Efficacy and safety of lenalidomide treatment in multiple myeloma (MM) patients--Report of the Polish Myeloma Group.

UNLABELLED: The aim of the multi-centre retrospective study was to evaluate the efficacy and safety of lenalidomide (LEN) therapy in patients with resistant or relapsed multiple myeloma (MM) as well as in patients with stable disease (LEN used due to neurological complications). The primary endpoint of this study was an overall response rate (ORR). The secondary endpoints were as follows: time to progression (TTP), overall survival (OS) and the safety of drug use. Data were collected in 19 centres of the Polish Multiple Myeloma Study Group. The study group consisted of 306 subjects: 153 females and 153 males. In 115 patients (38.8%, group A), a resistant myeloma was diagnosed; in 135 (44.1%, group B) a relapse, and in 56 (18.3%, group C) a stable disease were stated. In 92.8% of patients, LEN+DEX combination was used; in remaining group, LEN monotherapy or a combination therapy LEN+bortezomib or LEN+bendamustine and other were used. In the entire study group, ORR was 75.5% (including 12.4% patients achieving complete remission [CR] or stringent CR [sCR]). Median time to progression (TTP) was 20 months. Median overall survival (OS) was 33.3 months. The regression model for "treatment response" was on the borderline of statistical significance (p=0.07), however the number of LEN treatment cycles ≥ 6 (R(2)=17.2%), baseline LDH level (R(2)=1.1%) and no ASCT use (R(2)=1.7%) where the factors most affecting treatment response achievement. The regression model for dependant variable--"overall survival"--was statistically significant (p=0.0000004). Factors with the most impact on OS were as follows: number of LEN cycles treatment ≥ 6 (R(2)=16.7%), treatment response achievement (R(2)=6.9%), ß-2-microglobulin (ß-2-M) level (R(2)=4.8%), renal function (R(2)=3.0%) and lack of 3/4 grade adverse events (R(2)=1.4%). SUMMARY: LEN is an effective and safe therapeutic option, even in intensively treated resistant and relapsed MM patients, as well as in patients with stable disease and previous treatment-induced neurological complications. In particular, the number of LEN treatment cycles ≥ 6 was the factor which affected treatment response achievement the most, together with an important impact on OS.

Epithelial bone marrow cells in patients with advanced esophageal squamous cell carcinoma.

The aim of the current study was to examine epithelial cells in the bone marrow and peripheral blood of patients with various stages of esophageal squamous cell cancer prior to surgical treatment and to analyze the prognostic significance of these carcinoma cells deposits to the stage of the disease and applied surgical therapy. Thirty-two patients (25 men and 7 women), and 5 healthy bone marrow donors serving as controls were studied. Bone marrow samples were evaluated by light microscopy and examined by flow cytofluorometry. Cells were phenotypically analyzed for the antigens CD45- and CD18+ and/or EMA+. Results are presented as the number of cells revealing the investigated phenotype per 10 (5)analyzed cells. CD18 was expressed in the bone marrow cells of 15 of the 32 (47%) patients and EMA in 20/32 (62%), but not in peripheral blood. In 13 of the 32 pts (41%), co-expression of CD18 and EMA was observed. Patients with the proportion of marrow erythroblasts below 15% had higher numbers of CD18+ and EMA+ cells and there was a negative correlation between the number of erythroblasts and EMA+ cells (r=0.54, p=0.01). In patients with esophageal cancer and anemia, the number of EMA+ cells was higher (p=0.05) and the percentage of erythropoietic cells in the bone marrow was lower (p=0.01). In conclusion, flow cytofluorometry using anti-cytokeratin and anti-EMA antibodies may be useful in evaluating microdeposits of esophageal squamous cells in bone marrow. A dysfunctioning erythropoietic system causing anemia can be a first signal for the presence of malignant cell microdeposits in the marrow of patients with esophageal carcinoma.

Serum thrombopoietin levels in patients with reactive thrombocytosis due to lung cancer and in patients with essential thrombocythemia.

