Lenalidomide and dexamethasone in treatment of patients with relapsed and refractory multiple myeloma - analysis of data from the Czech Myeloma Group Registry of Monoclonal Gammopathies.

Lenalidomide (LEN) is an immunomodulator with clinical activity against myeloma cells. Based on the pivotal phase 3 trials MM-009 and MM010, the combination of lenalidomide and dexamethasone(DEX) was approved for patients with multiple myeloma who received at least one prior therapy. Here, we evaluated LEN/DEX therapy in unselected population and subsequently in selected sub-groups of patients with relapsed/refractory multiple myeloma followed in the Registry of Monoclonal Gammopathies of the Czech Myeloma Group. Altogether 858 patients were treated with LEN/DEX in the Czech Republic and Slovakia until end of 2017. The analyzed sub-groups were defined as patients with high risk cytogenetic aberrations and patients with relapsed and refractory MM. The overall response rate (ORR; partial remission or better response, PR) in the whole group of patients was 46.3% for all lines of therapy, 26.4% for high-risk group and 32.1% for relapsed and refractory group. Medians of overall survival (OS) in the same cohorts were as follows: 25.6, 15.7 and 18.5 months, progression free survival (PFS) was: 11.2, 6.4 and 9.0 months respectively. The most common adverse events were hematologic and infectious. In conclusion we found that our results correlated with those found in other studies in terms of response rates, survival measures, and also of treatment toxicity.

Incidence and Prognostic Value of Known Genetic Aberrations in Patients with Acute Myeloid Leukemia--a Two Year Study.

BACKGROUND: In this work, we evaluated the incidence and prognostic value of several genetic aberrations in patients with a diagnosis of acute myeloid leukemia (AML). PATIENTS AND METHODS: We analysed 90 patients: 42 males (mean age 54.5 years) and 48 females (mean age 59 years), with AML. The genetics of all leukemia samples was studied using conventional cytogenetics, the interphase fluorescence in situ hybridisation as well as the standardized RTPCR protocol. RESULTS: In 34.4% of patients, we detected at least one of the analysed genetic aberrations, except the CBFB MYH11, which we did not detect. Translocation t(8;21)/ AML1 ETO was found in 4.4% of patients with a mean age of 45.4 years, while none of these patients was older than 55 years. Translocation t(15;17)/ PMLRARA was found in 5.5% of patients with a mean age of 52.6 years and an almost equal distribution between younger and older patients. The MLL gene rearrangements were found in 6.6% of patients, the -5/ 5q- and/ or -7/ 7q- aberrations in 7.7% of patients, while the most frequent genetic abnormality in our study was trisomy 8 (10%). Moreover, we found a favorable clinical outcome in patients expressing fusion genes AML1-ETO or PMLRARA in contrast to an adverse clinical outcome with few remissions and death in AML patients with MLL, -5q/ -5 and -7q/ 7-. Finally, an intermediate prognosis was found in patients with trisomy 8. CONCLUSION: In this study, we found a good congruence with published literature on the incidence and prognostic value of several well established AML-associated genetic aberrations. This simple genetic-based classification system helps us to identify patients with a favorable, intermediate or unfavorable prognosis and to treat them with the best currently available therapy. However, analysis of new genetically defined abnormalities in AML is necessary for development of better therapeutic strategies and/or diagnostics.

Cytogenetic abnormalities predict treatment-free interval and response to therapy in previously untreated chronic lymphocytic leukemia patients.

We evaluated the prognostic impact of chromosomal abnormalities as detected by interphase fluorescence in situ hybridization (iFISH) in 86 chronic lymphocytic leukemia (CLL) patients. Overall, 39 of 86 (45%) patients displayed one (35%) or more (10%) chromosomal abnormalities, del13q (31%) being more frequently detected than trisomy 12 (19%) followed by del11q (17%), del17p (6%) and del6q (5%). Significant differences in the treatment free intervals (TFIs) were observed among individual cytogenetic subgroups (p=0.027) with the shortest mean TFIs in subgroups with del17p, del11q and trisomy 12 (10, 12 and 14 months, respectively) as compared to subgroups with normal cytogenetics (38 months) and del13q (68 months). Poor response to therapy was observed in subgroups with del11q (p=0.044) and trisomy 12 (p=0.047) while patients with normal cytogenetics had good response (p=0.003). Furthermore, del17p and del11q were associated with highest tumor burden and disease activity as reflected by corresponding laboratory data.

