Myelodysplastic syndromes according to FAB and WHO classification. Single center experience.

The results of clinical and laboratory observations of 119 MDS patients divided acc. to FAB, and - after excluding RAEB-t and CMML groups -- of 95 patients divided accordingly to WHO classification are presented. The diagnosis of MDS was based on medical interview, physical examination, blood biochemistry, peripheral blood (PB) and bone marrow (BM) cytomorphology and cytochemistry, trephine biopsy and cytogenetic examination. All hematologic examinations were done according to routine methods. Cytogenetic analyses were carried out on BM cells from 24-48 h cultures in standard conditions. At least 15-20 GTG-banded metaphases were analyzed in every patient. The survival time (ST) of patients differed significantly between the FAB or WHO groups, with p=0.0004 for FAB and p=0.02 for WHO. The progression to AML was more common in less favorable groups, with p=0.0001 for FAB and p=0.00016 for WHO. The distribution of IPSS prognostic index among the groups showed statistically significant difference (p=0.0004 for FAB, and p=0.0001 for WHO), whereas the distribution of karyotypic abnormalities did not. However, in univariate analysis statistically significant influence on ST showed, beside the both classification systems: cytogenetics, the presence of blasts in PB, age and IPSS index. In multivariate analysis the sole independent prognostic factors were: PB blasts and cytogenetics. The authors conclude that the WHO classification offers a good prognostic tool for MDS patients. However, the karyotype and the presence of blasts in PB should always be taken into account.

Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial.

The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m(2) per day for 5 consecutive days or Chl 12 mg/m(2) per day and P 30 mg/m(2) per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received Chl+P as a first-line treatment. CR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with Chl+P (12% and 57%, respectively) (P = .001). Progression-free survival was significantly longer in the 2-CdA-treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to Chl+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than Chl+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the Chl+P-treated group (40%; P = .02). Death rates have so far been similar in patients treated with 2-CdA (20%) and with Chl (17%). The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively). (Blood. 2000;96:2723-2729)

[Cytogenetic changes in Ph(+) chronic granulocytic leukemia under the influence of interferon alpha (IFN-alpha) therapy]. / Zmiany cytogenetyczne w Ph-dodatniej [Ph(+)] przewleklej bialaczce szpikowej w czasie leczenia interferonem alfa (IFN-alpha).

Chromosomal changes during therapy with IFN-alpha were analysed in 21 patients suffering of chronic granulocytic leukemia. Complete or major cytogenetic response (CgR) was obtained in 4 patients, minor in 5 minimal in 7, and no response in 5 patients. Patients showing a low Sokal index more often disclosed CgR. In 6 persons additional chromosomal aberrations were present at diagnosis or during the disease course. They disappeared on IFN-alpha therapy. This fact may be in favour of the influence of IFN-alpha not only on disappearance of Ph chromosome, but also of secondary aberrations, some of them indicating the possibility of an acceleration of the disease. No relation of the CgR, as well as Sokal index value to the survival time in presented small cohort could be observed, which may depend on short observation time. CgR did not depend on a type of fusion of BCR/ABL gene. However, survival time was longer in patients with b3a2 fusion.

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.

2-chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia and hairy cell leukemia variant: 7-year experience in Poland.

Between January 1991 and December 1997, 103 patients, 97 with typical hairy cell leukemia (HCL) and 6 with HCL-variant (HCL-V) were treated with 2-chlorodeoxyadenosine (2-CdA) given as 2-h infusion for 5 consecutive d at a daily dose 0.12 mg/kg. To our knowledge this is the largest cohort of HCL patients treated with this type of regimen. Median follow-up amounted to 36 months. Fifty-six of 97 patients with typical HCL were newly diagnosed and 41 were relapsed after previous treatment. Splenectomy as a first-line therapy was performed in 23 patients and 18 remaining patients received prednisone, chlorambucil or interferon-alpha (IFN-alpha) alone or in combinations. Seventy-five (77.3%) patients entered CR and 18 (18.6%) achieved PR, giving an overall response rate of 95.9%. The mean time of first CR duration amounting to 32 months (range 3-72) did not correlate to the number of 2-CdA cycles. 2-CdA was equally effective in treatment of newly diagnosed patients and patients who relapsed after previous therapeutic procedures. Relapse of the disease occurred in 20 of 75 patients who achieved CR after 2-CdA and was usually manifested by very discrete changes in peripheral blood counts (neutropenia and/or relative lymphocytosis). The mean progression-free survival (PFS) time in this group was 37.4 (range 10-66) months. Ten of 20 relapsed patients were retreated with 2-CdA given an identical course to the first one. Seven patients entered second CR lasting 19+ (range 8-47) months and 3 experienced PR. This confirms the previous observations that 2-CdA gives no resistance to leukemic clone. Ten remaining patients have not required retreatment so far and remain in a good clinical and hematological state. The results of HCL-V treatment with 2-CdA were poor. Only 2 patients achieved PR and 4 patients did not respond to this drug. Seven patients (5 with typical HCL and 2 with HCL-V) died, 3 of causes unrelated to the disease. Second neoplasms were noted in 5 patients. 2-CdA-related side effects resulted mainly from myelosuppression and infectious complications. In conclusion we confirm the effectiveness of 2-CdA in inducing CR in patients with typical HCL, but this drug is unable to completely eradicate the leukemic clone which results in the relapse of the disease. The real incidence of the relapse rate may be underestimated unless bone marrow biopsy is performed. The results of our study indicate that a 2-h infusion of 2-CdA in HCL patients is at least as effective as a 24-h infusion but more convenient to the patients, and may be given on an outpatient basis.

