Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia.

We conducted an international phase 2 trial to evaluate 2 dose levels of ofatumumab, a human CD20 mAb, combined with fludarabine and cyclophosphamide (O-FC) as frontline therapy for chronic lymphocytic leukemia (CLL). Patients with active CLL were randomized to ofatumumab 500 mg (n = 31) or 1000 mg (n = 30) day 1, with fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) days 2-4, course 1; days 1-3, courses 2-6; every 4 weeks for 6 courses. The first ofatumumab dose was 300 mg for both cohorts. The median age was 56 years; 13% of patients had a 17p deletion; 64% had ß2-microglobulin > 3.5 mg/L. Based on the 1996 National Cancer Institute Working Group (NCI-WG) guidelines, the complete response (CR) rate as assessed by an independent review committee was 32% for the 500-mg and 50% for the 1000-mg cohort; the overall response (OR) rate was 77% and 73%, respectively. Based on univariable regression analyses, ß2-microglobulin and the number of O-FC courses were significantly correlated (P < .05) with CR and OR rates and progression-free survival (PFS). The most frequent Common Terminology Criteria (CTC) grade 3-4 investigator-reported adverse events were neutropenia (48%), thrombocytopenia (15%), anemia (13%), and infection (8%). O-FC is active and safe in treatment-naive patients with CLL, including high-risk patients. This trial was registered at www.clinicaltrials.gov as NCT00410163.

High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial.

BACKGROUND: Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown. DESIGN AND METHODS: Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114). RESULTS: The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014). CONCLUSIONS: Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262).

Corticosteroid-responsive pulmonary toxicity associated with fludarabine monophosphate: a case report.

UNLABELLED: Fludarabine monophosphate is an effective drug for the treatment of lymphoid malignancies. Myelosuppression, opportunistic infections, and autoimmune hemolytic anemia are the most common side effects of fludarabine. Herein we report a 55-year-old female that presented with fever and dyspnea after completing her third cycle of FMD (fludarabine, mitoxantrone, and dexamethasone) chemotherapy for stage IV non-Hodgkin follicular lymphoma. Chest X-ray revealed bilateral pneumofibrotic changes and chest CT showed bilateral diffuse interstitial changes with fibrotic alterations. No evidence of infectious agents was noted. The patient had a reduced carbon monoxide transfer factor (45%). Her symptoms and radiographic findings resolved following treatment with prednisolone. The literature contains several cases of fludarabine-associated interstitial pulmonary toxicity that responded to steroid therapy. Fludarabine-induced pulmonary toxicity is reversible with cessation of the drug and administration of glucocorticosteroids. CONFLICT OF INTEREST: None declared.

High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study.

BACKGROUND: Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib. DESIGN AND METHODS: In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated. RESULTS: Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014). CONCLUSIONS: This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogenetic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: NCT00327262).

A combinative effect of low-molecular-weight heparin and intermittent pneumatic compression device for thrombosis prevention during laparoscopic fundoplication.

BACKGROUND. Venous thromboembolism is known to be an important social and health care problem because of its high incidence among patients who undergo surgery. For instance, 20-30% of patients develop this problem after general surgical operations, while 5.5% of patients have this complication when laparoscopic fundoplications are performed without any prophylaxis. The aim of our study was to evaluate the hypocoagulation effect of the following treatments during and after laparoscopic fundoplication: a) intermittent pneumatic compression (IPC) and b) combination of low-molecular-weight heparin (LMWH) and IPC. MATERIAL AND METHODS. The study was performed on 20 consecutive patients who were randomized into two groups. The first group received IPC during operation, the second group received IPC during operation and LMWH before operation. Plasma prothrombin fragment F1+2 (F1+2), thrombin-antithrombin complex (TAT) - markers of thrombogenesis - and plasma free tissue factor pathway inhibitor (fTFPI) - a marker of hypocoagulation effect - were measured 1 h before, during, and after the laparoscopic operation. RESULTS. In the IPC group, plasma F1+2 and TAT levels increased significantly during and after laparoscopic gastrofundoplication. In the IPC+LMWH group, F1+2 and plasma TAT levels did not change during or after the operation. fTFPI levels significantly increased during and after the operation in the IPC+LMWH group; however, fTFPI levels did not change during or after the laparoscopic operation in the IPC group. CONCLUSIONS. A combination of low-molecular-weight heparin and intermittent pneumatic compression during laparoscopic fundoplication caused hypocoagulation effect in the patients, which was not observed in the patients who were treated with intermittent pneumatic compression alone.