[Relation between Bcl-2 protein expression and results of therapy in patients with acute myeloblastic leukemia]. / Vzt'ah medzi expresiou Bcl-2 proteínu a výsledkami liecby u chorých s akútnou myeloblastovou leukémiou.

Flow cytometric expression of Bcl-2 protein was analyzed in 67 newly diagnosed acute myeloblastic leukemia (AML) patients using an anti-Bcl-2 monoclonal antibody by direct immunofluorescence technique and result were correlated with FAB subtype, CD34 expression and clinical outcome. The number of Bcl-2+ cells in each sample was heterogenous (range, 19% to 96%), with mean of 81%. The percentage of Bcl-2+ cells was higher in M0 and M1 types according French-American-British classification. The mean fluorescence index (MFI), expressed as the ratio of sample channel: control mean channel was significantly higher (p < 0.01) in M0 (19.0) and M1 (17.6) than M4 (11.7) and M5 (8.9) cytotypes. In addition, Bcl-2 MFI significantly correlated both with CD34 positivity and with CD34 MFI. High percentage expression of Bcl-2 and MFI index of Bcl 2 was associated with a low complete remission rate after intensive chemotherapy (40.4% in cases with 20% and more positive cells vs 72% in cases with less than 20% positive cells). By statistical analysis we also demonstrated that both Bcl-2 high MFI (> 16) and CD34 expression are independent prognostic factors for achieving CR in AML.

Fludarabine combined with cyclophosphamid is highly effective in the treatment of chronic lymphocytic leukemia.

Combined treatment of fludarabine (FLU) with cyclophosphamide (CY) may increase the complete remission (CR) rate, decreased minimal residual disease (MRD) and, possibly, prolong survival in B-chronic lymphocytic leukemia patient's (B-CLL). The aim of study was to evaluate the activity and toxicity of FLU in combination with CY, the FLU-CY schedule, in patients with previously untreated B-CLL. From May 1999 to December 2002, 57 patients with advanced or progressive B-CLL received treatment with FLU at a dose of 30 mg/m2 for three consecutive days and CY at a dose of 300 mg/m2 for three days. The cycles were repeated at four week intervals or longer if severe myelosupression occurred. Guidelines for the evalution of response and toxicity were those developed by the National Cancer Institute Sponsored Working Group. Minimal residual disease (MRD) was detected by immunophenotyping only in patients with CR by standard criteria. In the analyzed group an overall response (OR) rate (CR+PR) of 89.5% (95% CI 80.6-94.7%) was achieved, including complete response in 29.8%. At the time of analysis 15 of 17 patients with CR are still in remission. Median duration of follow up in these is 12 (range 4-29.2) months. MRD was detected only in five out of 17(29.4%) patients with CR. Grade III/IV thrombocytopenia was seen in 3 (5.2%) patients and grade III/IV neutropenia in 6 (10.5%). Severe infections were noted in 14 (24%) patients. Two (3.5%) patients died, one due to sepsis, one as a result of disease progression. The FLU-CY regimen is highly effective combination in previously untreated CLL patients with acceptable toxicity. The efficacy of the regimen seems to be higher than that observed earlier after treatment with FLU alone.

Efficiency of in vivo purging with autologous stem cell transplantation and monoclonal antibody in B-cell lymphomas.

