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7 patients with chronic lymphocytic leukaemia (CLL) associated with autoimmune haemolysis were treated with 2-chlorodeoxyadenosine (2-CdA) in 0.14 mg/kg/day 2 hour infusion for 5 consecutive days. 2 patients had concurrent immune thrombocytopenia. All patients received prior therapy and either failed or the continuation of prior therapy was contraindicated. The median follow up was 8 months. 5 patients responded: 2 patients experienced complete remission (for 3 months), 3 patients experienced partial remission; 2 patients did not respond. However the decrease of haemolysis was achieved in 6 patients. Therapy was well tolerated. Myelosupression associated with severe infections was the main toxicity. Our results show that 2-CdA may induce remission and resolution of haemolysis in some patients with CLL and concurrent autoimmune haemolytic anaemia.

Thirty seven hairy cell leukemia (HCL) patients, 35 males and 2 females with a median age of 53 years, were treated with a single course of 2-Chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily for 7 days by continuous infusion. Twenty nine (78%) achieved a complete remission (CR) and 8 (22%) a partial remission (PR); four of the latter progressed after 6, 12, 18 and 24 months. All have been retreated with 2-CdA and 2 achieved a CR, 1 a PR and the last one is not yet evaluable. The overall median duration of response was 18 months, ranging from 4 to 30 months from the end of therapy. Circulating hairy cells and spleen enlargement, when present, disappeared within 2 weeks after completing treatment. A significant neutropenia was observed in almost all patients mainly in those who had less than 1,000/microliters neutrophils when treatment was started, together with a significant lymphocytopenia which lasted for more than 12 months. The hemoglobin and platelet levels were marginally affected. Fever was observed in 14 patients; in 8 of them it was short-lived (< or = 48 hours) and apparently not infection-related, while in the remaining 6 it was attributed to infection. Clinical tolerance was very good and none of the patients complained of nausea, vomiting or hair loss. In conclusion, our study confirms the efficacy of 2-CdA in HCL, including patients who progressed after treatment with 2-CdA.

Six patients with hairy cell leukemia have been treated with 2-chloro-2'-deoxyadenosine in a dose 0.05 mg/kg/daily in 2 h intravenous infusions during 7 consecutive days. Two patients underwent splenectomy with no clinical or hematologic improvement. Complete remission has been achieved in 4 patients and partial remission in one. 2-CdA was not effective in a patient with HCL-variant. The longest unmaintained CR lasted 11 months. The drug was well tolerated. Only slight side effects were observed. The drug exerted, however, myelosuppressive action resulting in cytopenias in the peripheral blood. Clinical consequences of this activity require further investigation. 2-CdA seems to be a drug of choice in the management of HCL.

Since the introduction of adenosine deaminase analogues the vast majority of patients with Hairy cell leukemia obtain lasting complete remission. In this report we describe our experience with 2 CdA in 18 patients with Hairy cell leukemia (HCL). Ten of these had failed previous interferon therapy, 6 were splenectomized before and of these, 4 had also received interferon. Sixteen of the 18 patients receiving 2 CdA achieved complete remission (CR), 1 patient is in good partial response (GPR) and 1 patient has relapsed. These results are in keeping with those reported from other larger centers and confirm the efficacy of 2-CdA. In this report IL-2 receptor (sIL-2R) levels were performed in most of the patients and found to be an accurate indicator of disease activity. Mean levels prior to therapy were 17200 U/ml (+/- 2500) and after successful therapy 970 U/ml (+/- 160). We confirm that 2-CdA treatment is the treatment of choice in HCL and suggest that sIL-2 levels be used as a parameter of disease activity.

