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Background: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications.Methods: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT).Results: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P=.0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting.Conclusions: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. [ABSTRACT FROM AUTHOR]

Background : The implementation of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) has brought a significant improvement in the prognosis for CML patients and a decrease in the number of patients requiring allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, the impact of TKIs on allo-HCT outcomes has not been thoroughly explored. Objectives : The main endpoint of our research was to assess the impact of prior TKI treatment on acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD). Methods : In our retrospective analysis, we included 240 patients treated between 1993 and 2013 and divided them into three groups according to the therapy administered prior to haploidentical, matched-related, or matched-unrelated donor allo-HCT (imatinib group n = 41, dasatinib/nilotinib group n = 28, TKI-naïve group n = 171). Results : Both the cumulative incidence of aGvHD ( p = 0.044) and cGvHD ( p < 0.001) in individuals receiving second-generation TKIs (2G-TKIs) prior to allo-HCT were decreased compared to patients receiving no TKIs or imatinib (IMA) (40.7% vs. 61.4% vs. 70.7%, p = 0.044; 25.0% vs. 76.4% vs. 51.2%, p < 0.001, respectively). In the case of the 2G-TKI cohort, the number of low-grade aGvHD and cGvHD was significantly lower compared to the IMA and TKI-naïve groups ( p = 0.018, p = 0.004; p < 0.001 versus TKI-naïve, respectively). In terms of 3-year overall survival (OS), there were no important variations between TKI-naïve, IMA, and 2G-TKI (55% vs. 49.9% vs. 69.6%, p = 0.740). Conclusions : The results of our study suggest that TKI treatment prior to allo-HCT may have a protective impact on immune-mediated outcomes.

Background: The treatment of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is conducted according to well-defined risk stratification systems. We hypothesized that adherence to the guidelines, namely the decision to refrain from introducing cytoreduction in non-high-risk patients, is particularly difficult in patients diagnosed when they are between 40 and 59 years of age (intermediate-age group)., Objectives: To evaluate the group of intermediate-age PV and ET patients, focusing on a first-line treatment approach adapted at diagnosis., Material and Methods: The study group consisted of 308 PV and ET patients recruited from 6 Polish Adult Leukemia Group (PALG) Centers. Patients were analyzed with respect to disease phenotype, risk group, treatment approach, cardiovascular (CV) risk factors, and occurrence of bleeding or thrombosis., Results: Overall, 74% of patients in the study group were started on cytoreduction at diagnosis, including 70% of the low-risk PV patients and 85-89% of the non-high-risk ET patients. Factors influencing the decision to start the treatment included higher hemoglobin (Hb) concentration (in PV) as well as higher platelet (PLT) count, and the presence of CV risk factors (in ET). Introducing cytoreduction at diagnosis had no impact on thrombotic events. Patients harboring CV risk factors experienced a higher incidence of complications both at diagnosis and follow-up, independently of the treatment strategy., Conclusions: We underline the low adherence to recommendations in the treatment of intermediate-age PV and ET patients. Moreover, we emphasize the importance of CV risk factors and stress their impact on disease phenotype in this patient population.

Acute leukemia (AL) with a lineage switch (LS) is associated with poor prognosis. The predisposing factors of LS are unknown, apart from KMT2A rearrangements that have been reported to be associated with LS. Herein, we present two cases and review all 104 published cases to identify risk factors for LS. Most of the patients (75.5%) experienced a switch from the lymphoid phenotype to the myeloid phenotype. Eighteen patients (17.0%) experienced a transformation from acute myelogenous leukemia (AML) to acute lymphoblastic leukemia (ALL). Forty-nine (46.2%) patients carried a KMT2A rearrangement. Most of the cases involved LS from B-cell ALL (B-ALL) to AML (59.4%), and 49 patients (46.2%) carried KMT2A -rearrangements. Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.

Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8 + PD-1 + cells in patients losing TFR. The level of CD8 + PD-1 + cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8 + PD-1 + cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8 + PD-1 + cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib.