Elimination of tumor cells from hematopoietic stem cell products is a major goal of bone marow-suported high-dose cancer chemotherapy. In patients (pts) with low-grade lymphoma Gianni et al (2000) assessed the ability of Rituximab, given in combination with high-dose chemotherapy, to eradicate PCR-detectable disease and enable the harvesting of large amounts of uncontaminated circulating progenitor cells. Our study was conducted in 27 consecutive pts with untreated bcl2 positive NHL (follicular lymphoma--7, chronic lymphocytic leukemia--13 and NHL in leukemic phase--7), 14 pts received Rituximab. Patients received 4 courses of standard-dose chemotherapy (CHOP or FLU-CY), followed by one course of high-dose cyclophosphamid plus G-CSF. Patients allocated to Rituximab received i.v. infusions of 375 mg/m2 48 hours before stem cell collection and in 3 weekly doses after transplantation (R-CHT). Clinical response after transplantation was evaluated in 26 pts who completed the treatment. The complete response rate was in 100% in the Rituximab group (PCR negative in 79%) versus 50% of controls (p<0.01). Yield of purged CD34+ cells was with median 5.23x10(6)/kg in CHT and 8.76x10(6)/kg in R-CHT pts. Toxicity in the both arms was acceptated (no difference). No significant difference was observed between CHT and R-CHT group in the mean number of days spent with neutropenia and trombocytopenia. After a follow-up of 31 months, no patient relapsed. Aside from providing PCR-negative harvests, the chemoimmunotherapy treatment produced complete clinical (100%) and molecular remission in 79% of evaluable pts. We showed that Rituximab in combination with effective high-dose anti- lymphoma chemotherapy, allowed the harvesting of large amounts of tumor free progenitor cells in evaluable pts.

High expression of Bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy.

Flow cytometric expression of bcl-2 protein was analyzed in 67 newly diagnosed acute myeloblastic leukemia (AML) patients using an anti-bcl-2 monoclonal antibody by direct immunofluorescence technique and results were correlated with FAB subtype, CD34 expression and clinical outcome. The number of bcl-2+ cells in each sample was heterogenous (range, 19% to 96%), with a mean of 81%. The percentage of bcl-2+ cells was higher in M0 and M1 types according to French-American-British classification. The mean fluorescence index (MFI), expressed as the ratio of sample channel:control mean channel was significantly higher (p=0.01) in M0 (19.0) and M1 (17.6) than M4 (11.7) and M5 (8.9) cytotypes. In addition, bcl-2 MFI significantly correlated both with CD34 positivity and with CD34 MFI. High percentage expression of bcl-2 and MFI index of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (40.4% in cases with 20% and more positive cells vs 72% in cases with less than 20% positive cells). By statistical analysis we also demonstrated that both bcl-2 high MFI (>16) and CD34 expression are independent prognostic factors for achieving CR in AML.

[Occurrence of autoimmune complications in patients with chronic myelocytic leukemia during treatment with interferon alfa]. / Výskyt autoimunitných komplikácií u chorých s chronickou myelocytovou leukémiou pocas liecby s interferónom alfa.

UNLABELLED: Several prospective randomized studies have shown that the treatment of chronic myeloid leukemia with interferon alfa (IFN alpha) prolongs the survival by comparison with conventional chemotherapy. However, long-term treatment with Interferon alfa (IFN alpha) can produce or exacerbate immune-mediated complications (IMC). The purpose of this study was to analyze the experience with IMC in patients with chronic myelogenous leukemia (CML) undergoing IFN alpha treatment. PATIENTS AND METHODS: The occurrence of IMC was evaluated in 76 patients (47 male; 29 female) with Philadelphia chromosome (Ph)-positive CML. The median of age was 45 years and the duration of disease was 3.9 years. Diagnostic criteria of IMC were performed in patients with sign and symptoms suggestive of particular disorders. RESULTS: Well-documented and clinically evident complications developed in 7 patients after a median of 19 months (range 1-84) of IFN alpha treatment. These included 9.2% patients with Ph-positive CML treated with IFN alpha-containing regimens. Hypothyroidism (H) occurred in 1 patient (1.3%), immune-mediated hemolysis (HEM) in 2 patients (2.6%) and connective tissue disorders (CTD) in 4 patients (5.3%) [2-SLE, 1-Raynad's syndrome and 1-mixed connective tissue syndrome (MCTS)]. IFN alpha was discontinued in 3 patients and the dose was reduced in 2 patients. Five of 7 patients (75%) with immune-mediated complications had some degree of cytogenetic response at the time of the event. The association with female sex was strong and significant (86% vs 33.6%, x2; 48; p = 0.02). CONCLUSION: The frequency of IMC of clinical relevance with interferon alfa therapy in CML increased (long-term therapy). The patients treated with interferon alfa should be monitored for sign and symptoms of autoimmunity.

Immune-mediated complications during interferon alpha therapy in chronic myelogenous leukemia.

