Second malignancies and Richter's syndrome in patients with chronic lymphocytic leukaemia treated with cladribine.

The increased frequency of second malignancies in chronic lymphocytic leukaemia (CLL) is well known. Moreover, antineoplastic therapy additionally increases the risk of secondary cancers. In this study, we analysed whether treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA) during the course of CLL had an impact on the subsequent occurrence of either secondary solid tumours or Richter's syndrome. There were 1487 eligible patients, 251 treated with 2-CdA alone, 913 treated with alkylating agents (AA)-based regimens alone and 323 treated with both 2-CdA and AA. Median time from the start of CLL treatment to the diagnosis of secondary malignancy was 1.9 years (0.5-5.1 years) for the 2-CdA group, 1.8 years (0.3-7.9 years) for the AA group and 3.9 years (0.3-8.4 years) for the 2-CdA+AA group. A total of 68 malignancies were reported in 65 patients. Ten events were non-melanotic skin cancers and were excluded from the analysis, leaving 58 events in 58 patients. In the group of patients treated with 2-CdA alone, there were 15 (6.0%) cases, in the group of patients treated with AA alone there were 26 (2.8%) cases, and in the group treated with 2-CdA+AA there were 17 (5.3%) cases of secondary malignancies. The differences between the frequency of secondary malignancies in the 2-CdA and 2-CdA+AA versus AA alone groups were not significant (P=0.05 and P=0.06, respectively). Only lung cancers occurred significantly more frequently in the 2-CdA (2.8%) and 2-CdA+AA (2.2%) treated groups compared with the AA patients (0.3%) (P<0.001 and P<0.01, respectively). In conclusion, 2-CdA in CLL patients does not seem to increase the risk of secondary malignancies except for lung cancers. However, further studies are necessary to establish the real risk of lung cancer in CLL patients treated with 2-CdA.

Cladribine combined with cyclophosphamide and mitoxantrone as front-line therapy in chronic lymphocytic leukemia.

The objective of the study was to determine the effectiveness and the toxicity of a combined chemotherapy consisting of cladribine (2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of previously untreated B cell chronic lymphocytic leukemia (B-CLL). From August 1998 to December 2000 2-CdA was administered at a dosage of 0.12 mg/kg for 3 (CMC3) or 5 (CMC5) consecutive days, mitoxantrone at 10 mg/m2 on day 1 and cyclophosphamide at 650 mg/m2 on day 1 to 62 patients with advanced or progressive B-CLL. The cycles were repeated at 4 week intervals or longer if severe myelosuppression occurred. Twenty patients received CMC5 and 42 patients CMC3. Within the analyzed group an overall response (OR) rate (CR+PR) of 64.5% (95% CI: 52.7-76.3%) was reported, including 29.0% CR. There was no difference in the CR rate between the patients treated with CMC5 (30%) and CMC3 (28.6%) (P = 0.9), nor in the OR rate (55.0% and 69.0%, respectively, P = 0.3). Residual disease was identified in seven out of 18 (38.9%) patients who were in CR, including two treated with CMC5 and five treated with CMC3 protocols. CMC-induced grade III or IV thrombocytopenia occurred in 12 (19.4%) of patients, including four (20%) CMC5-treated and eight (19%) CMC3-treated patients (P= 0.8). Neutropenia grade III or IV was observed in seven (35%) and 11 (26.2%) patients, respectively (P = 0.8). Severe infections, including pneumonia and sepsis, occurred more frequently after CMC5 (11 patients, 55.0%) than CMC3 (10 patients, 28.6%) (P = 0.03) Fourteen patients died, including six treated with CMC5 and eight treated with CMC3 (30% and 19%, respectively). Infections were the cause of death in nine patients, including four in the CMC5 group and five in the CMC3 group. In conclusion, our results indicate that the CMC programme is an active combined regimen in previously untreated B-CLL patients; its efficiency seems to be similar to that observed earlier in B-CLL patients treated with 2-CdA as a single agent. However, toxicity, especially after CMC5 administration, is significant. Therefore, we recommend the CMC3 but not the CMC5 programme for further evaluation.

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)

Cladribine with or without prednisone in the treatment of previously treated and untreated B-cell chronic lymphocytic leukaemia - updated results of the multicentre study of 378 patients.