In patients with thrombocytosis normal to increased serum thrombopoietin (TPO) levels have been reported. The aim of this study was to investigate the relationship between serum TPO concentration, platelet number and plasma levels of fibrinogen in patients with reactive thrombocytosis (RT) due to lung cancer and in patients with essential (primary) thrombocythemia (ET). A total of 70 newly diagnosed patients with RT or ET (platelet counts >600 G/l) were studied: 45 with RT due to lung cancer (25 with non-small cell lung cancer, NSCLC and 20 with small cell lung cancer, SCLC), and 25 with ET. Twenty normal volunteers were used as controls. TPO was measured by immunoassay technique (ELISA). Mean serum TPO values in patients with RT due to lung cancer were statistically significantly higher than those in patients with ET or in controls. The highest platelet count was seen in patients with ET, and mean plasma fibrinogen levels were the highest in RT patients. In NSCLC patients mean serum TPO concentrations were higher (not statistically significant) than in SCLC, and a statistically significant relationship between TPO serum concentration and fibrinogen level was observed. No correlations between platelet counts and TPO serum concentrations were found. Our results indicate increased serum TPO levels in patients with thrombocytosis in lung cancer which may be related to the activity of neoplasms. In addition, it is postulated that the relatively low TPO values in patients with ET may result from a dysregulation of the feedback loop involved in platelet production.

Phenazone as a marker of liver-metabolic function in patients with acute leukemia.

OBJECTIVE: The aim of this work was to study the influence of neoplastic disease, especially acute myeloblastic leukemia (AML), and its chemotherapy on the activity of hepatic microsomal enzymes by using phenazone, as a marker of oxidative drug metabolizing activity. METHODS: The observations were carried out in 21 patients with AML and in 53 healthy volunteers. The influence of disease on phenazone kinetics was studied before chemotherapy and the effect of anticancer drugs administration after the first cycle of chemotherapy. RESULTS: The mean phenazone half-life time was significantly shorter in patients with AML (8.79 (3.01) h) than in control group (11.08 (3.61) h) (p < 0.012). Treatment with anticancer drugs, especially with epirubicine, inhibited phenazone elimination. The mean phenazone half-life time was significantly longer (18.08 (8.80) h) and the mean metabolic clearance rate was significantly smaller (33.92 (15.40) ml/min) after chemotherapy in comparison with the initial value, before treatment (10.22 (2.90) h), (p < 0.01) (50.33 (20.29) ml/min) (p < 0.008). CONCLUSION: Our results lead to the conclusion that phenazone is an important index of hepatic metabolic capacity in patients with acute myeloblastic leukemia. The evaluation of its kinetics allowed to early recognition of the presence and the degree of drug oxidizing modification. Acceleration of phenazone elimination before treatment and its inhibition after chemotherapy, particulary epirubicine, may suggest that in patients with AML elimination of the other drugs metabolized by the pathway similar to phenazone also may be changed. It should be considered in individualization of their dosage regimen.

CD3+ T lymphocytes and interleukin 2 in myelomatous blood hyperviscosity syndrome treated with plasmapheresis.

The study was aimed at testing changes of absolute CD3+ T lymphocyte counts and serum interleukin 2 (IL-2) concentrations in 20 patients suffering from myelomatous and macroglobulinemic hyperviscosity syndrome. Mean values have been calculated from assays made before treatment, immediately after plasmapheresis (PP) and after 1 month of subsequent chemotherapy. Patients showing hyperviscosity displayed initial IL-2 values ranging from 529 to 2722 pg/ml. These levels were significantly (p = 0.001) higher than in healthy subjects, in whom IL-2 was undetectable. Absolute CD3+ counts in patients with hyperviscosity ranged from 600 to 1290 G/l and were significantly (p = 0.05) lower than in healthy controls with a range of 1110-1520 G/l. In 6 patients in coma or precoma serum IL-2 concentrations were insignificantly and absolute CD3+ counts significantly (p = 0.02) lower than in hyperviscosity patients with less severe symptoms. After PP the previously elevated serum IL-2 levels diminished by 20%, but absolute CD3+ counts remained unchanged. After 1 month of chemotherapy IL-2 levels increased again in 15 multiple myeloma (MM) patients, but in all patients with Waldenstrom's macroglobulinemia (WM) a further decrease of serum IL-2 level was observed. By that time CD3+ counts increased significantly (p = 0.01) being higher than initial values. Effects of combined myeloma treatment and prognostic value of serum IL-2 level and absolute number of CD3+ determination are discussed.