Several prospective randomized studies have shown that the treatment of chronic myeloid leukemia with interferon alpha (IFNalpha) prolongs the survival by comparison with conventional chemotherapy. However, long-term treatment with Interferon alpha can produce or exacerbate immune-mediated complications (IMC). The purpose of this study was to analyze the experience with IMC in patients with chronic myelogenous leukemia (CML) undergoing IFNalpha treatment. The occurrence of IMC was evaluated in 76 patients (47 male; 29 female) with Philadelphia chromosome (Ph)-positive CML. Diagnostic criteria of IMC were performed in patients with symptoms suggestive of particular disorders. Well-documented and clinically evident complications developed in 7 patients after a median of 19 months (range 1-84) of IFNalpha treatment. These included 9.2% patients with Ph-positive CML treated with IFNalpha-containing regimens. Hypothyroidism (H) occurred in 1 patient (1.3%), immune-mediated hemolysis (HEM) in 2 patients (2.6%) and connective tissue disorders (CTD) in 4 patients (5.3%) (2 systemic lupus erythematosus--SLE, 1 Raynaud's phenomena and 1 mixed connective tissue disease--MCTD). IFNalpha was discontinued in 3 patients and the dose was reduced in 2 patients. Five of 7 patients (75%) with immune-mediated complications had some degree of cytogenetic response at the time of the event. The association with female sex was strong and significant (86% vs 33.6%, x2; 48; p = 0.02). The frequency of IMC of clinical relevance with interferon alpha therapy in CML increased (long-term therapy). The patients treated with interferon alpha should be monitored for signs and symptoms of autoimmunity.

Leukemic transformation of polycythemia vera after treatment with hydroxyurea with abnormalities of chromosome 17.

The leukemogenic risk attributed to therapy of polycythemia vera with radiophosphorus and alkylating drugs has led, over the last 20 years, to the increased use of myelosupressive nonmutagenic drugs, especially hydroxyurea. But there exist reports, which showed the development of polycythemia vera into acute leukemia not only in patients treated with alkylating agents and radiophosphorus but also with single hydroxyurea. In this article we present two cases of polycythemia vera, in which the development to acute myeloblastic leukemia occurred after long-term treatment with hydroxyurea. Significant is the fact, that in both presented cases cytogenetic and FISH analysis showed abnormalities of chromosome 17, in the one of case fullfilled criteria for "17p-syndrome". Due to the possibility of leukemogenic potential in the time of hydroxyurea treatment, it is necessary to be careful especially in young patients. The dynamic follow up of cytogenetic analysis is necessary, especially, in those, where long-term hydroxyurea therapy is supposed.

P-glycoprotein expression in adult acute myeloid leukemia: correlation with induction treatment outcome.

Drug resistance has become a major cause of the treatment failure in patients with acute leukemia. P-glycoprotein (P-gp), which is associated with multidrug resistance (MDR) phenotype, has been reported to be an important predictor of the treatment outcome. The aim of this study was to analyze the value of P-gp expression in bone marrow cells as a predictor of the response to remission induction chemotherapy, as well as duration of remission in adult patients with newly diagnosed acute myeloid leukemia (AML). We examined the expression of P-gp in 31 patients using the monoclonal antibody UIC2. Direct immunofluorescent labeling was performed and samples were analyzed by flow cytomery. Kolmogorov-Smirnov test (D-value) was used to estimate UIC2 staining. A D > or = 0.3 for labeling of gated leukaemic blasts as compared to that of the isotypic control was defined positive (+) and compared to clinical data. P-gp expression was found in 14/31 (45.6%) patients, 17/31 (54.8%) of the samples were found P-gp negative(-). No correlation was found regarding age, sex and FAB subtype, altough 6/14 (43%) cases with more than 50% of cells having P-gp expression, were CD34+/CD7+. Complete remission rates were significantly lower in UIC2+ patients than in UIC2- cases (70% vs 35%, p < 0.01). Complete remission duration was also shorter in UIC2+ patients (6 vs 12.4 months). Our data indicate, that P-gp expression is a reliable marker of resistance to induction treatment in patients with de novo AML and can help to identify patients who may require alternative regimens designed to overcome therapy resistance.

