleen. Specific therapy with bortezomib and dexamethasone was initiated in 2006 and proved to be inefficient. After splenectomy there was a 50% reduction in IgGkappa concentration. Splenic histological examination revealed monoclonal infiltration by the pleomorphic plasma cells expressing a kappa light chain.

[Efficiency of treatment of adult patients with acute T-lymphoblastic leukemia according to the ALL-2009 protocol of the Russian Acute Leukemia Study Group].

AIM: To present the results of treatment in adult patients with acute T-lymphoblastic leukemia (T-ALL) according to the ALL-2009 protocol of the Russian Acute Leukemia Study Group, the basic principle of which is continuation of cytostatic treatment, early switch from prednisolone to dexamethasone, and long-term use of L-asparaginase. SUBJECTS AND METHODS: The results of diagnosis and treatment were analyzed in 70 patients with different immunological variants of T-ALL treated in the Russian multicenter trial. RESULTS: Out of the 70 patients with T-ALL, its early immunotype was determined in 32 (45.7%) cases, the thymic and mature immunotypes were found in 31 (44.3%) and 7 (10%) cases, respectively. The median age of the patients with T-ALL was 28 (ranged from 15 to 54) years; men were twice more than women (48 and 22, respectively). Bone marrow lesion was noted in all the patients with early T-ALL and in 80% of the patients with thymic and mature T-ALL. The enlarged mediastinum was significantly more frequently detected in mature T-ALL (100%) than in its early (53.4%) and thymic (60.7%) variants. Therapeutic effectiveness was evaluated in 58 patients. An analysis was made in January 2013. Induction therapy resulted in complete remission in 49 (84.5%) patients. The refractory course of the disease was recorded in 5 (8.6%) cases; early death was in 4 (6.9%). The rate of complete remission in thymic T-ALL, unlike in the early (72%) and mature (71.4%) variants, was significantly higher (100%) due to the absence of resistant forms and early mortality. Moreover, it should be noted that only the patients with early T-ALL (16%) died during the induction phase. In the patients with different variants of T-ALL, the overall and relapse-free survival rates were not significantly different, accounting for 67.2 and 76.2%, respectively. Multivariate analysis revealed no prognostically unfavorable factors that determined long-term results. CONCLUSION: The ALL-2009 protocol is reproducible in any regions of the Russian Federation and highly efficient in treating patients with T-ALL.

[Clinical efficiency of transfusion of pathogen-inactivated platelet concentrates].

AIM: To evaluate the effect of pathogen-inactivated platelet concentrates (PIPC) on posttransfusion platelet increments, hemorrhagic syndrome relief, and transfusion intervals. SUBJECTS AND METHODS: This prospective study included 29 hemoblastosis patients (13 women, 16 men), median age 38 years (20-66 years). Pathogens were inactivated by the photodynamic method using the Intecept system. Each patient received two PC transfusions: one PIPC transfusion and one control one. Posttransfusion platelet increments one hour and one day after PC transfusion, the course of hemorrhagic syndrome, and the time to next platelet transfusion were analyzed. RESULTS: Pathogen inactivation with amotosalen and ultraviolet irradiation reduced posttransfusion platelet increments in recipients by 24% after one hour and by 29% after one day after PIPC transfusion versus control ones. CONCLUSION: The clinical efficiency of transfusions of amotosalen-induced PIPC was comparable with that of untreated platelet concentrates. Despite a reduction in post-transfusion platelet increment with the use of PIPC, this caused no significant increase in the frequency of transfusions.

[The first results of treatment for adult acute myeloid leukemia according to the AML-01.10 protocol of the Research Group of the Hematology Centers of Russia].

AIM: To give the preliminary results of the AML-01.10 Russian multicenter randomized trial to treat adult acute myeloid leukemia (AML), the basic principle of which is to use high-dose anthracycline antibiotics in induction/consolidation. SUBJECTS AND METHODS: By December 2011, 145 patients with AML had been randomized from 18 hematology centers of 15 cities and towns of the Russian Federation; the median age of all the patients was 44 years. Seventy-one patients were analyzed in August 2011 (a 1.5-year follow-up). RESULTS: The efficiency of 2 courses 7+3 using high-dose daunorubicin (60 mg/m2 per administration) and continuous infusion of cytarabine during the second course was high and comparable with that in the use of a high-dose HAM protocol as a second induction course and can achieve a complete remission in 74.6%. The protocol toxicity evaluated from its early mortality (11.3%) and its death in complete remission (16.6%) was permissible, particularly by taking into consideration the multicenter pattern of the trial. At the completion of analysis, 53 (68.8%) out of the 77 patients on whom the data on their vital status were available were alive. In this follow-up period, the frequency of recurrences was 19.2% (10/52). Only 3 (4.2%) patients out of the 71 patients in whom the efficiency of the protocol had been completely evaluated underwent allogeneic bone marrow transplantation. CONCLUSION: The total high dose (720 mg/m2) of anthracycline antibiotics, which is used in the period of induction and consolidation, determines the long periods of myelosuppression and intercourse intervals. Protocol deviations (no course of consolidation therapy, lower-dose idarubicin during consolidation therapy, a course of low-dose cytarabine, between the courses of induction and consolidation chemotherapy, and very long intercourse intervals) were recorded in a total of 20 (28%) patients.