[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.

The effect of 2-h infusion of 2-chlorodeoxyadenosine (cladribine) with prednisone in previously untreated B-cell chronic lymphocytic leukaemia.

2-Chlorodeoxyadenosine (2-CdA) is a new antimetabolite chemotherapeutic agent active in indolent lymphoid malignancies. In this retrospective study, 69 previously untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL) were treated with 2-CdA administered at a dose of 0.12 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. 45 patients also received prednisone 30 mg/m2 orally each day for 5 days starting with 2-CdA courses. Patients were given 2-6 courses (mean 4.6) of 2-CdA repeated usually at monthly intervals. If a complete response was achieved, no further 2-CdA courses were administered. Guidelines for response were those developed by the NCI Sponsored Working Group. Complete response (CR) was achieved in 26 (38%) and partial response (PR) in 27 (39%) cases, giving an overall response rate of 77%. 16 patients (23%) did not respond to 2-CdA. In the subgroup of 45 patients receiving 2-CdA with prednisone, CR was obtained in 15 (33%) and PR in 20 (44%) patients giving an overall response rate of 78%. CR was achieved in 11 (46%) out of 24 patients treated only with 2-CdA and in 7 cases (29%) PR was observed, giving an objective response rate of 75%. The differences between both subgroups were not statistically significant. However, we observed a relationship between the response and the number of courses of 2-CdA given in patients receiving and those not receiving prednisone. In the subgroup receiving 2-CdA with prednisone, an earlier response to 2-CdA was observed. In this group a response was achieved in 9 (20%) patients after two courses of 2-CdA and in 18 (40%) after four courses. In the subgroup receiving only 2-CdA, 17 (71%) responses were obtained after six cycles.

Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia.

The purpose of our study was to determine the effectiveness of 2-CdA in 2-hour intravenous infusions in the treatment of B-CLL. One hundred and ten patients with B-CLL received 1 to 10 courses of 2-CdA (median 2.5) at a dosage of 0.12 mg/kg daily for 5 consecutive days. Eighteen of them were untreated and 92 relapsed or became refractory to previous therapeutic modalities. Complete remission (CR) was achieved in 8 (7.3%) and partial remission (PR) in 35 patients (31.8%) giving an overall response rate of 39.1%. In 3 patients, cross-resistance to fludarabine was noticed. Toxic effects of 2-CdA were more frequently observed in previously treated patients. Hemorrhagic complications due to drug-induced thrombocytopenia were noticed in 25 (22.7%) and severe infections including sepsis in 14 (12.7%) patients.

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.

The expression of mRNA for fibrinogen in megakaryocytes isolated from patients with T-cell lymphoma.

The expression of fibrinogen mRNA was studied by in situ hybridization in freshly isolated megakaryocytes in 14 newly-diagnosed patients: seven with non-Hodgkin's lymphoma (NHL), three with immune thrombocytopenic purpura (ITP) and four haematologically normal patients prior to coronary artery bypass surgery. Fibrinogen mRNA in megakaryocytes was not detected in ITP, B-cell lymphomas or in healthy donors. However, it was present in all patients with the high-grade T-cell lymphomas, both with and without thrombocytopenia.

[Evaluation of early treatment results in Hodgkin's disease during the cytostatic protocol containing methotrexate]. / Ocena wczesnych wyników leczenia choroby Hodgkina wedlug protokolu cytostatycznego zawierajacego metotreksat.

28 patients suffering from advanced Hodgkin's disease were treated according to protocol containing 7 cytostatic drugs including methotrexate and corticosteroids, but not cyclophosphamide, chlormethine or procarbazine. 22 patients i.e. 78.5% attained complete remission and 5 i.e. 17.8% a partial one. Drug tolerance was satisfactory: out of side-effects the most common was myelosuppression, especially granulocytopenia. Our early results were similar to those obtained with MOPP-like protocols, but early undesirable effects less often and of a smaller degree. Because the protocol has been aimed at avoiding late toxicity of cytostatics, its final evaluation will be possible in the future.