[Hematologic and cytogenetic response to treatment in patients with chronic myeloid leukemia]. / Hematologická a cytogenetická odpoved na liecbu u chorých s chronickou myeloickou leukémiou.

BACKGROUND: The Interferon alpha therapy increases the number of cytogenetic responses in patients with chronic myeloic leukaemia. The addition of cytarabine can reduce the number of Ph positive metaphases. The achievement of cytogenetic response is connected with longer survival of patients with chronic myeloic leukaemia. The aim of the study was the evaluation of the achievement of hematologic and cytogenetic response as well as adverse effects of the treatment in chronic myeloic leukaemia patients. METHODS AND RESULTS: The followed was the group of 87 previously untreated CML Ph positive patients. 34 patients with the median age of 44.6 years were treated with hydroxyurea, 42 patients were treated with single interferon alpha and 11 patients with the median age of 41.3 years with the combined interferon plus cytarabine therapy. The complete hematologic remission occurred in only 17.5% of patients treated with hydroxyurea, but in 35.7% treated with interferon and in 54.5% patients treated with the combined therapy. The cytogenetic response we have not found in any of hydroxyurea treated patients, in the group of interferon alpha in 38%. The highest number of cytogenetic responses was in the group treated with interferon plus cytarabine. As we have expected, the addition of cytarabine increased hematotoxicity and gastrotoxicity. CONCLUSION: Based on the published date, that show a better survival of patients with the achieved cytogenetic response as well as the higher number of cytogenetic responses in the group of interferon plus cytarabine therapy from our observation, we believe, that combined therapy should be suitable as a front-line therapy of chronic myeloic leukaemia patients.

Hematological and cytogenetic response of interferon alpha 2b alone and combined interferon alpha plus cytarabine as a first-line treatment in chronic myeloid leukemia.

Treatment with interferon-alpha (IFNalpha) prolongs survival in chronic myeloid leukemia (CML). Additionally, cytarabine (AraC) can reduce the number of Ph + metaphases. Fortythree previously untreated patients with CML in chronic phase were randomly assigned to receive either. IFNalpha 2b (5 MU sqm/daily) or IFNalpha 2b in the same dosages plus monthly courses of low-dose AraC. The aim were complete hematologic remission at 6 months and cytogenetic response at 12 months. A complete hematologic remission occurred in 60.4% patients with single IFNalpha 2b in 76.2% patients with combination therapy. A cytogenetic response was present in 13.9% (major in 2 patients) with IFN therapy and in 38.1% patients with combination therapy. Two of 21 patients treated with IFNalpha/AraC therapy achieved major (9.52%), 4 partial (19.04%) and 2 minor (9.52%) cytogenetic response. Major side effects were cytopenia (20.1%), flu-like syndromes (42.4%) and increase of hepatic transaminases (3.4%). The side effects were more significant in the group receiving combination therapy. Based on published data that show a survival advantage for patients who achieved any cytogenetic response, and high rate of cytogenetic response which we observed in our study we believe that IFN plus AraC regimen could be a front-line therapy for CML.

[The 6M 12M trial--study of the effectivess and tolerance of treatment in chronic myeloid leukaemia with a combination of interferon alfa and cytarabine]. / Stúdia 6M 12M--Ucinnost' a tolerancia liecby chronickej myeloickej leukémie kombináciou interferonu alfa s cytosinarabinosidom.

OBJECTIVE: Comparing the conventional treatment after the interferon alpha treatment the number of hematologic as well as cytogenetic responses increases. With the cytogenetic response is associated a longer survival. Today is interferon alpha considered to be the first line treatment in those patients with chronic myeloic leukaemia, who are not candidates for alogenic bone marrow transplantation. The combination with cytosinarabinoside can reduce the number of Ph positive metaphases. DESIGN AND METHODS: Forty-three previously untreated patients with CML in chronic phase were randomly assigned to receive either IFN alpha 2 b (5MU sqm/daily) or IFN alpha 2 b in the same dosage plus monthly courses of low-dose AraC. The aim were complete hematologic remission at 6 months and cytogenetic response at 12 months. RESULTS: A complete hematologic remission occured in 61.9% patients with single IFN alpha 2 b and in 78.9% patients with combination therapy. A cytogenetic response was present in 28.5% and in 42.2% patients with combination therapy. One of 21 patients treated with IFNalpha/AraC therapy achieved complete (5.2%), 4 partial (21%) and 3 minor (16%) cytogenetic response. The side effects were more significant in the group receiving combination therapy. CONCLUSIONS: Based on published data that shows a survival advantage for patients who achieved any cytogenetic response and high rate of cytogenetic response which we observed in our population we believe that IFN plus AraC regimen could be a front-line therapy for CML.