[Deposition of 51Cr-labeled donor platelets in health and myelosuppressive thrombocytopenias].

AIM: To study the deposition of donor platelets (DP) in myelosuppressive thrombocytopenia (TP) in patients with acute leukemia (AL) or lymphosarcoma (LSA), by using a radionuclide label (51Cr) for DP. SUBJECTS AND METHODS: Complex clinical, hematological and radionuclide studies were conducted in 63 patients divided into 3 groups: 1) 7 healthy volunteers (a control group); 2) 37 patients with AL; 3) 19 patients with LSA. RESULTS: Changes were found in the deposition of labeled DPs used to prevent and treat hemorrhagic syndrome in myelosuppressive TP in patients with AL or LSA. In AL, this function was established to be virtually completely suppressed whereas in LSA, some functional activity of mononuclear phagocytes was preserved. Different degrees of suppression of this function were probably related to the nature of these diseases and particularly due to varying degrees of leukemic infiltration of depot organs. A mechanism for increased consumption of transfused DP in profound TP, one of the causes of which is the myelosuppression as a result of programmed polychemotherapy, cannot be ruled out. CONCLUSION: By and large, the radionuclide labeling technique for DP may be useful in specifying a number of uncertain mechanisms for derangements of the thrombocytic component of hemostasis in oncohematologic diseases.

[First results of Ph-negative acute lymphoblastic leukemia therapy of adults according to the protocol of Research Group of Russian Hematological Centers ALL-2009].

AIM: To review results of 2-year experience in execution of the protocol on the treatment of adult acute Ph-negative lymphoblastic leukemia ALL-2009. MATERIAL AND METHODS: Of 111 patients registered in the study from November 2008 to December 2010 the analysis covered 96 patients from 23 hematological centers in 18 towns of the RF. RESULTS: Treatment according to the Protocol ALL-2009 resulted in achievement of a complete remission in 91.2% patients with low early lethality of 5.5%. Postremission lethality fell to 3.7% versus previous studies (22%). Overall 2-year survival and recurrence-free survival reached 77.6 and 78.4%, respectively. Detection of any chromosomic aberrations significantly affected recurrence-free survival: 74 vs 100% in patients with normal karyotype. CONCLUSION: Protocol All-2009 demonstrates high efficacy in moderate toxicity and good reproducibility in any hematologic center.

[Toxicity of different treatment protocols for acute myeloid leukemias in adults: the results of four Russian multicenter studies].

AIM: To comparatively analyze the toxicity of 4 treatment protocols in patients with acute myeloid leukemia (AML), which were used in the Russian multicenter center in 1992 to 2009. MATERIALS AND METHODS: The information obtained in 4 Russian multicenter studies conducted in 33 hematology departments of 26 cities and towns of the Russian Federation in 1992 to 2009 was analyzed. Randomization was made in 243 patients with AML (median age 38 years) in 1992-1995, 396 patients (median age 39 years) in 1995-1999, 392 patients (median age 39 years) in 2001-2006, and 137 patients (median age 40 years) in 2006-2009. The analysis excluded patients with acute promyelocytic leukemias who were recruited in the AML-92 and AML-95 studies. These patients' statutory forms adequately filled in were 60-70% therefore toxicity was analyzed on the basis of the data of 631 patients. RESULTS: The baseline clinical and laboratory parameters in the patients enrolled in the studies in different years slightly differ in the count of leukocytes at the onset of the disease and in the level of lactate dehydrogenase (LDH): the recent studies revealed a larger number of high-risk group patients (leukocytes more than 30 10(9)(/l; LDH more than 500 units) possibly due to the later diagnosis of AML. During the studies, the number of complete remissions remained as before (55%) after the first course and increased from 65 to 78% after the second course using cytosine arabinoside in high doses. Despite treatment intensification, mortality in the induction period remained as before (19-21%). Remission mortality decreased from 18 to 10-13%. The long-term results of using the aggressive therapy did not differ from those obtained during the standard treatment protocols. The duration of leucopenia after standard induction courses during the all studies remained equal (17-19 days); the exclusion was a HAM course as the second induction course after which the duration of neutropenia was much more than that of the standard course (17 and 10 days, respectively). During the study years, there was an increase in platelet transfusion volumes (from 20 to 53 doses during the first course and from 7 to 28 doses during the second course) and a reduction in the percentage of severe hemorrhagic complications. The incidence of pneumonias remained at the same level (40-50%) during the induction courses and that of septic complications and necrotic enteropathy considerably decreased from 40-46 to 17-19%. The incidence of invasive aspergillosis during the current programs from AML treatment was 10% (two induction courses), that of invasive candidiasis was 4.7% (two induction courses). CONCLUSION; The long-term results of treatment for AML were virtually unchanged regardless significant therapy intensification. Mortality remained high during induction treatment and in the postremission period. Its cause is severe infectious complications developing during myelotoxic agranulocytosis. The results of the analysis provide the basis for developing a new AML treatment protocol that should take into account all the merits and demerits of the previous protocols and provide a toxicity-treatment efficiency balance.