Background: 2-chlorodeoxyadenosine (2-CDA) is a new purine analogue which has been shown to be highly active in lymphoproliferative disorders. In this clinical trial we assessed 2-CDA toxicity and response rate in patients with various haematological malignancies who were heavily pre-treated and mostly refractory to standard treatment regimens., Patients and Methods: Twenty-two refractory patients, 51 relapsing after standard chemotherapy and seven non-pre-treated patients were treated in a non-randomized prospective phase II multicentric study. Their median age was 54 years (range 18-84) and 56 of them were male. Thirty-one had non-Hodgkin's lymphoma (NHL), 11 chronic lymphocytic leukaemia (CLL), 1 prolymphocytic leukaemia (PLL), 13 hairy-cell leukaemia (HCL), 2 mycosis fungoides (MF), 3 multiple myeloma, 7 acute myeloblastic leukaemia (AML), 2 acute lymphoblastic leukaemia (ALL), 6 chronic myeloid leukaemia (CML) in blast crisis, 2 Hodgkin's disease, 1 Waldenström's macroglobulinemia and 1 Langerhans histiocytosis. 2-CDA 0.1 mg/kg/day was given as a continuous intravenous infusion for 7 days and recycled every 4 weeks., Results: One hundred thirty-two courses of 2-CDA were administered to 80 patients, 76 of whom were evaluable for response. A) Toxicity: Myelosuppression: Neutropenia to over 50% of initial value occurred in 46% of patients, thrombocytopenia in 8%, and lymphopenia < 0.5 x 10(9)/l was seen in 41%. Infections occurred in 34/80 patients (43%). The risk of severe infections (WHO grades 3-4) correlated with increasing number of years after first diagnosis (p = 0.01) and low lymphocyte counts on days 1 and/or 14 (p = 0.04); 21 infections were opportunistic. B) Response: 70% patients with lymphoproliferative disorders of low malignancy attained complete or partial response (low-grade NHL 12/16, CLL + PLL 9/12, HCL 13/13, MF 2/2, myeloma 0/3); in patients with AML, ALL, CML in myeloid (n = 4) or lymphoid (n = 2) blast crisis and high-grade lymphoma responses were seen in only 11%. Response was inversely related to the number of pretreatments (p = 0.045). In responding NHL patients the mean lymphocyte count on day 14 of cycle 1 was significantly lower (median 0.6 x 10(9)/l) than that of non-responders (1.2 x 10(9)/l, p = 0.04)., Conclusion: 2-CDA had a high activity even in heavily pretreated and refractory patients with low-grade lymphoproliferative disorders. In contrast to previously published studies, infections, mainly opportunistic, were a serious side effect in our study. In patients with severe lymphopenia at therapy initiation, the value of prophylactic anti-infective treatment should be studied.

2-Chlorodeoxyadenosine (2-CdA), a purine nucleoside, has been shown to be remarkably effective in the treatment of patients with hairy cell leukemia (HCL). We hereby report on the results achieved in 26 HCL patients treated with one single course of 2-CdA at a dose of 0.1 mg/kg daily for 7 days continuous infusion. Twenty-four were males and 2 females, with a median age of 56 years; all but 5 had been previously treated with Interferon-alpha (IFN-alpha). All cases are fully evaluable for their clinical and hematological response. Twenty of them (77%) achieved a complete remission and 6 a partial remission; two of the latter progressed after 6 and 12 months, respectively. The median duration of response was 13.8 months, ranging from 7 to 22 months from the end of therapy. Circulating hairy cells and spleen enlargement, when present, disappeared within 2 weeks after completing treatment; furthermore, a rapid normalization of soluble Interleukin-2 receptor serum levels was observed in all complete responders but one, and in 2 of the 6 partial responders. A significant lymphocytopenia was observed in almost all patients, whilst a severe neutropenia (< 500/microliters) was registered mainly in the 10 patients who had less than 1,000/microliters neutrophils when treatment was started; the hemoglobin and platelets were marginally affected in only a few cases. Eight of the 10 patients who developed severe neutropenia experienced fever; in 4 of them it was short-lived (24 hours) and apparently not infection-related, while the remaining 4 probably had an infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Cladribine (2-chloro-2'-deoxyadenosine) is an adenosine deaminase-resistant analogue of deoxyadenosine. In the treatment of hairy cell leukaemia, cladribine has demonstrated excellent efficacy (complete response in 33 to 92% of patients) in noncomparative studies. Cladribine appears to compare favourably with other systemic agents in this indication as it achieves a high degree of efficacy after a single 7-day course, with an acceptable tolerability profile. However, long term data and direct comparative studies with interferon-alpha and pentostatin (deoxycoformycin) are required to confirm the finite advantages offered by cladribine. Preliminary results obtained in other indications including chronic lymphocytic leukaemia, non-Hodgkin's lymphoma, cutaneous T cell lymphoma, Waldenström's macroglobinaemia and acute myeloid leukaemia in children have been sufficiently encouraging to warrant further study. Early pharmacokinetic data suggest that cladribine may be administered by oral and subcutaneous routes, both of which permit convenient outpatient therapy. Myelosuppression, the dose-limiting toxicity of cladribine, and culture-negative fever are the most common adverse effects associated with therapy. However, cladribine appears to be only rarely associated with many of the other adverse effects that characterise antineoplastic therapy. In the weeks post-treatment, there is a small but definite risk of serious infection; infections with a fatal outcome have been reported in a number of studies with cladribine. In conclusion, preliminary data concerning cladribine have been extremely encouraging. Should early response rates in patients with hairy cell leukaemia be sustained, the efficacy of the drug, together with a short treatment regimen, a favourable tolerability profile, and the possibility of oral therapy, suggest that cladribine is likely to supersede other agents available for this indication.