Prognostic value of reticulocyte hemoglobin content to diagnose iron deficiency in 6-24-month-old children.

OBJECTIVE: The aim of our study was to evaluate the prognostic value of reticulocyte hemoglobin content for diagnosis of iron deficiency in 6-24-month-old children. MATERIAL AND METHODS: Children aged 6 to 24 months were consulted for suspected iron deficiency in the outpatient department in 2006-2007. Criteria for inclusion into the study were normal birth time and weight, no infection during the last two weeks before blood sampling (C-reactive protein <5 mg/L), no iron supplements 1 month before the study. Red blood cell, reticulocyte indices and biochemical tests were analyzed. A total of 180 children were enrolled in our study. Iron deficiency was diagnosed when at least two of four parameters (ferritin, transferrin, transferrin saturation, and soluble transferrin receptors) reflected iron deficiency. RESULTS: According to our criteria of iron deficiency, patients were divided into two groups: 116 had iron deficiency and 64 had normal iron stores. The iron deficiency group had significantly lower hemoglobin, mean corpuscular hemoglobin, mean corpuscular volume, reticulocyte hemoglobin content, ferritin, soluble transferrin receptors, iron and higher red cell distribution width, transferrin, and transferrin saturation (P<0.05) compared with the normal iron store group. Reticulocyte hemoglobin content, ferritin, and transferrin saturation had the highest sensitivity and specificity (76.6% and 78.4%, 81.3% and 81.9%, 85.9% and 87.9%, respectively). CONCLUSION: Reticulocyte hemoglobin content is comparable test with ferritin and transferrin saturation and can be used to detect iron deficiency in 6-24-month-old children.

[Successful treatment with continuous infusion of coagulation factor concentrates in severe hemophilia A complicated with mixed trauma, crush syndrome and acute renal failure]. / Sunkios hemofilijos A, komplikuotos misrios traumos, ilgalaikio suspaudimo sindromo ir uminio inkstu nepakankamumo, veiksmingas gydymas pastoviomis kresejimo faktoriaus infuzijomis.

Treatment method of hemophilia with continuous infusion of clotting factor concentrates is not widespread. We report our experience with the use of continuous infusion of factor VIII in patient with mixed trauma, crush syndrome and acute renal failure. Patient was successfully treated with fasciotomy of left upper arm and forearm, 6 procedures of hemodialysis, 34.500 units of clotting factor VIII concentrate, and 13 red blood cells units. Our experience confirms the safety, efficiency, and economy of the method of the constant infusion of clotting factor concentrates for hemophilia patient requiring replacement therapy, surgical intervention, and hemodialysis.

Reference ranges of the dilute tissue thromboplastin inhibition and dilute Russell's viper venom tests revisited.

Reference ranges for two well-recognized tests for the lupus anticoagulant were determined utilizing 98 healthy subjects. The purpose of the study was to compare the reference ranges for the dilute tissue thromboplastin inhibition test on this group of healthy subjects calculated by parametric and nonparametric statistical methods, and to compare these results with results obtained on subsets of 20 and 40 randomly selected individuals from the group of 98. The same procedures were followed for the dilute Russell's viper venom test. Results were recorded in seconds of clotting times and in ratios (subject/mean of that set or subset). Statistical analysis revealed Gaussian distribution of the results in the large group as well as in each subset for both tests. The results showed more variation between sets of the dilute tissue thromboplastin inhibition test than of the dilute Russell's viper venom test. Nonparametrically calculated reference ranges were wider than those determined by a parametric method, especially if confidence intervals are provided for both reference ranges in the group of 94 controls or in a subset of 40 subjects. The nonparametric technique utilizes all data for the calculation of reference ranges of such sample sizes no matter how wide the results are spread. There was no significant difference between the reference ranges of subsets and the whole group (p > 0.05) calculated by both statistical techniques.