[Level of interleukin-6 (IL-6), soluble interleukin-6 receptors (sIL-6R) and tumor necrosis factor alpha (TNF-alpha) in untreated and progressing multiple myeloma]. / Stezenie interleukiny-6 (IL-6), rozpuszczalnego receptora dla interleukiny-6 (sIL-6R) i czynnika martwicy nowotworów alfa (TNF-alfa) w szpiczaku mnogim nie leczonym i w progresji.

36 MM pts in advanced stage, 17 recently diagnozed (group I) and 19 in the progression of the disease (group II) were examined. 10 pts of group I and 12 of group II had renal failure. Levels of II-6, sII-6R and TNF-alpha were measured in pts sera before cytostatic therapy or plasma exchange (PE) and after 4-week therapy. The plasma concentration of II-6, sIl-6R and TNF-alpha before chemotherapy were 47-426 pg/ml, 33-III ng/ml and 19-350 pg/ml respectively and were significantly higher than in healthy control (group III) but no significant changes were observed between group I and group II. Patients with renal failure showed significantly higher II-6 and sIl-6R plasma levels than those with normal renal function. After 4 weeks of chemotherapy plasma concentration of the examined parameters decreased only in those pts of both groups, who later, after 6 mos disclosed a therapeutic response. Median survival time (m-ST) of recently diagnosed MM pts was 38 mos and in those with progression of underlying disease-43 mos. M-ST of 5 pts whose levels of Il-6 > 150 pg/ml, sIl-6R > 55 ng/ml and TNF-alpha-150 pg/ml was only 18 mos, but when only one of them was so much elevated it attained 55 mos. (p = 0.01).

[Massive pericardial effusion during the course of hematological diseases]. / Masywne wysieki osierdziowe w przebiegu chorób hematologicznych.

7 patients, 4F/3M aged 20-63 years (x = 39.5 yrs) with high grade non-Hodgkin lymphoma (4 pts), Hodgkin's disease (1), acute leukaemia (1) and blastic crisis of CML (1), complicated by massive pericardial effusion with impending cardiac tamponade were presented. Symptoms of neoplastic pericardium infiltration have appeared at the diagnosis of underlying disease in 2 pts, in the remaining 5.5-24.5 months (mean = 12.5 months) since the diagnosis and onset of cytostatic treatment was established. In 6 pts pericadiocentesis or pericardium drainage have been applied, resulting in evacuation of 100-1450 ml (mean = 680 ml) of fluid. In 3 pts pericardial effusion was bloody and in two some neoplastic cells were found. In 4 pts intrapericardially 5-20 mg mitoxantrone, 5-20 mg, was administered 7 times. The survival time since the diagnosis of a massive pericardial effusion ranged 0.5-10 months. One person remains alive 7 months after diagnosis of cardiac effusion and 19 months from the diagnosis of n-HL. The authors conclude that pericardiac involvement in the course of haematologic malignancies is a very unfavorable event.

[Rheumatoid arthritis as a risk factor for development of multiple myeloma]. / Reumatoidalne zapalenie stawów jako czynnik ryzyka w rozwoju szpiczaka plazmocytowego.

7 out of 154 patients with multiple myeloma (MM) with concomitant rheumatoid arthritis (RA) (5 persons) and Bechterev disease (BD) (2 persons) have been presented. There were 5 women and 2 men at age from 52 to 67 years. Four of them had joint's disease for 4, 5, 24 and 25 years prior to MM, and in the next there MM was diagnosed simultaneously with RA. Two patients are still living (50 and 55 months from the diagnosis of MM), the mean survival time of the five already dead was 34.5 months, and did not differ from the survival of patients with MM alone. The contribution of interleukin-6 (Il-6) and adhesion molecules ICAM-1, VCAM-1, CD44 in pathogenesis of both diseases are discussed.

