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.     

Cladribine in combination with mitoxantrone and cyclophosphamide(CMC) in the treatment of heavily pre-treated patients with advanced indolent lymphoid malignancies

The aim of our study was to determine the effectiveness and toxicity of combined chemotherapy consisting of cladribine (2-chloro-deoxyadenosine, 2-CdA), mitoxantrone and cyclophosphamide (CMC regimen) in the treatment of refractory or relapsed indolent lymphoproliferative disorders. The treatment course consisted of 2-CdA given at a dose of 0.12 mg/kg/24 h in a 2-h intravenous infusion for 5 (CMC5) or 3 (CMC3) consecutive days, mitoxantrone 10 mg/m2 on day 1 and cyclophosphamide 650 mg/m2/iv on day 1. Thirty-three patients (19 with B-CLL and 14 with LG-NHL) entered the study and all of them were eligible. Twenty patients (60.6%) were recurrent after prior therapy and 13 (39.4%) had refractory disease. All patients received 5 or more cycles of chemotherapy before CMC treatment. Twenty-one patients were treated with CMC5 regimen and 12 with CMC3 regimen. The overall response rate, including CR and PR, was 48.6% (95% CI 32-66). There were no differences in the frequency of responses between the CMC3 and CMC5 treated groups (p>0.05). One patient with B-CLL and three patients with lymphocytic lymphoma achieved CR (12.1%). Among 12 patients (36.4%) who achieved PR there were 6 CLL patients, and 6 lymphoma patients. The major toxicity was myelosuppression. Severe neutropenia was seen in 11/33 (33.3%) patients, more frequently in patients who received CMC5 than in the patients who received CMC3, both in the CLL (50.0% and 28.5%, respectively) and in the LG-NHL group (22.2% and 0%, respectively). The rate of thrombocytopenia was similar in both groups. Infections and fever of unknown origin complicated the treatment with CMC5 more often than with CMC3: five episodes were seen in 3 patients treated with CMC3 when compared to 15 episodes in 12 patients treated with CMC5. In conclusion, the CMC programme is an active combined regimen in heavily pre-treated CLL and LG-NHL patients. However, its toxicity is significant and we suggest a shortening of 2-CdA infusion from 5 to 3 d in further studies. Whether a combination of 2-CdA with cyclophosphamide and mitoxantrone would result in improved outcome as compared to 2-CdA alone, is being investigated in a prospective, randomised trial.     

Cladribine combined with cyclophosphamide is highly effective in the treatment of chronic lymphocytic leukemia

The aim of the study was to evaluate the activity and toxicity of cladribine (2-CdA) in combination with cyclophosphamide (CY), the CC schedule, in patients with previously untreated B-cell chronic lymphocytic leukemia (B-CLL). From November 1998 to May 2002 82 patients with advanced or progressive B-CLL received treatment with 2-CdA at a dose of 0.12 mg/kg for three consecutive days and CY at a dose of 650 mg/m(2) on day 1. The cycles were repeated at four week intervals or longer if severe myelosuppression occurred. Guidelines for the evaluation of response and toxicity were those developed by the National Cancer Institute sponsored Working Group. Minimal residual disease (MRD) was detected by immunophenotyping only in patients with CR by standard criteria. In the analysed group an overall response (OR) rate (CR+PR) of 87.8% (95% CI 80.7-94.9%) was achieved, including complete response (CR) in 29.3% patients (95% CI 19.4-39.1%). Twenty-two of 24 patients with CR and 39 of 48 patients with PR are still in remission. Median duration of follow-up in these patients is 11.8 months (range 3-25.4). MRD was only detected in six out of 24 (25%) patients with CR. Grade III/IV thrombocytopenia was seen in four patients (4.9%) and neutropenia in 10 (12.2%). Severe infections were noted in 21 (25.6%) patients. Thirteen patients died, including seven with treatment related toxicity, one because of CLL progression and five because of reasons not related to CLL. In conclusion, the CC schedule is a highly active regimen in previously untreated B-CLL, with acceptable toxicity. The efficacy of the regimen seems to be higher than observed earlier after treatment with 2-CdA alone. A randomized clinical trial is in progress in our institutions.     

