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.

Incidence of second malignancies during treatment of chronic myeloid leukemia with tyrosine kinase inhibitors in the Czech Republic and Slovakia.

Tyrosine kinase inhibitors (TKI) have completely changed the prognosis of patients with Ph+ chronic myeloid leukemia (CML). The occurrence of a second malignancy (SM) in CML patients successfully treated with TKI may significantly affect their prognosis. In a retrospective study of 1,038 patients with CML treated at 10 centers in the Czech Republic and Slovakia between 2000 and 2009, SM was detected in 35 (3.37%) patients after TKI therapy was initiated. The median intervals from the diagnosis of CML and from the start of TKI therapy to the diagnosis of SM were 58 months (range 2 - 214) and 32 months (range 1 - 102), respectively. The observed age-standardized incidence of SM after the start of TKI therapy was 8.95 / 1,000 person-years. Comparison of the incidence of SM in CML patients with population data was performed only for patients from the Czech Republic. The age-standardized incidence rate of all malignant tumors except non-melanoma skin cancers was 6.76 (95% CI: 6.74; 6.78) / 1,000 person-years in 2000 - 2007 while the incidence rate of SM in 708 CML patients from the Czech Republic treated with TKI was 9.84 (95% CI: 6.20; 13.48) / 1,000 person-years, i.e. 1.5-fold higher, although the difference was statistically insignificant. The distribution of SM types in CML patients treated with TKI was similar to that in the age-standardized general Czech population. The median overall survival (OS) of patients treated with TKI who also developed SM (57 months) was shorter than the OS of patients treated with TKI but not suffering from SM (median OS not reached, log rank test p < 0.001. Prospective long-term population-based studies in CML patients treated with TKI as first-line therapy are needed to determine the relationship of SM to KTI therapy.

Preparation of As4S4/Fe3O4 nanosuspensions and in-vitro verification of their anticancer activity.

Multifunctional nanoparticulate systems, especially those used in medicine, are currently of great interest. In this work, the in-vitro anticancer activity of As4S4/Fe3O4 composites dispersed in a water solution of Poloxamer 407 on breast MCF-7 and tongue SCC-25 cancer cells was verified. An increase in apoptotic cells as a consequence of higher caspase activities, a decrease in mitochondrial membrane potential and an accumulation of cells in the G2/M and subG0/G1 phases were detected after treatment with the As4S4/Fe3O4 nanosuspensions. The sterically stabilized nanosuspensions were characterized in relation to their particle size distribution, zeta potential and long-term stability properties. The interaction between the solid and liquid phases of the nanosuspensions was also studied using Fourier transform infrared spectroscopy.

Imatinib mesylate in Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon alpha.

Imatinib mesylate (STI 571; Glivec) is a potent and selective tyrosine kinase inhibitor. The introduction of imatinib has chanced the philosophy of mechanisms of cancer therapy and already changed current management of patients with chronic myeloid leukemia (CML). A total of 49 patients with later chronic phase CML in whom previous therapy with interferon alpha had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for hematologic and cytogenetic responses. Time to progression, survival, and toxic effects were also evaluated. Complete hematologic responses were reported for 48 of 49 patients studied (98 percent). The median time to a complete hematologic response was 1.2 month; 89% of patients who had a response did so within 4 months. Imatinib induced major cytogenetic responses in 73%; 62% had a complete responses. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 98% of patients, and 100 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were manageable. No one of patients discontinued treatment due to of drug-related adverse events, and no treatment-related deaths occurred. The results of current study indicate that imatinib has a significant therapy benefit in CML patients in whom treatment with IFN alpha had failed. Therefore, has favorably changed the prognosis for patients with chronic myelogenous leukemia.

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.

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.

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.

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.

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.

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.

[Mixed myelodysplastic and myeloproliferative syndromes]. / Smísené myelodysplastické a myeloproliferativní syndromy.