[Extraintestinal salmonellosis in patients with blood diseases caused by Salmonella enteritidis]. / Pozajelitowa salmoneloza u osób z chorobami krwi, wywolana przez Salmonella enteritidis.

Four cases of extraintestinal salmonellosis caused by Salmonella enteritidis were described. Underlying diseases in the three patients were haematological neoplasms (2 splenectomized and 1 with massive leukemic infiltrations of the spleen) and in the fourth haemophilia B: only that patient had a prior symptomatic intestinal infection. Blood cultures for S.ent. were positive in all patients and additionally in that suffering from Hodgkin's disease urine, lymph node and stool cultures also showed S.ent. In the haemophiliac patient culture of suppurated hematoma was positive. All patients recovered from S. sepsis but three then died of their neoplastic diseases. The haemophiliac patient is in a good condition. Various disturbances in the immunological tests were observed.

[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.

[Treatment of drug induced agranulocytosis with granulocyte-macrophage colony stimulating factor (G-CSF)]. / Leczenie ostrej agranulocytozy polekowej czynnikiem stymulujacym kolonie granulocytowe (G-CSF).

G-CSF was applied in three patients with acute, iatrogenic, immunological agranulocytosis (after ticlopidine, thimazol and aminoglutethimide) complicated by severe infections. Before this treatment was started no improvement had been achieved despite the administration of antibiotics, and corticosteroids for 4 to 9 days. Two patients had anaemia and one--thrombocytopenia probably due to the damage to the earlier, common progenitor cells. In bone marrow smears a plasmocytic reaction reaching 11-13% of total cell counts was observed. After G-CSF all patients showed a prompt amelioration of clinical symptoms, and the leucocyte count raised in several days up to 11.0-73.0 x 10(3)/microliters. Simultaneously young cellular forms of granulocyte lineage appeared in peripheral blood.

[Undesirable side-effects of some cytokines]. / Niepozadane dzialania niektórych cytokin.

Undesirable side-effects of some cytokines (including haematopoietic growth (factors) were overviewed. Effects of the secondary release of proinflammatory cytokines stimulation were discussed as well as means of overcoming them.

[Results of alternating treatment of multiple myeloma--cytostatics VBMCP and recombinant interferon alfa-2B]. / Wyniki naprzemiennego leczenia szpiczaka mnogiego--cytostatykami VBMCP i rekombinowanym interferonem alfa-2B.

In 19 patients with recently diagnosed multiple myeloma 3-week cycles of vincristine, BCNU, melphalan, cyclophosphamide and prednisone alternating with interferon were administered over 6-12 months. Results were compared with a control group of 33 myeloma patients treated exclusively with VBMCP cytostatics. In interferon treated patients objective response was more frequent (76%) and median survival time longer (above 35 months).

[Long-term (over 10-years) survival in Hodgkin's disease]. / Dlugotrwale (ponad 10-letnie) przezycie w chorobie Hodgkina.

61 patients with Hodgkin's disease, i.e., 40.9% of all HD pts hospitalized in the years 1970-1981 are more than 10 years survivors: 46 are alive and 15 died of underlying disease or its complications. The most important prognostic factor at diagnosis was clinical advancement and the form A or B of HD. Age and sex also influenced survival but to a lesser degree. Patients living in CCR were more likely to have MC histology than those with relapsing disease, who more often showed LD and LP type. Among 5 persons with second neoplasms four disclosed NS type of HD. No statistical differences in clinical prognostic factors were encountered between further alive and those who died after more than 10-yrs. Almost all patients were able to normally continue their familial and professional lives.

[Activity of natural cytotoxic cells in non-Hodgkin's lymphoma]. / Aktywnosc naturalnych komórek cytotoksycznych w nieziarniczych chloniakach zlosliwych.

Cytotoxic activity of NK cells in the peripheral blood has been determined in 30 patients with malignant non-Hodgkin lymphomas prior to and following therapy. In the whole group as well as in subgroups classified according to the criteria of Working Formulation as lymphomas of the low, moderate and high degree of malignancy, activity of NK cells has been statistically significantly lower than that in healthy individuals. Marked increase in this activity has been noted in 19 patients in the state of clinical remission after the treatment with cytotoxic agents, and sometimes radiotherapy. The value of mean cytotoxic activity reached normal limits in the lymphoma of high degree of malignancy, and exceeded these limits in the lymphomas of moderate and low malignancy.