Reference intervals of the dilute tissue thromboplastin inhibition and dilute Russell's viper venom tests revisited.

Reference intervals for two well-recognized tests for the lupus anticoagulant were determined using 98 healthy subjects. The purpose of the study was to compare the reference intervals for the dilute tissue thromboplastin inhibition test on this group of healthy subjects calculated by parametric and nonparametric statistical methods, and to compare these results with results obtained on subsets of 20 and 40 randomly selected individuals from the group of 98. The same procedures were followed for the dilute Russell's viper venom test. Results were recorded in seconds of clotting times and in ratios (subject/mean of that set or subset). Statistical analysis revealed Gaussian distribution of the results in the large group as well as in each subset for both tests. The results showed more variation between sets of the dilute tissue thromboplastin inhibition test than of the dilute Russell's viper venom test. Nonparametrically calculated reference intervals were wider than those determined by the parametric method, especially if confidence intervals are provided for both reference limits in a group of 94 controls or in a subset of 40 subjects. The nonparametric technique uses all data for the calculation of reference interval of such sample sizes no matter how widely spread the results are. There was no significant difference between the reference intervals of subsets and the whole group (p > 0.05) calculated by both statistical techniques. Very few outliers were observed among these subjects in both tests.

Differential effects of DX-9065a, argatroban, and synthetic pentasaccharide on tissue thromboplastin inhibition test and dilute Russell's viper venom test.

New synthetic direct and indirect factor Xa or factor IIa inhibitors are increasingly used for the prevention and treatment of thrombotic disorders, including patients suffering from antiphospholipid syndrome. In this study, the effects of the synthetic direct factor Xa inhibitor DX-9065a, the indirect synthetic heparinomimetic pentasaccharide, and the direct factor IIa inhibitor Argatroban were studied. These two widely used assays for the detection of lupus anticoagulant, namely the tissue thromboplastin inhibition (TTIT) and the dilute Russell viper venom tests (DRWT) proved useful. The drugs were added to a normal human plasma pool ranging in concentration from 0.04 to 10 microg/mL. Using the two tests named above, DX-9065a and Argatroban showed a dose-related prolongation of TTIT and DRWT in the concentration range from 0.04 to 5 micromol/mL, but the pentasaccharide only slightly prolonged the clotting times of these assays even at high concentrations. Argatroban had the more pronounced effect on both tests when compared with DX-9065a (p < 0.001). The most responsive assay for DX-9065a up to a concentration of 2.5 micromol/mL was the DRWT. For Argatroban both TTIT and DRWT were equally responsive. Patients whose plasma was tested for suspected lupus anticoagulant and who have been given DX-9065a or Argatroban may have false-positive results with the TTIT tests and DRWT. This effect should be considered during patient management. These results indicate that these assays could be used for the effective quantitation of the direct factor Xa or factor IIa inhibitors when suitable controls are used.

[Clinical and laboratory features and prognostic implications in myeloma with and without renal impairment]. / Mielomine liga ir jos sukelto inkstu pazeidimo klinikiniai ir laboratoriniai duomenys bei prognoze nulemiantys faktoriai.