Relapse of hairy cell leukemia after 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University experience

Although 2-chlorodeoxyadenosine (2-CdA) is effective in inducing complete remissions (CRs) in the majority of patients with hairy cell leukemia (HCL), neither the actual relapse rate, the clinical factors that may predict relapse, the long-term outcome, nor the response rate to re-treatment at relapse has been clearly determined. Fifty-two consecutive patients with previously untreated or treated HCL were treated with 2-CdA at a dose of 0.1 mg/kg/d by continuous intravenous infusion for 7 days. Of 50 assessable patients, 40 (80%) achieved CR, and 9 (18%) achieved partial remission (PR). A total of 7 patients (14%) have relapsed, at a median duration of 24 months (range, 12 to 44). Of the 7 relapsed patients, 5 were re-treated with a second cycle of 2-CdA; 2 achieved a second CR and 3 attained a PR. The progression- free survival (PFS) rate is 72% at 4 years for all 52 patients and 83% for patients achieving CR. The overall survival (OS) rate is 86% at 4 years. Only prior therapy was predictive of relapse. The majority of patients achieve durable CRs with a single cycle of 2-CdA. The relapse rate is low and the long-term prognosis is excellent. The few patients who relapse can attain second remissions after re-treatment with 2-CdA.     

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)     

A single cycle of 2-chlorodeoxyadenosine results in complete remission in the majority of patients with hairy cell leukemia.

Twenty-six patients with hairy cell leukemia (HCL) were treated with 2-chlorodeoxyadenosine (2-CdA), a purine analogue resistant to adenosine deaminase, at 0.1 mg/kg/d for 7 days by continuous intravenous infusion. Fifteen patients were previously untreated, while 11 patients had received prior treatment with splenectomy alone (three patients), interferon alpha alone (four), splenectomy, then interferon alpha (two), or splenectomy, interferon alpha, then 2-deoxycoformycin (2-DCF) (two). Sixteen (80%) of 20 patients evaluable at 3 months achieved complete remission (CR), and four (20%) achieved partial remission (PR) following a single cycle of therapy. All four patients in PR had complete recovery of their peripheral blood counts (except one patient whose platelet count remained 84,000/microL), but had residual HCL in the bone marrow (three patients) or residual splenomegaly (one). Patients with bulky adenopathy, massive splenomegaly, and severe pancytopenia responded as well as those with only modest marrow involvement. The three patients with residual marrow disease received a second cycle of 2-CdA, and two have attained CR. Therefore, 18 of 20 (90%) achieved CR with either one or two cycles of therapy. No patient achieving CR has relapsed at a median follow-up of 12 (+/- 2.1) months. Toxicities included myelosuppression and culture-negative fever. A community-acquired pneumonia was the only infectious complication. Since a single cycle of 2-CdA induces sustained CR in the vast majority of patients with minimal toxicity, this agent is emerging as the treatment of choice for all patients with HCL.     

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

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.     

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.     

Long-term outcome of hairy cell leukemia treated with 2-chlorodeoxyadenosine

 The long-term results of both pretreated and previously untreated patients with hairy cell leukemia (HCL) using uniformly a single 7-day course of 2-chlorodeoxyadenosine (2-CdA) by continuous infusion are reported. In addition, the probability of obtaining another response with this drug in patients who relapsed after 2-CdA treatment will be addressed. Forty-two consecutive patients (32 men, 10 women) with a median age of 56 years (range 32–75) at the time of initiation of 2-CdA treatment were analyzed. Ten patients were pretreated with either splenectomy (n=6) or interferon a (n=8) or deoxycoformycin (dCF) (n=3) or with all procedures in sequence. Two patients who did not respond to dCF did respond to 2-CdA. Median time to start of 2-CdA treatment of the ten pretreated patients was 47 months (10–160); 41 of the 42 (98%) achieved CR, and one patient reached a good partial response with a single cycle of 2-CdA. Ten of the 42 patients had no toxicities at all. Toxicities (WHO grades I–IV) were mainly of grades I and II; in one patient with a preexisting brain injury grade III neurotoxicity was seen, and one patient suffered a grade-IV infectious complication. Bone marrow biopsies were performed at the time of recovery of hematopoiesis, thereafter at 2- to 3-month intervals, then at 6 months, and finally annually in all 42 patients. Median follow-up is 32 months (2–72). Disease-free survival from start of 2-CdA treatment is 75% at 6 years; 6/42 patients relapsed. Three of these patients were treated with 2-CdA again. All three patients reached another CR (+1, +2, +13). Four of the 42 patients had a second malignancy (carcinomas of the bladder, breast, cervix, prostate gland) before receiving 2-CdA. One patient died in CR due to the second malignancy. 2-CdA is a safe and effective treatment of HCL, inducing complete remissions in the majority of patients with only a single cycle of 2-CdA and a paucity of toxities. Responses are durable and long lasting. Patients relapsing following a treatment with 2-CdA seem to respond to this drug again. Received: July 30, 1998 / Accepted: October 26, 1998     