[Evaluation of phenazone oxidation and sulfadimidine acetylation in patients with hematologic neoplasms]. / Ocena procesów utleniania fenazonu i acetylacji sulfadimidyny u chorych na nowotwory krwi.

The aim of our study was to estimate of phenazone oxidation and sulfadimidine acetylation in patients with Hodgkins disease, non Hodgkins lymphoma and acute leukemia. We observed increase in liver microsomal enzyme activity and predominance of the rapid acetylator phenotype in these pathological states. It should be taken into account when dosing drugs which are metabolized as markers of the liver metabolic efficiency like phenazone and sulphadimidine. One can also expect these patients to have a genetic predisposition to the development of cancer disease.

[A case of light chain disease characterized by non-secretory myeloma]. / Przypadek choroby lekkich lancuchów o charakterze szpiczaka niewydzielajacego.

A rare case of a 45 yr old woman with non-secretory light chain disease has been presented. The disease course was aggressive and survival time from diagnosis was 24 months. The new classification of literature of non-secretory multiple myeloma and a discussion of pathogenesis of non-secretory monoclonal Ig is delivered.

2-chlorodeoxyadenosine (2-CdA) in 2-hour versus 24-hour intravenous infusion in the treatment of patients with hairy cell leukemia.

Forty one patients with hairy cell leukemia (HCL) were treated with 2-chloro-deoxyadenosine (2-CdA) administered in various schedules. Complete remission (CR) was achieved in 31 (76%) patients and partial remission (PR) in 9 (22%). The mean duration of remission (CR + PR) was 25.2 months (range 9-45 months). One patient did not respond to therapy. Twelve out of 16 patients (75%) achieved CR after 5-day intravenous infusions of 2-CdA and 19 out of 25 patients (76%) after 7-day courses. In 19 out of 23 patients (82.6%) CR was achieved after intermittent 2-hour infusions and in 12 out of 18 (66.7%) after continuous 24-hour infusion. The differences were not statistically significant. Side effects of 2-CdA were similar in both groups except for infections, which were less frequently observed in the group treated for 5 days. The results of our study suggest that 2-CdA can be effectively administered to patients with HCL using 5-day courses and a 2-hour daily infusion.

Molecular characterization of mouse monoclonal antibody BIII.136 and the epitope recognized by the antibody in human band 3 protein.

The monoclonal antibody BIII.136, which recognizes the cytoplasmic part of the band 3 protein from human erythrocytes, also detects products of proteolytic degradation of that protein caused by endogeneous proteases in erythrocytes. Now we extend and confirm these observations by finding that in very young erythrocytes from patients with hemolytic anemias the band 3 protein is almost intact, which suggests that proteolytic degradation of that protein proceeds in vivo during the life span f the erythrocyte. Interesting properties and applicability of this antibody for following the band 3 degradation in vivo and for detection of the band 3 variant forms have prompted us to characterize its primary structure and the epitope recognized in band 3. A set of solid phase-synthesized peptides allowed us to establish that MAb BIII.136 is directed against sequence EDPDIP, which corresponds to amino acid residues 22-27 in band 3 protein. Replacement analysis revealed that only E22 and P24 can be replaced by several other amino acids without a significant loss of reactivity, while the remaining four amino acids seem to be an essential part of the epitope. No reactivity of the antibody with band 3 from several other species was found. Analysis of the heavy and light chain variable region cDNAs revealed that the VH is encoded by a member of VH8(VH3609) family, while the VL is encoded by a member of the Vk12/13 family.

[Polyneuropathy in non-Hodgkin lymphoma]. / Polineuropatia w przebiegu chloniaka neiziarniczego.

In a group of patients with non-Hodgkin lymphoma axonal sensorimotor polyneuropathy was found in 15%. It appeared in the treated patients, those receiving doses of oncovin. Polyneuropathy was not correlated with the type of malignancy. Treatment seems to be the important factor which can cause polyneuropathy.