[Leukemic transformation of polycythemia vera after treatment with hydroxyurea and chromosome 17 abnormalities]. / Leukemická transformácia polycytemia vera po liecbe s hydroxyureou s abnormalitami chromozómu c. 17.

The authors present two patients with polycythemia vera where they recorded after several years' treatment with hydroxyurea development of acute myeloblastic leukaemia. In both instances they found, associated with leukaemia, abnormalities of chromosome no.17, in one case meeting criteria of the so-called 17p-syndrome. Progression of polycythemia vera into acute leukaemia is explained by the possible association with the long-term use of the drug and loss of chromosomal material (short arm of chromosome 17), the part where genes important in the process of leukaemogenesis are located. The authors draw attention to contemplated long-term administration of hydroxyurea to young patients with polycythemia vera. As cytogenetic analysis is a suitable method for evidence of progressing polycythemia vera into acute leukaemia, dynamic follow up of chromosomal changes is necessary, in particular in patients where long-term treatment with hydroxyurea is assumed.

[Primary hepatosplenic (gamma delta) T-cell lymphoma: clinico-pathologic analysis of 3 cases]. / Primárny hepatosplenický (gamma delta) lymfóm T-pôvodu: klinicko-patologický rozbor troch prípadov.

The authors analyze three cases of hepatosplenic (gamma-delta) T-cell lymphoma which is a newly defined unit in the spectrum of primary splenic lymphomas. The first two were diagnosed in sequential biopsies of bone marrow, splenectomic material and the liver of female patients aged 38 and 67 years. In the clinical picture dominated symptoms of progressing splenomegaly, hepatomegaly, haemolytic anaemia and different manifestations of leuco- and thrombocytopenia with expulsion of tumour cells into the peripheral blood. The first patient died after complete remission with signs of heart failure, the second one is surviving for 11 months in partial remission. The third case, a 66-year-old male patient, died suddenly during a 16-day hospitalization on account of diagnosis of hepatopathy and anaemic syndrome, as a result of cardiorespiratory failure. The diagnosis was established only post mortem. In none of the patients signs of affected lymph nodes were present. The authors analyze problems of bioptic diagnosis of the mentioned lymphoma, in particular biopsy of bone marrow in the stage of its initial infiltration. The key to diagnosis is in addition to knowledge of clinical manifestations the typical morphology and intrasinusoid propagation of tumour cells and immunohistochemical evidence of their T-phenotype. The predominance of initial manifestations of haemolytic anaemia calls for differential diagnosis of haemolytic conditions and confirmation of their secondary character.

[Recombinant interferon alfa in the treatment of essential thrombocythemia]. / Rekombinantný interferón alfa v liecbe esenciálnej trombocytémie.

Essential thrombocythaemia, a clonal myeloproliferative disease characterized by a persisting increase of the number of thrombocytes, their abnormal morphology and function, is a special clinical and therapeutic problem which calls for a comprehensive approach. Based on a group of their own patients and on data from the literature, the authors discuss the asset of interferon alpha in the treatment of essential thrombocythaemia.

[Interferon alpha in the treatment of chronic myeloid leukemia]. / Interferon alfa v liecbe chronickej myeloickej leukémie.

The authors present their results assembled in patients with chronic myeloid leukaemia (CML) to whom they administered interferon alpha (IFN) in the chronic stage of the disease. They evaluated the survival of patients and the haematological and cytogenetic response. They recorded a favourable haematological response in patients with CML to IFN treatment comparable with data reported in the literature. They assume that the smaller number of cytogenetic responses is due to the smaller percentage of patients in the early chronic stage and short period of hydroxyurea administration at the onset of treatment. They consider interferon alpha, similarly as other authors, a successful drug in the treatment of the chronic stage of chronic myeloid leukaemia.