Lech Konopka

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.

2‐Chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia and hairy cell leukemia variant: 7‐year experience in Poland

Abstract: 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‐α (IFN‐α) 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.

Autoimmune haemolytic anaemia in patients with chronic lymphocytic eukaemia treated with 2‐chlorodeoxyadenosine (cladribine)

Abstract: Autoimmune haemolytic anaemia (AIHA) is one of the major complications in chronic lymphocytic leukaemia (CLL). Treatment with alkylating agents and the adenosine analogue, fludarabine, might trigger the development of AIHA in CLL patients despite the reduction of leukaemic clone. The influence of 2‐chlorodeoxyadenosine (2‐CdA) on AIHA in patients with CLL is undefined so far. In a group of 114 patients treated at our clinics with this agent, AIHA with direct antiglobulin test (DAT) positively was observed in 25 (21.9%) patients. In 23 patients AIHA was noticed before the starting of 2‐CdA and in 2 patients DAT became positive after 2‐CdA treatment. In 6 patients the drug caused complete resolution of haemolysis and DAT became negative. Eight patients exhibited partial resolution of haemolysis with significant improvement in haemoglobin level but DAT test remained positive. In 11 patients there was no response to 2‐CdA in relation to autoimmune haemolysis. Two patients with no previous history of haemolysis developed AIHA after 5 and 6 courses of 2‐CdA therapy and their DAT became positive 1–2 months after the last course of the drug. One of them entered severe haemolytic crisis and severe thrombocytopenia and died because of haemorrhagy to the central nervous system. In the other patient AIHA was controlled by steroids and chlorambucil treatment. Our study indicates that 2‐CdA may suppress autoimmunohaemolytic process in some patients with CLL and trigger the development of AIHA in others.

Activity of Cladribine Combined With Cyclophosphamide in Frontline Therapy for Chronic Lymphocytic Leukemia With 17p13.1/ TP53 Deletion : Report From the Polish Adult Leukemia Group

The 17p13.1 deletion that causes loss of the p53‐encoding TP53 gene is the most powerful predictor of a poor response to conventional therapy and shortened survival in patients with chronic lymphocytic leukemia (CLL). The results of this study have demonstrated that the cladribine and cyclophosphamide regimen may improve treatment results in this poor‐risk patient population.

G-CSF Administered in Time-sequenced Setting During Remission Induction and Consolidation Therapy of Adult Acute Lymphoblastic Leukemia has Beneficial Influence on Early Recovery and Possibly Improves Long-term Outcome: A Randomized Multicenter Study

Sixty-four untreated adult acute lymphoblastic leukemia (ALL) patients were randomized to receive chemotherapy alone, n =31 or chemotherapy and granulocyte colony stimulating factor (G-CSF), n =33. During induction patients received G-CSF for 5 days between four weekly Epirubicin+Vcr administrations, starting 36 h after each application and finishing 48 h before the next one with the intention to possibly generate a cell cycle dependent protection of normal hematopoietic progenitors and to stimulate granulopoiesis. The complete remission (CR) rate equaled 94% in the G-CSF group and 87% in controls. Patients who received G-CSF, if compared to the controls, had shorter granulocytopenia during induction and consolidation, displayed a lower infection rate, completed the induction-consolidation quicker and stayed shorter in hospital during induction, p <0.001-0.04. Follow-up at 2 years revealed a rather higher probability of survival (59 vs. 27%, p =0.04 ) and a lower relapse rate (32 vs. 60%) in G-CSF arm than in controls. The beneficial influence of G-CSF administered in time-sequenced fashion on survival needs further confirmation.

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-Hodgkins 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.

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.