Primary refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) and mixed phenotype myeloid/T-cell acute leukemia have dismal prognoses. New treatment approaches, preferably targeting specific leukemic aberrations to overcome resistance, are urgently needed. The bright expression of the CD38 antigen found in several cases of T-ALL led to an investigation into the role of anti-CD38 antibodies in the treatment of T-ALL. Here, we present three cases of resistant and relapsed T-ALL and myeloid/T-cell treated with daratumumab-based therapy, including venetoclax and bortezomib (Dara-Ven-Bor). All patients achieved complete remission, with minimal residual disease negativity within four weeks of treatment, allowing them to proceed to allogeneic hematopoietic cell transplantation. The toxicity of the triple schema was acceptable. Our patients and other cases reviewed here suggest that daratumumab combined with venetoclax and bortezomib may be a very effective and relatively safe salvage treatment, even in primary resistant T-ALL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Prejzner, Piekoś, Bełdzińska, Sadowska-Klasa, Zarzycka, Bieniaszewska, Lewandowski and Zaucha.)

Introduction: Functional single-nucleotide polymorphisms (SNPs) in genes regulating cellular uptake, elimination, and metabolism of xenobiotics may potentially influence the outcome of chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). Dasatinib, a second-generation TKI, is a substrate of the ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are involved in the control of expression of ABCB1 and ABCG2., Aim of the Study: In this study, we assessed the impact of inherited variants in ABCB1 , ABCG2 , PXR , and CAR genes on dasatinib efficacy and toxicity in CML., Materials and Methods: Sixty-one tagging SNPs in ABCB1 , ABCG2 , PXR , and CAR genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy., Results: We found the associations between SNPs rs7787082 ( ABCB1 , OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 ( ABCG2 , OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 ( ABCG2 , OR = 0.24; 95% CI = 0.08-0.71; p = 0.010) and the probability of achieving CCyR. Furthermore, progression-free survival (PFS) was significantly influenced by SNPs rs3732357 (HR = 0.2, 95% CI = 0.26-0.70; p = 0.001), rs3732360 (HR = 0.59; 95% CI = 0.38-0.93; p = 0.020), rs11917714 (HR = 0.58; 95% CI = 0.36-0.92; p = 0.020), and rs3732359 (HR = 0.57; 95% CI = 0.36-0.91; p = 0.024) in PXR ; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in CAR ; and rs2235023 (HR = 2.49; 95% CI = 1.13-5.50; p = 0.011) and rs22114102 (HR = 1.90; 95% CI = 1.00-3.63; p = 0.028) in ABCB1 . Moreover, overall survival (OS) was impacted by rs3842 (HR = 1.84; 95% CI = 1.01-3.33; p = 0.012) and rs2235023 (HR = 2.28; 95% CI = 1.03 = 5.02; p = 0.027) in ABCB1 , rs11265571 (HR = 1.59; 95% CI = 0.82-3.08; p = 0.037) and rs2307418 (HR = 73.68; 95% CI = 4.47-1215.31; p = 0.003) in CAR , and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in PXR . Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the ABCB1 rs7787082 (OR = 4.46; 95% CI = 1.38-14.39 p = 0.012) and hematological complications assuming the codominant gene inheritance model as well as a significant correlation between the presence of minor allele (G) of SNP rs2725256 in the ABCG2 gene (OR = 4.71; 95% CI = 1.20-18.47; p = 0.026) and the occurrence of non-hematological complications assuming a recessive gene inheritance model., Conclusion: Our data suggest that inherited variants in the genes encoding for proteins involved in the transport of xenobiotics may modify the toxicity and efficacy of dasatinib therapy in CML patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Madejczyk, Canzian, Góra-Tybor, Campa, Sacha, Link-Lenczowska, Florek, Prejzner, Całbecka, Rymko, Dudziński, Orzechowska and Jamroziak.)