Between January 1992 and January 1999, we treated 378 B-chronic lymphocytic leukaemia (CLL) patients with cladribine (2-CdA), and 255 of the patients were also treated with prednisone. A total of 194 patients were previously untreated, and 184 had relapsed or refractory disease after previous other therapy. Complete response (CR) was obtained in 111 (29.4%) and partial response (PR) in 138 (36.5%) patients, giving an overall response (OR) rate of 65.9%. CR and OR were achieved more frequently in patients in whom 2-CdA was a first-line treatment (45.4% and 82.5% respectively) than in the pretreated group (12.5% and 48.4% respectively) (P < 0.0001). The median duration of OR for previously untreated patients was 14.7 months and for pretreated patients 13.5 months (P = 0.09). The median survival evaluated from the beginning of 2-CdA treatment was shorter in the pretreated group (16.3 months) than in the untreated group (19.4 months) (P < 0.0001). A total of 117 (63.9%) patients died in the pretreated group and 63 (32.6%) in the untreated group. In pretreated patients, 2-CdA + prednisone (P) and 2-CdA alone resulted in similar OR (51.0% and 45.0% respectively; P = 0.4). In contrast, in untreated patients, 2-CdA + P produced a higher OR (85.4%) than 2-CdA alone (72.1%) (P = 0.04). Infections and fever of unknown origin, observed in 91 (49.4%) pretreated and 74 (38.1%) untreated patients (P = 0.03), were the most frequent toxic effects. Our results indicate that 2-CdA is an effective, relatively well-tolerated drug, especially in previously untreated CLL.

[Chronic eosinophilic leukemia]. / Przewlekla bialaczka eozynofilowa.

In this research one case of chronic myelogenous eosinophilic leukemia (pbe) transformed into myeloblastic crisis in male patient aged 24, efficiently treated chemotherapy with following performing allogenic bone marrow transplantation was represented. The patients was admitted to the Department of Hematology with the cause of increased leucocytosis (up to 19.9 x 10(9)/l), eosinophilia (up to 15.3 x 10(9)/l), enlarged percentage of eosinophillic granulocytes in bone marrow, splenomegaly, anaemia and thrombocytopenia. Cytogenetic tests did not reveal any chromosomal disturbances, and PCR test did not detect bcr/abl rearanzation. After 7 monthly period of chronic phase of disease there was appeared symptoms of blastic acceleration myelogenous disease i.e. enlargement of splenomegaly, intensification of anaemia and thrombocytopenia, very fast increasing leucocytosis in short time together with presence of myeloblasts in blood and bone marrow smear tests. Blastic acceleration pbe with eosinophils dominant in bone marrow was confirmed by flow cytometry. Induction chemotherapy according to schedule HAR (Hydroxyurea--H, Arabinoside Cytosine--A, Doxorubicin--R), consolidation and irradiation of spleen allowed to receive complete remission. The patients was undergone allogenic bone marrow transplantation (allo-BMT) from related donor (younger brother). The follow-up with the period 18 months after allo-BMT has not revealed the relapse of disease.

Activity of 2-chlorodeoxyadenosine (Cladribine) in 2-hour intravenous infusion in 94 previously treated patients with low grade non-Hodgkin's lymphoma.

The purpose of our study was to determine the efficacy of 2-chlorodeoxyadenosine (2-CdA) administered in 2-hour intravenous infusions in previously treated patients with low grade non-Hodgkin's lymphoma (LGNHL). We treated 94 LGNHL patients with 2-CdA at a dosage of 0.12 mg/kg/24h in 2-hour intravenous infusion for 5 consecutive days. The treatment consisted of from 1 to 7 courses (median 3), repeated usually at monthly intervals. All patients were refractory to or relapsed after standard chemotherapy. Of these 94 patients 78 (83%) had clinical stage IV of the disease. Complete response (CR) was obtained in 12 (12.8%) and partial response (PR) in 36 (38.3%) giving an overall response rate of 51.1%. In 12 (12.8%) grade 4 thrombocytopenia with haemorrhagic diathesis was noted, grade 4 neutropenia was observed in 12 (12.8%) and infections complicated the course of treatment in 38 (40.4%) patients. 2-CdA treatment was the cause of death of 3 patients. The results of our study show that 2-CdA given in 2-hour infusions is an effective agent in advanced, heavily pretreated patients with LGNHL.

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.