[Neurosurgical treatment for chronic subdural hematoma in a patient with chronic autoimmune thrombocytopenic purpura].

Intracranial hemorrhage in patients with chronic autoimmune thrombocytopenic purpura (CATP) is a rare and severe complication of the disease. By taking into account a concomitance of chronic subdural hematoma (CSH) and CATP and no generally accepted approaches to managing the patients with this concomitance, the authors describe a clinical case of mini-invasive CSH drainage in a patient with CATP.

[The survival and sequestration of transfused donor platelets in cytostatic cytopenias].

AIM: To study the survival and sequestration of transfused donor platelets labeled with 51Cr in patients with acute leukemia (AL). SUBJECTS AND METHODS: Seven donor volunteers and 39 patients with different forms with AL at various stages of polychemotherapy (PCT) were examined. Cytostatic therapy was accompanied by 51Cr-labeled platelet concentrate (PC) transfusions. The patients were on appropriate high-dose (HD) PCT. RESULTS: The duration of donor platelet circulation was 8-10 days in healthy individuals. No platelet hypersequestration was recorded in both the spleen and the liver. Donor platelet survival was shorter in all patients with in a state of cytostatic cytopenia. There was an inverse correlation between the degree of circulation shortening and some clinical and hematological parameters (the bone marrow level of blastemia and blastosis, the XIIa-dependent fibrinolysis parameters). Four variants of radioactivity trends above the spleen and liver were identified. The findings suggest that there is platelet hypersequestration in the spleen, liver, and both organs. In some patients, the above both organs are uninvolved in the hypersequestration processes and the possible mechanism for increased consumption of transfused donor platelets, which is associated with recovery of the HD PCT-damaged vascular endothelium is considered. CONCLUSION: Shortening of transfused donor platelet circulation was found in relation to the level of blastosis. The described procedure may be used as one of the additional methods for evaluating the efficacy of donor PC transfusion and for specifying the pathogenesis of thrombocytopenias in AL patients on programmed HD PCT. A procedure is proposed to time the circulation of 51Cr-labeled platelets, by assessing deposit phenomena and estimating the level of their sequestration in the spleen and liver for the prediction of the efficiency of TC transfusions.

[Treatment and survival of multiple myeloma patients on programmed hemodialysis].

AIM: To analyse clinical picture of multiple myeloma (MM) and treatment results in MM patients on programmed dialysis (PD). MATERIALS AND METHODS: Case histories of 22 MM patients were analysed. They had a terminal stage of chronic renal failure (CRF) in the onset of the disease. Chemotherapy (CT) was performed in 20 patients (10 patients received VAD program, the other 10--melfalan). RESULTS: Early lethality was 28%. The patients died of septic complications. Neutropenia was observed significantly more frequently on melfalan treatment than on VAD therapy (9 and 2 patients, respectively; chi-square 5.6; p = 0.009). Survival median, excluding early lethality, was 16 months. Differences by therapy were not registered. Three patients on MP program survived more than 3 years. Function of the kidneys improved in 4 (20%) patients. Hemodialysis was avoided in 2 patients. Survival of patients with reestablished renal function was maximal (44 and 84 months). CONCLUSION: Standard CT for MM with terminal CRF is associated with high toxicity and frequent septic complications. Survival is better if renal function improves and HD discontinues. Reversibility of CRF at a terminal stage in MM does not depend on completeness of hematological response. Programs with melfalan CT provoke more frequent myelotoxic cytopenia, early lethality is higher but the number of longer survivals is more.