Introduction: Tyrosine kinase inhibitors (TKIs) have greatly improved the treatment outcome for most patients with chronic myeloid leukemia (CML). Ponatinib is a new pan-inhibitor of TK active in resistant CML. This study aimed to evaluate the efficacy and safety of ponatinib in patients suffering from CML., Patients and Methods: This multicenter, non-randomized, observational, retrospective study evaluated the efficacy and safety of ponatinib administered in adult CML patients in any disease phase, including those with a detected ABL T315I mutation, which were resistant or intolerant to previous-generation TKIs. The study comprised 43 patients benefiting from the ponatinib donation program who were treated in 16 Polish centers., Results: For patients who started treatment with ponatinib in chronic phase (CP) (n = 23) and in accelerated phase (AP) (n = 3) the median time on ponatinib was 19.5 months (range: 1.0-35.4), and 31.7 months (range: 31.0-34.1), respectively. All these patients were in CP after 1 month of treatment and at the end of observation - none of them progressed to AP or blastic phase (BP) during the study, meaning that progression-free survival was 100% at the end of observation (35.4 months). The estimated 2-year survival in this group of patients was 84%. For all 43 patients, median survival was not reached (lower quartile 6.3 months), and estimated 2-year survival was 60%., Conclusion: Our analysis confirmed ponatinib efficacy in a significant proportion of patients heavily pre-treated with TKIs achieving durable responses in both CP and AP/BP CML groups., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10 -7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate., (© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Composition of the gut microbiota seems to influence early complications of allogeneic hematopoietic cell transplantation (HCT) such as bacterial infections and acute graft-versus-host disease (GVHD). In this study, we assessed the impact of colonization with multidrug-resistant bacteria (MDRB) prior to HCT and the use of antibiotics against anaerobic bacteria on the outcomes of HCT. We retrospectively analyzed the data of 120 patients who underwent HCT for hematologic disorders between 2012 and 2014. Fifty-one (42.5%) patients were colonized with MDRB and 39 (32.5%) had infections caused by MDRB. Prior colonization was significantly correlated with MDRB infections (P < 0.001), especially bacteremia (P = 0.038). A higher incidence of MDRB infections was observed in patients with acute (P = 0.014) or chronic (P = 0.002) GVHD and in patients aged > 40 years (P = 0.002). Colonization had a negative impact on overall survival (OS) after HCT (64 vs. 47% at 24 months; P = 0.034) and infection-associated mortality (P < 0.001). Use of metronidazole was correlated with an increased incidence of acute GVHD (P < 0.001) and lower OS (P = 0.002). Patients colonized with MDRB are more susceptible to life-threatening infections. Colonization with virulent flora is the most probable source of neutropenic infection; therefore, information about prior positive colonization should be crucial for the selection of empiric antibiotic therapy. The use of metronidazole, affecting the biodiversity of the intestinal microbiome, seems to have a significant impact on OS and acute GVHD.

Bexarotene, a synthetic retinoid licensed for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been used clinically in Poland since 2007 in 21 patients. The objective of our retrospective, multicenter study was to evaluate our experience with bexarotene therapy, including efficacy, safety, and survival outcomes. We retrospectively identified 21 adult patients who were treated with bexarotene between the years 2007 and 2012. Starting dose of bexarotene was 300 mg/m per day. The analysis included 3 patients with early-stage mycosis fungoides (MF), 16 patients with advanced-stage MF, and 2 patients with Sézary syndrome (SS). The mean duration of therapy with bexarotene was 14.5 months. Use of bexarotene resulted in an overall response rate of 81.0%, although the overall mortality rate was 52.8%. In our study, early-stage CTCL responded better than advanced-stage CTCL (100.0% vs. 77.8%, respectively). The mean time to observable response was 1.8 months, and the mean duration of the response was 16.4 months. Most significant side effects were hyperlipidemia, hypothyroidism, and a bleeding gastric ulcer. Based on the results of our analysis, bexarotene is a valuable tool in the treatment of refractory early-stage CTCL. Although a majority of patients initially responded to therapy, the high mortality rate in the advanced-stage group suggests that bexarotene does not completely resolve the therapeutic problems in all stages of CTCL. Patient stratification for bexarotene treatment may need a thorough reassessment, in that bexarotene may not be an effective drug in the very advanced stages of CTCL.