BACKGROUND: An injury to the hemopoietic stem cell may lead to the aplasia of hemopoiesis, myelodysplasia and to an unregulated myeloproliferation. There is not a strict demarcation of them, so that mixed syndromes can develop as are hypoplastic syndromes on one side and mixed myelodysplastic and myeloproliferative syndromes (MDS-MPS) on the other side. METHODS AND RESULTS: Among our 616 pts with MDS we looked for those cases, who had beside myelodysplasia signs of myeloproliferation with increased number of blood cells. They were examined in detail including bone-marrow histology, bone marrow cultivation, cytogenetics and bcr-abl gen. Signs of MDS-MPS were found in 22 patients at the first contact with the patient (13 patients had thrombocytemia and 9 patients had leukocytosis). Further 7 patients were diagnosed as MDS, proliferative syndrome developed after several months (MDS-MPS in evolution). The level of thrombocytemia was relatively stable, the number of leukocytes was progressive. All subtypes of MDS were found. All subjects had variable degree of anemia. Ring-sideroblasts and myelofibrosis were frequent finding in MDS-MPS. Men prevailed in patients with leukocytosis. Cytogenetic and cultivation findings were similar to MDS cases, deletion of long arm of chromosome 20 was present in 3 patients. Five patients transformed to acute myeloid leukemia. CONCLUSIONS: Sings of myelodysplasia and myeloproliferation were found in 4% of our MDS patients, designated as mixed myelodysplastic and myeloproliferative syndrome (MDS-MPS). In this syndrome beside evident signs of myelodysplasia thrombocythemia or leukocytosis with the release of bone marrow precursors are present. In only one case polycythemia was encountered.

[New views on the treatment of chronic myelocytic leukemia. Literature review]. / Nový pohlad na liecbu chronickej myelocytovej leukémie. Literárny prehlad.

The expansion of knowledge of molecular biology and pathophysiology of chronic myeloid leukaemia (CML) indicate a new therapeutic approaches of the disease. Besides less toxic nonmyeloablative regimes of allogenEic transplantation and the introduction of modified interpherone regimes attracts our interest therapy more specific, aimed to a primary reason of a disease, BCR/ABL gene, and its products, that are responsible for leukaemic transformation. The paper is a summary of experimental, as well as first clinical experiences with application of thyrosinkinase-inhibitors, farnesyl-transferase-inhibitors and vaccination therapy of CML. Even thought is allogeneic transplantation the only curative therapy of CML, first clinical experiences with thyrosinkinase inhibitors show, that these are the medicaments that can become in a near future its important alternative.

[Clinical use of hematopoietic growth factors in the treatment of acute myeloblastic leukemia]. / Klinická aplikácia hemopoetických rastových faktorov v liecbe akútnej myeloblastovej leukémie.

Contemporary anti-tumourous treatment of acute myeloblastic leukaemia (AML) is more and more aggressive and myelotoxic and increasing numbers of patients are threatened with serious infectious complications. The administration of haematopoietic growth factors (CSF) during the period of severe postcytostatic neutropenia holds an important place in the treatment of AML. Administration of G-CSF and GM-CSF during the period of severe neutropenia leads to regeneration of granulopoiesis, it reduces the incidence, severity and duration of neutropenia and the number of infectious complications. Haematopoietic growth factors are also part of programmes of allogenic and autologous transplantation, in treatment as well as in the preparation peripheral stem cell concentrates. An open question is the administration of CSF during cytostatic treatment of AML because of possible stimulation of the leukaemic clone. The author presents in the submitted paper a review of the literature on contemporary approaches to the administration of haematopoietic growth factors in patients with acute myeloblastic leukaemia.

[Changes in hemostasis in ischemic heart disease in advanced age]. / Zmeny hemostázy pri ischemickej chorobe srdca vo vyssom veku.

In a group of 178 patients with different forms of ischaemic heart disease and in a group of 40 healthy controls the authors made complete examinations of haemostasis to provide laboratory evidence of a state of hypercoagulation. They assessed the relationship of different coagulation factors between patient groups and healthy controls formed by a group of blood donors. They draw attention to the significant age dependence of the majority of coagulation factors. As apparent from the results, the highest incidence of hypercoagulation was recorded in patients with myocardial infarction.

[Changes in fibrinolysis in diabetes mellitus]. / Zmeny fibrinolýzy pri diabetes mellitus.

The authors examined in a group of 165 diabetics and 50 healthy subjects the basal fibrinolytic activity after venostasis and in a selected group of diabetics also after stimulation with adiuretin. They revealed not only a retarded fibrinolytic activity in diabetics with angiopathy, as compared with healthy subjects, but also a significant deterioration of the response in this group to stimuli such as venostasis and adiuretin. The authors draw attention to the fact that changes of the fibrinolytic activity which were more marked in diabetics with angiopathy may be conditioned not only by age, the duration of the disease and the elevated inhibitors of plasma fibrinolysis but also by a poorer release of the tissue activator plasminogen.

[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.