[Visual and somatosensory evoked potentials in the patients with non-Hodgkin lymphoma]. / Wzrokowe i somatosensoryczne potencjaly wywolane u chorych z chloniakiem nieziarniczym.

Visual (VEPs) and somatosensory (SEPs) evoked potentials in a group of 33 patients (mean age 49 years) with non-Hodgkin lymphoma (n-HL) without CNS involvement were recorded. There were 24% of patients with pathological VEPs and 30% of patients with pathological SEPs. Pathological VEPs and SEPs were both recorded in 42% of patients. In comparison to the controls the statistically significant prolongation of mean latencies of VEPs, SEPs and transit time to cortex were found in the group of n-HL patients. These abnormalities were noted much more often in patients with long duration of the disease and with intermediate type of malignancy. In the untreated patients evoked potentials were normal. In 6 patients despite normal neurological status and normal eeg the evoked potentials were abnormal. The evoked potentials examination seems to be very sensitive method of afferent pathways involvement estimation and can be used for diagnosis and prognosis in n-HL patients. This method reveals CNS lesions more often than physical examination or eeg.

[Effect of epirubicin on left ventricular function in patients with malignant lymphoma]. / Wplyw epirubicyny na funkcje lewej komory serca u chorych na chloniaki zlosliwe.

The effect of epidoxorubicin (epiDX) on contractility of left ventricle was followed up in patients treated according to protocols containing the drug. The examined group comprised 30 pts with Hodgkin's disease. 16 women and 14 men, aged 17-70 years, and 9 pts with high grade malignant lymphoma, 3 females and 6 males in the age of 21-64 years. Using Hewlett-Packard echocardiograph diastolic and systolic diameter of left ventricle in typical place was evaluated, 24 hrs before and after 40 mg of epiDX application as well as after completing therapy (total dose epiDX 80-480m mg). The percentages of fractional shortening of the left ventricle dimension (FS%) and ejection fraction (EF%) were calculated from the above parameters. There were no changes in measurements of cardiac function after the first dose of the drug. The fractional shortening of left ventricle dimension and EF in patients who have completed therapy were statistically significantly lower in comparison with those before therapy and control group. Heart failure was not observed. Decreased indices of heart muscle contractility and ejection fraction found in our patients may be connected with the epiDX therapy, though in dosis lower than 50% of the cumulative one, and may express the late toxicity of the drug.

[Diagnostic difficulties with a tumor in deep tissues of the buttock]. / Trudnosci diagnostyczne guza glebokich tkanek posladka.

Diagnostic difficulties in a case of a large tumor localized in the deep tissue of buttock in a 29-year old woman is described. The patient was very severely ill presenting with neurological symptoms and immobilization of the left coxal joint, what strongly suggested a neoplasm and this was supported by the CT scan. USG examination allowed diagnosis of a deep hematogenic staphylococcal abscess of the buttock, probably due to extensive oral sepsis and staphylococcal septicaemia. Systemic antibiotic therapy as well as evacuation of pus caused a complete recovery of the patient.

[Actinomycosis as a complication of blood diseases]. / Promienica jako powiklanie chorób krwi.

Two cases of actinomycosis in chronic myelogenous leukaemia (CML) and Hodgkin's disease (HD) are presented. The first patient with blastic crisis in CML had painful infiltration above and beneath the clavicular region, affecting the right humeral joint, what required differentiation from neoplastic infiltration. Specific infiltration, formation of fistuli and good response to antibiotic therapy suggested actinomycosis. Finally actinomycosis was diagnosed by microbiological and histopathological examination. The infection with actinomycosis in the other patient interfered with early diagnosis of coexistant Hodgkin's disease. The histopathologic examination of right cervical lymph nodes indicated the chronic inflammatory process. The subsequent histo pathologic examination of the axillary lymph node showed Hodgkin's disease, type LD. Culture from the exudating wound after lymph node excision was positive for actinomyces. Simultaneous treatment with cytostatics and antibiotics resulted in complete recovery of patient. In the above reported patients, actinomycosis complicated the course of CML and HD. The immune deficiency of the organism in both patients facilitated the development of the actinomycosis.