[Synchronous and metachronous myeloid and lymphoid tumors].

AIM: To determine the clinical features of multiple primary tumors (MPT) in patients with hemoblastoses, to develop treatment policy for synchronous and metachronous tumors, and to determine the impact of chemotherapy for one disease on the course and prognosis of another one. SUBJECTS AND METHODS: The investigation included 20 patients with multiple primary synchronous and metachronous myeloid and lymphoid tumors, who had been followed up at the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation. The distribution of patients by nosological entities was as follows: 17 (85%) patients with myeloproliferative diseases (MPDs) concurrent with lymphoproliferative diseases (LPDs) and 3 (15%) with two types of MPD. A special group comprised 3 patients who successively developed 3 malignant diseases: cancer/B-cell chronic lymphocytic leukemia (B-CLL)/Ph-positive chronic myeloid leukemia (Ph+CML); cancer/polycythemia vera (PCV)/B-CLL; cancer/essential thrombocythemia (ETC)/multiple myeloma (MM). RESULTS: The Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, followed up 20 patients with synchronous and metachronous tumors in 1996 to 2013. The patients' age was 42 to 82 years (64 years). The female/male ratio was 1:1.2. Metachronous tumors were 1.5-fold higher than synchronous ones. The time to detection of secondary hemoblastosis averaged 3.3 years; the longest interval was 14 years; the mean coexistence of 2 tumors was 4.8 years (1-11 years). The total length of the follow-up was 8 years (1-19 years). Among them, there were 17 (85%) patients with 2 chronic hematologic tumors with a myeloid or lymphoid phenotype; 3 (15%) of the 20 patients had 3 malignant diseases (cancer/ B-CLL)/Ph+CML, cancer/PCV/B-CLL, cancer/ETC/MM. In the group of 17 patients, 13 (76%) were diagnosed as having Ph-negative MPDs (PCV in 4 patients, primary myelofibrosis in 4, ETC in 4, undifferentiated MPD in1) and 4 (24%) patients had Ph+CML. This patient group was found to have the following LPDs: CLL in 5 (30%), hairy cell leukemia in 1 (5%), paraproteinemic hemoblastoses in 11 (65%). MPD preceded LPD in 8 (47%) patients; the development interval between two tumors averaged 6 years (1 to 14 years). LPD preceded MPD in 3 (18%) patients; the interval averaged 5 years (2 to 17 years). MPD and LPD appeared synchronously in 6 (35%) patients. CONCLUSION: The fact that 2 malignancies or more may occur in one patient determines the need for a careful follow-up of patients with blood system diseases. The activity of one hematologic disease or another is a leading criterion for choosing a therapeutic tactic.

[Mastocytosis. Review of the literature and description of clinical cases].

The term mastocytosis (MC) encompasses a group of rare diseases characterized by the tumorous proliferation of clonal mast cells and the infiltration of one or several organs. The clinical picture of MC is extremely diverse from skin lesions that can spontaneously regress to the aggressive disease forms associated with organ dysfunction and short survival. Nowadays, the 2008 WHO classification identifies 7 MC subtypes. The disease is diagnosed on the basis of its clinical manifestations and detection of tumorous mast cell infiltrations via morphological, immunohistochemical, immunophenotypic, genetic, and molecular examinations. Abnormal mast cells are characterized by the atypical morphology and pathological expression of CD25 and CD2 antigens. Enhanced serum tryptase activity is a common sign in all MC subtypes. More than 90% of the patients have D816V KIT mutations in the mast cells. This paper reviews the literature. Three cases are described as a clinical example in patients with different MC subtypes.

[Trisomy of chromosome 8 in Ph-negative cells of the bone marrow in patients with chronic myeloid leukemia treated with inhibitors of BCR-ABL tyrosine kinases].

AIM: To analyse clinical implications of chromosome 8 trisomy in Ph-negative cells of the bone marrow in patients with chronic myeloid leukemia (CML) treated with inhibitors of tyrosinkinases (ITK). MATERIAL AND METHODS: A total of 386 patients with CML (chronic phase--288, acceleration phase--77) received imatinib (400-800 mg/day). Because of resistance and/or intolerance some patients were switched to ITK II (nilotinib, dasatinib, bozutinib). This study included 8 CML patients (7 in a chronic phase, 1 in acceleration phase) treated with BCR-ABL ITK inhibitors of the first (imatinib) and the second line (ITK-II). The standard cytogenetic examination, on demand--investigation of the interphase nuclei with FISH, in some cases morphological, cytochemical and histological examinations of the bone marrow were made. RESULTS: The existence of a Ph-negative clone with trisomy of chromosome 8 had no negative effect on the course of the disease. The patients showed a stable hematological and cytogenetic response and no need in changing treatment policy. In long-term follow-up Ph-negative clone with trisomy of the chromosome 8 persisted without a clear trend to rise in most patients. CONCLUSION: Detection of a Ph-negative clone with chromosome 8 trisomy at early stages suggests parallel existence of Ph-positive and Ph-negative clones. None of the patients had myelodisplasia.

[Dasatinib treatment of imatinib-resistant and imatinib-intolerant patients with chronic myeloid leukemia in a chronic phase].