2-Chloro-deoxyadenosine (CdA) is a new adenosine-deaminase (ADA) resistant purine analogue with high specificity for lymphoid cells. It was shown that CdA is very effective in hairy cell leukemia (HCL), refractory chronic lymphocytic leukemia and cutaneous T-cell lymphoma leading to lasting remissions in the majority of patients with HCL. We report the successful treatment of five patients with HCL at different stages of their disease using CdA, who were either previously untreated or had received interferon, splenectomy and deoxycoformycin (dCF), an ADA-inhibitor with high therapeutic efficacy in HCL. After one 7-day course of treatment, all patients reached remission. CdA was well tolerated and, only mild side effects such as skin rash, headache, fever, nausea were observed. Aplasia was pronounced in all instances with a slow recovery. The type of histomorphological procedure in preparing and evaluating bone marrow biopsies is emphasized to detect minimal residual infiltration by hairy cells.

Objective: To determine whether clinical cross-resistance and intolerance exists between the nucleosides 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) in the treatment of patients with hairy cell leukemia despite similar structures and mechanisms of action., Design: Phase II clinical study., Setting: Referral cancer center., Participants: Five patients with hairy cell leukemia who had been previously treated with DCF., Intervention: Single course of 2-CdA at 0.1 mg/kg body weight per day for 7 days by continuous intravenous infusion., Results: Of five patients, three were resistant to and two were intolerant of (having had life-threatening toxic reactions) DCF therapy. Four patients obtained a complete response with a median follow-up period of more than 11 months. The other patient in whom splenectomy, interferon, and DCF treatments were unsuccessful had a partial response lasting 2 months and subsequently died of Streptococcus pneumoniae bacteremia. Three of the four patients with complete responses remain in unmaintained remission, whereas the fourth has progressive splenic enlargement with stable hematologic parameters. The median leukocyte count increased from 2.0 x 10(9)/L to 3.8 x 10(9)/L, the median absolute neutrophil count increased from 0.56 x 10(9)/L to 2.73 x 10(9)/L, the median hemoglobin level increased from 112 g/L to 140 g/L, and the median platelet count increased from 55 x 10(9)/L to 123 x 10(9)/L. Two patients had culture-negative neutropenic fever associated with treatment., Conclusions: 2-Chlorodeoxyadenosine induced complete responses in patients with hairy cell leukemia resistant to DCF, suggesting a lack of cross-resistance. Also, 2-CdA is not prohibitively toxic in patients intolerant of DCF.