Re-treatment with cladribine-based regimens in relapsed patients with B-cell chronic lymphocytic leukemia: Efficacy and toxicity in comparison with previous treatment

Abstract: The aim of the study was to determine the effectiveness and toxicity of cladribine (2‐CdA) used alone or in combination with prednisone (P) or cyclophosphamide and mitoxantrone in re‐treatment of patients with progressive B‐cell chronic lymphocytic leukemia (B‐CLL). We analyzed treatment outcome in 40 patients who had responded to previous treatment with 2‐CdA‐based regimens. Criteria for re‐treatment were the same as for the first treatment. The patients were retreated with the same agents if they responded to the first treatment and then relapsed with progressive disease not earlier than 3 months after achieving the first response. Eight patients received 2‐CdA alone (0.12 mg kg−1 d−1) i.v. for 5 d, and 21 patients additionally were given P (30 mg m−2 d−1) orally, also for 5 d. Eleven patients received 2‐CdA for 3 d combined with cyclophosphamide (650 mg m−2) i.v. and mitoxantrone (10 mg m−2) i.v. on day 1 (CMC regimen). The cycles were repeated usually at 4 wk intervals or longer if severe myelosuppression or infections occurred. The therapy was finished if complete remission (CR) was achieved or until maximum of six courses. Overall response (OR) in re‐treatment was obtained in 16 out of 40 (40%) patients (95% CI 16–64), including 62% after 2‐CdA, 33% after 2‐CdA +P and 36% after CMC. CR was obtained in four (10%) patients. Residual disease evaluated in the patients with CR by surface immunophenotyping had been demonstrated in 5 out of 16 (31%) patients after the first treatment and in one out of four (25%) patients after re‐treatment. The median progression‐free survival (PFS) was 16 months (range 3–39) for the first treatment and 9.5 months (range 3–18) for re‐treatment (P=0.34). Grade III or IV neutropenia was observed in 20% patients during the first treatment and in 35% patients during re‐treatment (P=0.1). 2‐CdA‐induced thrombocytopenia occurred in 20% and 42% of the patients, respectively (P=0.05). Anemia was also more frequent during re‐treatment (35%) than during the first treatment (7%) (P=0.007). Autoimmune hemolytic anemia developed in four (10%) of the patients during or after re‐treatment. Severe infections, including pneumonia and herpes reactivation, occurred in 11 patients during the first treatment and in 10 patients during re‐treatment. Twelve (30%) patients died during the study. Infections were the cause of death in six and AIHA in two patients. In conclusion, 2‐CdA applied in monotherapy or in combination with prednisone or cyclophosphamide and mitoxantrone has therapeutic activity in some B‐CLL patients in whom these drugs induced earlier complete or partial remission. However, since the second response is usually shorter and myelotoxicity more pronounced than during the first therapy, more clinical trials to find other therapeutical approaches are necessary.

Karyotype changes during long-term targeted therapy of chronic myeloid leukemia with imatinib.

The main risk factors during imatinib therapy of chronic myeloid leukemia are still subject to discussion. A group of 39 patients was cytogenetically examined and monitored before and during long-term treatment with imatinib. The cytogenetic response was investigated using karyotype analysis and fluorescence in situ hybridisation method. Different therapy effects were shown for three subgroups distinguished before the start of treatment: patients with the sole translocation t(9;22) with a typical pattern of BCR/ABL fusion vs. patients with submicroscopic deletion in the fusion region ABL/BCR of the sole t(9;22) vs. patients with aberrations additional to t(9;22) and without submicroscopic deletion. Of the two group with sole t(9;22) the group with deletion in the ABL/BCL region suffered a poorer treatment outcome than the group without deletion. The risk of progression of cytogenetic changes in group with deletion was more than nine times higher than in patients with sole t(9;22) without deletion (statistically significant).

Impact of granulocyte colony stimulating factor administered during induction and consolidation of adults with acute lymphoblastic leukemia on survival: long-term follow-up of the Polish adult leukemia group 4-96 study.

Department of Clinical Oncology, Comprehensive Cancer Centre, Maria Sklodowska-Curie Memorial Institute Branch Gliwice, Gliwice, Poland, Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice, Poland, Department of Hematology, Institute of Internal Diseases, Gdansk Medical Academy, Gdansk, Poland, Department of Hematology and Bone Marrow Transplantation, Lublin Medical Academy, Lublin, Poland, Department of Hematology, Oncology and Internal Medicine, Warsaw Medical University, Warsaw, Poland, Department of Hematology, Lodz Medical University, Lodz, Poland, Department of Internal Diseases, Institute of Haematology and Blood Transfusion, Warsaw, Poland, Department of Hematology, Institute of Haematology and Blood Transfusion, Warsaw, Poland, and Department of Hematology, Collegium Medicum, Jagiellonian University, Krakow, Poland