AIM: To analyse resistance to imatinib therapy, efficacy and safety of dasatinib. MATERIAL AND METHODS: A total of 18 patients with chronic myeloid leukemia (CML) in a chronic stage received dasatinib for 9-30 months (median 30 months) to September 2008. RESULTS: Lethal outcomes during dasatinib treatment were absent. To September 2008, 16 (89%) patients were alive, 2 (11%) patients died of the disease progression after dasatinib discontinuation. A complete clinicohematological response was observed in all the patients. Major cytogenetic, complete cytogenetic, major molecular, complete molecular responses were achieved in 12 (67%), 10 (55%), 7 (39%) and 5 (28%) patients, respectively. Hematological and non-hematological toxicity occurred in 9 (50%) patients. Now 12 (67%) patients continue dasatinib treatment, in 6 (33%) patients the drug was discontinued. CONCLUSION: The results from trials in Russian Hematological Research Center are the same as in the international study. Dasatinib is effective and well tolerated therapeutic option for imatinib-resistant patients with a chronic phase of CML.

[Prognosis factors in imatinib mesilate therapy in patients with a chronic phase of Ph-positive chronic myeloid leukemia: data from a multicenter non-randomized trial in Russia].

AIM: To reveal prognostically significant factors affecting efficacy of glivek therapy in untreated (duration of the disease < or = 6 months) and pretreated (duration of the disease > 6 months) patients with chronic myeloid leukemia (CML) in a chronic phase. MATERIAL AND METHODS: A total of 338 patients (64 untreated and 274 pretreated) with a chronic-phase CML on glivek therapy entered the trial. RESULTS: Five-year survival on glivek was high (89, 98 and 88% in untreated and pretreated patients, respectively). Incidence of transformation in the acceleration phase and blast crisis was low both in untreated and pretreated patients (1.6 and 11%, respectively) and correlated with the rate of a complete cytogenetic response (CCR). Untreated patients had no factors affecting treatment efficacy negatively, CCR probability was 96%. Blastemia, thrombocytosis and splenomegaly reduced CCR probability significantly in pretreated patients. Slow reduction of the tumor mass, late achievement of a complete hematological response and a cytogenetic response decreased probability of CCR. CONCLUSION: Glivek is a drug of choice for patients with chronic-phase CML. High probability of CCR both in untreated and pretreated patients lowers the risk of the disease transformation into the phase of acceleration/blast crisis and raises overall survival in both groups.

[Factors of an unfavorable prognosis in patients with B-cell chronic lymphoid leukemia: a retrospective analysis of 206 cases]. / Faktory neblagopriiatnogo prognoza u bol'nykh B-kletochnym khronicheskim limfoleikozom: retrospektivnyi analiz 206 sluchaev.

AIM: To assess factors of an unfavourable prognosis in a group of intermediate risk of B-cell chronic lymphoid leukemia (BCCLL). MATERIAL AND METHODS: 206 BCCLL patients (mean age 55.5 years, male/female = 1.66) entered the study conducted by Hematological Research Center in 1992-2000. RESULTS: Nine patients under 35 years of age did not survive 5 years except one female who achieved a complete remission on fludarabin. The type of bone marrow infiltration (diffuse vs interstitial and nodular), the time of lymphocyte count doubling (under or over 12 months) discriminate the patients by prognosis in the group of intermediate risk: medians of overall survival 65 months vs 148 months and 72 vs 133 months, respectively (p < 0.005 for both curves, log-rank criterion). Survival medians in groups with low (< 50% cells) and high (> 50% cells) expression of CD38+ cells in the group of intermediate BCCLL risk comprise 55 and 106 months (p = 0.005). The type of bone marrow infiltration and time of doubling of lymphocyte count overlap: > 70% patients with a diffuse type of bone marrow infiltration have the time of doubling under 12 months and vice versa while expression of CD38 do not overlap with these values. Combination of two signs (type of bone marrow infiltration and CD38 expression or time og lymphocyte count doubling and CD38 expression) allows more precise identification of prognostically unfavourable groups. Medians of survival for combination of the first two signs (two positive against two negative) comprise 51 months vs 169 months (p < 0.0001), for combination of the latter two signs 55 months vs 106 months was not reached (p < 0.001). Although most patients with a tumor form of BCCLL are referred to stage II, the prognosis in this form is much worse than in stage II, survival medians are 44 and 69 months, respectively (p < 0.05). A mutation status of the genes of a variable region of immunoglobulins enable identification of the group of patients with a relatively benign course of BCCLL (survival medians 61 and 289 months, p < 0.0001). CONCLUSION: In patients under 35 years of age BCCLL runs unfavourably and seems to require intensive polychemotherapy. Usage of a combination of the signs (CD38, time of doubling of lymphocyte count and type of bone marrow infiltration) is a simple and reliable method of identification of prognostically different categories of patients in the group of an intermediate BCCLL risk. Prognosis in patients with a tumor form of BCCLL is unfavourable: medians of survival in patients with a tumor form and stage III-IV are comparable. Mutational status of the genes of immunoglobulin variable region may serve a marker of a long-term prognosis.