Purpose: This study attempted to characterize the response of previously treated patients with B-cell chronic lymphocytic leukemia (CLL) to the purine analog 2-chloro-2'-deoxyadenosine (CdA) and to assess factors that predict response., Patients and Methods: We treated 18 CLL patients with about-monthly courses of five daily 2-hour intravenous infusions of 0.12 mg CdA/kg., Results: Complete remissions (CRs) were achieved in seven patients (39%), with a total response rate of 67%. CR patients received a median of 4.5 courses. One patient with CR relapsed and died 14 months from start of CdA treatment, whereas the other six patients with CR remain in remission following a mean observation period of 14 months. The median duration of partial remissions (PRs) was 9 months, with a median treatment-free interval of 15 months. Thrombocytopenia was the most common dose-limiting toxicity. Non-responding patients had a median survival of 3.5 months, and systemic fungal infections were the most common cause of death. Immunoglobulin (Ig) levels improved significantly in hypogammaglobulinemic patients during CdA treatment. Responses were predicted by a rapid decrease of blood lymphocyte counts following the first treatment course., Conclusion: A high CR rate was achieved with limited toxicity. A treatment strategy to enable high-quality response and limitation of treatment-related toxicity is provided.

Purpose: We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses., Patients and Methods: Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis., Results: Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness., Conclusion: The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

Objective: To evaluate the activity of 2-chlorodeoxyadenosine (2CdA) in the treatment of patients with Waldenstrom macroglobulinemia., Design: Uncontrolled phase II trial., Setting: Tertiary, referral cancer center., Patients: Twenty-nine consecutive, symptomatic patients with Waldenstrom macroglobulinemia, of whom 9 were previously untreated., Intervention: 2-Chlorodeoxyadenosine was administered as a continuous intravenous infusion at a dose of 0.1 mg/kg body weight per day for 7 days. Only two courses of 2CdA were given and responding patients were then followed without further treatment., Measurements and Main Results: A total of 17 (59%) patients responded, including all of those who were newly diagnosed and 40% of those who had failed previous therapies. Treatment was well tolerated except for one death in a patient who had presented with severe pancytopenia. With a median follow-up of 7 months, only one responding patient has relapsed., Conclusion: 2-Chlorodeoxyadenosine is a nucleoside analog that was effective in most patients with Waldenstrom macroglobulinemia and was associated with little toxicity.

2'-Chlorodeoxyadenosine (2CDA) is a purine analogue selectively active against both resting and dividing lymphoid cells. Twenty-one patients with a variety of previously treated lymphoid malignancies received a total of 41 courses of 2CDA (0.1-0.15 mg/kg/day over 7 days continuous intravenous infusion) on compassionate grounds. The profile of the patient population was as follows: low grade non-Hodgkin's lymphoma (NHL) = 8, intermediate grade NHL = 2, transformed (intermediate grade NHL) = 6, Hodgkin's disease = 1, lymphoplasmacytoid NHL = 3 and lymphoblastic NHL = 1. The overall response rate was 53%, with three patients attaining complete remission (CR) and eight partial remission (PR). Three of 16 patients with primary resistant or resistant recurrent disease entered either CR (1) or PR (2). Ten patients had no response or progressive disease. The latter group was comprised of patients who had extensively pre-treated lymphoplasmacytoid tumours and/or poor performance status (WHO grades 2-4). The median duration of response is 6 months (range 1 to 12 months). Treatment was well tolerated and the chief toxicities were leucopenia and thrombocytopenia which were most pronounced when there was bone marrow involvement. As a result of dose limiting myelotoxicity, a dose escalation to 0.15 mg/kg/day was possible on just three occasions. These data confirm other reports of the activity of 2CDA in low grade NHL and indicate it may have activity in Hodgkin's disease. There was no demonstrable activity in poor performance status patients or those with extensively pre-treated lymphoplasmacytoid tumours.

Sixty-eight patients with Waldenstrom's macroglobulinemia were treated either with fludarabine (28 patients) or 2-chlorodeoxyadenosine (40 patients) and responding patients were followed without further treatment. Both programs were well tolerated and myelosuppression was moderate but reversible. Overall, 35 patients responded including 93% of previously untreated patients, 83% of those relapsing off therapy, 48% of patients with primary refractory disease and 15% of those treated during refractory relapse. With a median follow up of 18 months, only two of 15 previously untreated patients have relapsed whereas the median remission duration and survival of previously treated patients were 38 and 43 months respectively. Fludarabine and 2-chlorodeoxyadenosine are both highly active agents against Waldenstrom's macroglobulinemia, especially when administered early in the disease course.