Aim of the Study: The majority of patients with chronic myeloid leukaemia (CML) respond to tyrosine kinase inhibitors (TKI), while allogeneic haematopoietic cell transplantation (HCT) is indicated in selected clinical situations. HCT carries the risk of severe complications, while the toxicity profile of dasatinib and nilotinib may lead to adverse reactions affecting the quality of life (QoL). We present the results of observational analysis of CML patients who underwent HCT after exposure to second-generation TKI (TKI2), with respect to their quality of life assessed comparatively after transplantation., Material and Methods: Eligible subjects included 19 patients. The quality of life and global health assessment were performed with a questionnaire comparing the signs and symptoms present during the TKI2-therapy with those related to post-transplant complications, including psychosocial problems., Results and Conclusions: Most patients had no/few problems with exhausting activities, no/few difficulties during long-distance walks, and do not/rarely rest in the daytime. Seventeen (89.5%) patients reported at least one symptom related to TKI2-therapy and most of them disappeared after HCT. Thirteen (68.4%) patients noted no serious complication after HCT. Most patients claimed to have a very good QoL and general health compared to the period prior to HCT. We found statistically significant improvement in global health ( p = 0.016) and QoL ( p = 0.043) after HCT. From the survivors perspective, HCT influence positively general health and QoL comparing to TKI2-therapy period. Further studies on larger group of patients will more precisely define the QoL level and possible predictors of changes in QoL, to assess which group of patients needs psychological support., Competing Interests: The authors declare no conflict of interest.

Introduction: Allogeneic hematopoietic cell transplantation (HCT) was a standard therapy in chronic phase (CP) chronic myeloid leukemia (CML). As a result of the effective therapy with tyrosine kinase inhibitors (TKI), HCT was shifted to defined clinical situations. We present the results of observational prospective analysis of 28 CML patients undergoing HCT after exposure to, at least, two lines of TKI (including dasatinib and/or nilotinib), with respect to response, overall survival (OS), treatment toxicity, graft versus host disease (GVHD), and progression/relapse incidence., Results: All the patients but one engrafted with median time 19 days. OS for patients in CP1 and CP2/accelerated phase (AcP) were 92.9 and 85.7 %, respectively. Six patients allotransplanted in blast crisis (BC) CML died early after HCT. Eighteen patients achieved deep molecular remission (MR(4.5) or MR(4.0)). Relapse incidence was 29.6 %. Median time to progression (TTP) differs significantly depending on the CML phase prior to HCT, the best response achieved after HCT and development of chronic GvHD. NRM yielded the values 7.1, 12.5, and 50 % in CP1, CP2/AcP, and BC, respectively. Fatal outcome, due to veno-occlusive disease (VOD), was observed in two (7 %) patients. In five (17.9 %) patients, mild or moderate VOD was observed with no negative impact of preceding therapy with TKI2. Acute GvHD was diagnosed in 25.9 % of patients, while chronic GvHD developed in 42.9 % of individuals., Conclusion: Pretransplantation therapy with TKI2 in CP CML is safe and reasonable. In BC, the optimal approach before HCT is to reduce the leukemic burden and achieve subsequent CP.