[The results of a multicenter randomized trial on the treatment of acute myeloid leukemia of adults].

AIM: Systematization of the results of 20-year multicenter randomized trial of the efficacy of treatment of acute myeloid leukemia (AML) of adults; presentation of the design of the study of the strategy of consolidation and maintenance therapy after high-dose consolidation initiated in 2007. MATERIAL AND METHODS: Treatment outcomes on the protocol AML-01.01 are presented for 354 AML patients from 29 hematological centers located in 22 towns of Russia and 2 towns of Ukraine. The patients were randomized into 3 groups by variant of therapy: 124 patients (62 males and 62 females; age median 42 years) received 4 courses of 7+3+VP-16 and 5 courses of maintenance therapy (7+3 with thioguanin); 130 patients (65 males and 65 females, age median 41 year) received 2 courses of 7+3+VP-16, 2 courses 7+3, maintenance--5 courses 7+3 with thioguanin; 126 patients (57 males and 68 females, age median 40 years) were given 2 courses of 7+3+VP-16, 2 HAD courses, treatment discontinuation. RESULTS: A complete remission after the first course of 7+3+VP-16 was achieved in 55% patients, after the second course--in 30% after the course 7+3+VP-16 or 7+3 with mitoxantron, in 70%--after NAM. Overall and recurrence-free survival were 18 and 35%; 30 and 20%; 36 and 30%, respectively. There was no significant difference in efficacy of the treatment scheme. CONCLUSION: The multivariate analysis has shown that a leading factor having impact on treatment results was the number of randomized patients: the less patients were randomized, the worse were the results.

[Primary diffuse large B-cell lymphosarcoma of the spleen].

AIM: To investigate characteristics of the course and efficacy of treatment of diffuse large B-cell lymphosarcoma (DLBL) with primary lesion of the spleen. MATERIAL AND METHODS: From 1998 to 2006, primary splenic lesion was registered in 15 of 120 patients with DLBL and affected lymph nodes (LN), spleen and Waldeyer's ring. The diagnosis was made according to WHO criteria. Of them 14 patients had splenectomy as the first stage of therapy. The operation was followed with 6 to 8 courses of CHOP-21 (8 patients), 4 courses of R-CHOP-21 and radiotherapy (one patient). One patient received 7 courses of CHOP-21 followed by splenectomy. Because of the presence of several signs of unfavourable prognosis 5 patients under 60 years were given intensive therapy: 4-6 courses of the modified program NHL-BFM-90, 2 of 5 patients received radiotherapy. RESULTS: All the patients with primary DLBL of the spleen had two and more signs of unfavourable prognosis: elevated concentration of serum LDG, size of the tumor more than 10 cm, high proliferative activity of tumor cells, B-symptoms, severe condition. Seven patients had centroblastic, 8--anaplastic variants of DLBL. Tumor cells in primary DLBL of the spleen had no specific immunophenotype. Complete remission of the disease was achieved in 9 (90%) of 10 patients treated on programs CHOP-21, R-CHOP-21, in 4 of 4 patients on the modified program NHL-BFM-90. Mean follow-up was 39.3 months (from 7 to 103 months). CONCLUSION: For primary DLBL of the spleen characteristic are long-term remissions on first line therapy according to CHOP-21 program irrespective of morphology and immunophenotype.

[A CHOP-21 course efficacy in therapy of diffuse large B-cell lymphosarcoma].

AIM: To examine efficacy of polychemotherapy (PCT) CHOP-21 in patients with diffuse large B-cell lymphosarcoma (DLBCL). MATERIAL AND METHODS: Fifty-five DLBCL patients received first-line therapy according to CHOP-21 program in 1996-2004. The diagnosis was made by WHO criteria. RESULTS: Initially, 37 patients had lymph node lesions, 18--nonlymphatic lesions. Complete remissions were achieved in 49% (56.7% in nodal lesions, 33.3% in extranodal ones). Overall 5-year survival was 35%, event-free--25%, for patients with nodal lesions--36 and 32%, respectively, extranodal lesions--35 and 22%, respectively. Overall 5-year and event-free survival in patients with local lesions was 85 and 75%, generalized--25 and 20%, respectively. In patients with involvement of the gastrointestinal tract 3-year overall and event-free survival reached 50 and 45%. Event-free survival was not seen in patients with extranodal lesions of other locations in overall 3-year survival 45%. CONCLUSION: PCT program CHOP-21 was effective in DLBCL patients with local nodular lesions except cases with large-size tumors, invasion in the adjacent organs and tissues and isolated gastric lesion.

[Invasive pulmonary aspergillesis].

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.