Presenting clinical and laboratory features, prognostic implications and survival in 124 multiple myeloma patients were reviewed in a retrospective study based on hospital records. The median age was 65 years. Out of all patients, 2.42% were younger than 40 years and 62.9% were 60 years and older. The main presenting clinical features were bone pain (70.16%), fatigue (31.45%), recurrent infections (9.68%) and weight loss (0.3%). Renal failure was present in 35.48% of patients. The higher means of ionised calcium, uric acid, erythrocyte sedimentation rate, M protein were correlated with the higher mean of serum creatinine. The acturial survival of myeloma patients without renal failure at 1 and 2 years was 95.08% and 89.23% respectively, while acturial survival of myeloma patients with renal failure at 1 and 2 years was 82.5% and 73.35% respectively (p<0.01). One-year survival in myeloma patients maintained on chronic hemodialysis was 68.75% while it is reported as 90.91% for myeloma patients not on dialysis (p<0.006).

[The comparative role of computed tomography and magnetic resonance imaging in the diagnosis of extracapsular spread of malignant lymphomatous masses invading blood vessels]. / Kompiuterines tomografijos ir magnetinio rezonanso lyginamoji svarba diagnozuojant stambiuju kraujagysliu peraugimo pozymius esant piktybinei limfomai.

Aim of the study was to search for an optimal method an of investigation in diagnosis of extracapsular spread of the malignant lymphomas and invading the blood vessels. In the period of 1998 to 2002, 81 patients with malignant lymphomas with coverage of neck and body areas were examined in the Department of Tomography of Kaunas University of Medicine Hospital. It was performed by computed tomography (CT) and magnetic resonance imaging (MRI), with or without iv. application of contrast media. The data were processed with SPSS 10.1 (Statistical package for Social Sciences 10.1 for Windows), including application of chi(2), t-test. Specificity, sensitivity and diagnostic accuracy of CT and MRI methods were calculated and compared according to recommendations by Gefland D. W. and Ott D. J., 1985. Diagnosis of extracapsular spread of the lymphomatous tissue and invading the blood vessels was best performed by MR method (specificity, sensitivity, accuracy in this case 91-95%). Bolus CT angiography because of low resolution in the range of soft tissues, insufficient opacification of blood vessels with contrast medium and differences in blood flow was not informative enough (specificity, sensitivity, accuracy in this case 80-85%).

[The assessment of chemotherapy and radiation therapy effect in malignant lymphomas by computed tomography and magnetic resonance imaging]. / Piktybiniu limfomu chemoterapijos ir spindulinio gydymo veiksmingumo ivertinimas kompiuterine tomografija ir magnetiniu rezonansu.

Aim of this study was to estimate the diagnostic possibilities of computed tomography (CT) and magnetic resonance imaging (MRI) in the assessment of treatment effect in malignant lymphomas. In the period of 1998 to 2002, 196 patients with histologically proven malignant lymphoma were examined in the Department of Tomography of Kaunas University of Medicine Hospital. The data were processed with SPSS 10.1, including application of standardized t-test and classification of Fisher's statistics. In this group the density of lymphomatous masses prior and post treatment has no difference on CT images, thus the differentiation of active tissue and relapse is not possible. On MR images the difference of signal intensity of the active component (not treated) and fibrous remnant is significant. MRI is a radiological method which provides information about activity of lymphomatous tissue and is able to delineate the active component (recidive or partial remission) and inactive remnant (total remission) of the tumor mass and thus facilitating the diagnosis of possible relapse of malignant lymphomas for hematology, chemotherapy and radiotherapy specialists.

[Erythema nodosum association with malignant lymphoma]. / Mazgines raudones ir piktybines limfomos sasajos.

Erythema nodosum is the most frequent clinicopathological variant of the panniculitides. The disorder is a cutaneous reaction consisting of inflammatory nodular lesions, usually located on the lower extremities. It may be associated with a wide variety of diseases, infections, sarcoidosis, rheumatologic diseases, inflammatory bowel diseases, medications and malignancies. Relationship between erythema nodosum and malignant lymphoma is described in the article. A review of the literature suggest that the diagnosis of Hodgkin's and non-Hodgkin's disease should be considered in patients with unexplained erythema nodosum.