Background: Identification of patients with myelofibrosis being at increased risk of acquired von Willebrand syndrome (avWS) would likely facilitate individualization of treatment and improve its outcomes., Objectives: To determine the prevalence of avWS in patients with myelofibrosis, and to verify if individuals with and without this bleeding disorder differ in terms of their baseline clinical parameters., Material and Methods: The study included 32 consecutive patients with myelofibrosis. avWS was diagnosed on the basis of abnormally low levels of von Willebrand factor and other routine tests. Patients with and without concomitant avWS were compared in terms of their demographic characteristics, present and past medical histories and laboratory parameters., Results: Concomitant avWS was found in 5 patients (15.6%). In 1/5 patients with avWS and in 8/27 persons without this bleeding disorder, myelofibrosis developed secondarily to polycythemia vera (n = 7) or essential thrombocytopenia (n = 2). As many as 4/5 individuals with avWS presented with clinical evidence of a bleeding disorder. The subjects with avWS differed from the remaining patients with myelofibrosis in terms of significantly lower activity of von Willebrand factor (vWF) and lower vWF to vWF antigen ratio., Conclusions: All patients with myelofibrosis should be routinely evaluated for avWS with the panel of specific tests. Further, avWS should be the primary suspicion in each patient with myelofibrosis in whom clinical evidence of a bleeding disorder has emerged.

Introduction: The aim of this study was to verify if PV patients with and without avWS differ in terms of their baseline clinical parameters., Material and Methods: The study included 142 consecutive patients with PV. avWS was diagnosed on the basis of abnormally low levels of von Willebrand factor and other routine tests. Patients with and without concomitant avWS were compared in terms of their demographic characteristics, present and past medical histories and laboratory parameters., Results: Concomitant avWS was found in 17 PV patients (12.0%). Individuals with avWS have been diagnosed with PV at significantly younger age than those without, and significantly less often were in remission at the time of testing for bleeding disorders. Most of them (58.8%) presented with typical signs of bleeding disorder. Moreover, they showed significantly higher erythrocyte, leukocyte and platelet counts, abnormalities of coagulation profile corresponding to defects of primary hemostasis and abnormal values of all parameters used in the routine diagnosis of avWS., Conclusions: Even every tenth patient with PV may develop avWS. Young age at diagnosis of PV and poor response to previous treatment of this condition are potential risk factors of avWS that should be considered during history taking. Sings of bleeding disorder observed in a person with PV necessitate evaluation for avWS., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: The identification of patients with essential thrombocythemia (ET) who are at increased risk of acquired von Willebrand syndrome (AVWS) would likely facilitate individualization of treatment and improve its outcomes., Objectives: The aim of the study was to determine the prevalence of AVWS in patients with ET and to verify whether individuals with and without this bleeding disorder differ in terms of their baseline clinical parameters., Patients and Methods: The study included 170 consecutive patients with ET. AVWS was diagnosed on the basis of reduced levels of von Willebrand factor and abnormal results of other routine tests. Patients with and without concomitant AVWS were compared in terms of their demographic characteristics, past and current medical histories, and laboratory parameters., Results: Concomitant AVWS was found in 34 patients (20%). Individuals with AVWS were diagnosed with ET at a significantly younger age than those without the syndrome. In addition, these patients significantly less often were in remission at the time of testing, had significantly higher erythrocyte and platelet counts, and showed abnormalities of the coagulation profile corresponding to defects of primary hemostasis as well as abnormal values of most parameters used i n the routine diagnosis of AVWS., Conclusions: Even every fifth patient with ET may develop AVWS. Young age at diagnosis of ET and the lack of response to its previous treatment are potential risk factors for AVWS that should be considered during the management of the primary condition. All patients with ET and signs of a bleeding disorder, irrespective of the platelet count, should be tested for the presence of AVWS.

Introduction: The presence of BCR-ABL oncogene mutations in patients with chronic myeloid leukemia (CML) may be responsible for the failure of tyrosine kinase inhibitor treatment., Objectives: The aim of the study was to evaluate the frequency of BCR-ABL gene mutations in patients with CML (the MAPTEST study) treated with imatinib (IM)., Patients and Methods: Direct sequencing analysis of BCR-ABL gene was performed in 92 patients treated with IM for more than 3 months. The mean time of IM treatment was 18 months. At the time of the analysis, 75 patients were in the first chronic phase (CP), 4 in the second CP, 5 in the acceleration and 8 in the blastic phase. Fifty-seven patients (62%) were treated with IM at a daily dose of 400 mg and 35 patients with higher doses (600 or 800 mg daily). Inclusion criteria were based on the European Leukemia Net definitions for failure and suboptimal response to IM., Results: Twelve mutations were detected in 11 of 92 patients, including 4 mutations (36.7%) diagnosed during CP, 3 (27.3%) in acceleration, and 4 (36.7%) in blast crisis. In 1 patient with lymphoid blast crisis of CML coexisting F359V and Y253F mutations were detected. In the whole group mutations were detected in 2 of 5 patients (40%) with primary resistance (M351T, F359V + Y253F) and in 9 of 87 patients (10.3%) (E255K, T315I-3x, M351T, E355G, F359V-2x) with acquired resistance to IM., Conclusions: The study confirmed the usefulness of BCR-ABL gene mutation screening in patients with CML resistant to IM therapy.

Five patients with type 2 diabetes, three of them treated with insulin and two with oral antidiabetic drugs, receiving imatinib due to chronic myeolid leukaemia are reported. Treatment with imatinib 400 mg/day for 7 to 37 (mean 24.2) months had no positive effect on clinical course of type 2 diabetes.

Previous clinical trials with the tyrosine kinase inhibitor imatinib in chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) resulted in 95% of hematologic and 60% major cytogenetic remissions in patients who failed a previous interferon-alpha-containing regimen. In an identical clinical trial setting with 39 chronic-phase CML patients we achieved comparable cytogenetic response rates after a median follow up of 30.1 weeks, with an almost identical toxicity profile. In order to identify predictive markers for the therapeutical use of imatinib, we monitored apart from standard hematology parameters bcr/abl fusion transcripts by quantitative real-time fluorescence RT-PCR. As previous investigations demonstrated that the plasma protein alpha-1 acid glycoprotein might inactivate circulating levels of free imatinib by protein binding with high affinity, we assessed plasma alpha-1 acid glycoprotein concentrations in our study cohort as well. Median bcr/abl fusion transcripts declined gradually over the entire treatment period and became significantly lowered at month 3 after initiation of imatinib therapy. Further, we observed elevated pretreatment levels of alpha-1 acid glycoprotein in patients who relapsed with leukemia, whereas initial bcr/abl mRNA copy numbers were not of predictive value. In addition, we provide data showing molecular response to this therapy in the vast majority of patients. Finally, our results support the hypothesis, that initially elevated plasma levels of alpha-1 acid glycoprotein might serve as a predictive marker for the clinical outcome of treatment with imatinib., (Copyright 2003 Wiley-Liss, Inc.)

Background: Chronic myeloid leukemia is characterized by the presence of the Philadelphia chromosome. At the molecular level a fusion of part of the ABL and BCR genes is observed. The breakpoint locations in the BCR gene fall between exons b2a2 or b3a2 (5' and 3', respectively). Depending on the BCR gene breakpoint two types of mRNA are created. Differences in the types of transcripts and/or the breakpoint site may have an influence on the clinical course of the disease. This prompted the present author to separate subtypes of chronic myeloid leukemia on the molecular level., Material/methods: 71 patients diagnosed with chronic myeloid leukemia in the chronic phase were enrolled in the study. In 61 patients the type of BCR/ABL transcript was determined, and in 27 patients BCR breakpoints were established. Possible correlations between the clinical course, prognostic indexes, survival and the type of transcript and breakpoint were examined., Results: No correlation between the clinical course, prognostic index, or survival was observed in patients with 5' and 3' breakpoints. The patients with b3a2 transcript experienced longer survival than the patients expressing b2a2 transcript. However, no significant differences were observed in the duration of the chronic phase between the two groups., Conclusions: The type of BCR gene breakpoint seems to have no prognostic value in patients with chronic myeloid leukemia. The longer survival of patients expressing the b3a2 transcript may be caused by the less aggressive course of the accelerated or blastic phase.

Large Granular Lymphocyte (LGL) Leukaemia is uncommon proliferative disorder of LGL lymphocytes. Classification, clinical features and treatment of LGL leukaemia are described.