Effect of a 2-hour infusion of 2-chlorodeoxyadenosine in the treatment of refractory or previously untreated Waldenström's macroglobulinemia

2-Chlorodeoxyadenosine (2-CdA) is a new purine analogue active in indolent lymphoid malignancies. In this retrospective study 22 patients with Waldenström's macroglobulinemia (MW) were treated with 2-CdA given in 2-h intravenous infusions. Nine of them were untreated and 13 relapsed or were refractory to previous therapeutic modalities with chlorambucil/prednisone (11 patients) or COP (2 patients). The patients were given 1–11 (median 4) courses of 2-CdA at the dose of 0.14 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. The courses were repeated every 28–35 d. If severe myelosuppression or infection developed, 2-CdA therapy was stopped until the haematological parameters increased. The effectiveness of the treatment was evaluated after the 3 cycles and after completion of therapy. None of the patients has achieved complete response (CR) after 3 courses of treatment and only one (4.5%) has obtained CR after 5 courses. Partial response (PR) was achieved in 8 (36.4%) patients, giving an overall response rate of 40.9%. Ten further patients (45.4%) responded to the treatment with less than 50% decrease in monoclonal protein (defined as stabilisation). There was no significant difference between the response rate in previously pretreated (38.5%) and untreated (44.4%) patients (p >0.05). Mean observed decrease in monoclonal protein was 41%. In the group of 9 patients responding to 2-CdA treatment mean duration of response was 12 months (range 3–34). Myelosuppression was the most prominent side-effect. Neutropenia was present in 17 (77.3%) and thrombocytopenia in 7 (31.8%) patients. In 6 patients myelosuppression was the reason for treatment discontinuation after 1 or 2 courses without significant therapeutic effect. Seven patients died, including 4 from the responding group and all three non-responding patients. Treatment-related thrombocytopenia and fatal haemorrhage was the course of death in 1 patient. In conclusion, the results of our study show that 2-CdA given in 2-h infusions is an effective agent in WM and may be given on an outpatient basis. However, myelosuppression is frequent and the drug must be administered with caution.     

2-Chlorodeoxyadenosine in the treatment of relapsed/refractory chronic lymphoproliferative disorders

Abstract: 2-Chlorodeoxyadenosine (2-CdA) is a purine analog with cytotoxic activity on both resting and cycling lymphocytes which has been used as salvage therapy in advanced/resistant chronic lymphoproliferative disorders. In our study 39 patients (19 B-CLL, 5 B-PLL, 9 low-grade B-NHL, 5 CTCL and 1 high-grade T-NHL) who relapsed or became resistant after 1–4 chemotherapy regimens were treated with 2-CdA 6 mg/m² per day by 2 h infusion for 5 d every 28 d. The overall clinical response rate, including complete remission (CR) and partial remission (PR), was 66%. Two of 19 (10%) B-CLL patients achieved a CR lasting 9 months, while 11/19 B-CLL (58%) and 4/5 B-PLL (3 B-PLL/B-CLL and 1 B-PLL) (80%) achieved a PR. Interestingly, 5 of 6 patients who had been previously treated with fludarabine obtained a clinical response (2 CR and 3 PR). One of 9 (11%) low-grade B-NHL patients achieved a CR and relapsed after 26 months, and 5/9 (55%) achieved a PR. One of 5 (20%) CTCL achieved a CR lasting 32 months, while 2/5 (40%) achieved a PR. The overall mean duration of PR was 7.4 months and no differences were observed among different groups of patients. Toxicity was acceptable, as only a transient severe hematological impairment was observed in 20% of the patients while nonhematological toxicity was not documented. Two patients died because of bacterial pneumonia, 1 of meningitis due to Listeria and 9 from progression of the disease. In conclusion, treatment with 2-CdA in heavily pretreated patients with chronic lymphoproliferative disorders is well tolerated and obtains high response rates, even in patients relapsed after treatment with fludarabine.     

Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic,untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712)

Recent studies have suggested that rituximab has clinical activity and modulates antiapoptotic proteins associated with drug resistance in chronic lymphocytic leukemia (CLL). We performed a randomized phase 2 study to determine the efficacy, safety, and optimal administration schedule of rituximab with fludarabine in previously untreated CLL patients. Patients were randomized to receive either 6 monthly courses of fludarabine concurrently with rituximab followed 2 months later by 4 weekly doses of rituximab for consolidation therapy or sequential fludarabine alone followed 2 months later by rituximab consolidation therapy. A total of 104 patients were randomized to the concurrent (n = 51) and sequential (n = 53) regimens. During the induction portion of treatment, patients receiving the concurrent regimen experienced more grade 3 or 4 neutropenia (74% versus 41%) and grade 3 or 4 infusion-related toxicity (20% versus 0%) as compared with the sequential arm. The consolidation rituximab therapy was tolerated well in both arms. All other toxicities were similar in the 2 arms. The overall response rate with the concurrent regimen was 90% (47% complete response [CR], 43% partial response [PR]; 95% confidence interval [CI], 0.82-0.98) compared with 77% (28% CR, 49% PR; 95% CI, 0.66-0.99) with the sequential regimen. With a median follow-up time of 23 months, the median response duration and survival have not been reached for either regimen. Rituximab administered concurrently with fludarabine in previously untreated CLL patients demonstrates marked clinical efficacy and acceptable toxicity. Phase 3 studies using this combination approach for patients with CLL are warranted.     

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): long-term follow-up of the Northwestern University experience

2-Chlorodeoxyadenosine (2-CdA), a purine analog, has become universally accepted as the agent of choice in treating hairy cell leukemia (HCL). However, few studies have reported long-term outcomes after 2-CdA treatment. Between January 1990 and June 2003, 86 consecutive patients with HCL were treated with a single 7-day course of 2-CdA by continuous infusion at a dose of 0.1 mg/kg per day. Of the 86 patients (mean age: 49 years), 67 patients (79%) achieved a complete remission (CR); 18 patients (21%) achieved a partial remission (PR); and 1 patient's response was unable to be assessed. The progression-free survival (PFS) for initial relapse after 12 years was 54%. At a median follow-up of 9.7 years (range, 0.3-13.8 years), 31 (36%) of 85 patients relapsed. There were 23 relapsed patients treated with a second cycle of 2-CdA; 2 patients were treated with alternative agents; and 6 patients were observed. Of the 23 relapsed patients retreated with 2-CdA, 12 (52%) achieved a CR and 7 (30%) patients achieved a PR (overall response rate: 83%). The overall survival (OS) rate after 12 years was 87%. There were 15 patients (17%) who developed other malignancies. Long-term follow-up of up to 14 years (median: 9.7 years) showed an excellent PFS and OS for HCL patients after 2-CdA treatment.     

Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma [see comments]

We investigated the efficacy of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF) and the Sezary syndrome (SS). Between February 1991 and November 1993, 21 patients with relapsed or refractory MF/SS were treated with 2-CdA. 2-CdA was administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days initially (13 patients), but was subsequently reduced to 5 days (nine patients) due to hematologic toxicity. All patients had failed to respond to at least one prior treatment for MF/SS (median number of total prior therapies, five; median number of systemic prior therapies, three) and had an Eastern Cooperative Oncology Group performance status of two or better. Cycles were administered at 28-day intervals. Assessable patients received at least 5 days of 2-CdA. Fourteen patients received more than one cycle of 2-CdA. An overall response rate of 28% was achieved. Three patients (14%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (14%) had a partial response with a median duration of 2 months (range, 2 to 4). Fifteen patients (72%) had no response. The most significant toxicities encountered were bone marrow suppression (62% of patients) and infectious complications (62% of patients). Thirty-eight percent of patients experienced no toxicity from 2-CdA. 2-CdA has activity as a single agent in patients with previously treated relapsed MF/SS. Studies in less heavily pretreated individuals with 2-CdA alone or in combination will be undertaken.     

A multicenter, open, noncomparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, granulocyte colony-stimulating factor and mitoxantrone as induction therapy in refractory acute myeloid leukemia: a report of the Polish Adult Leukemia Group

Purine nucleoside analogues, cladribine (2-chlorodeoxyadenosine, 2-CdA) and fludarabine (FAMP) are active agents in acute myeloid leukemias (AMLs). Synergistic interaction between FAMP or 2-CdA with cytarabine (cytosine arabinoside, Ara-C) has been demonstrated in preclinical and clinical studies. The current multicenter phase II study was initiated to evaluate the efficacy and toxicity of induction treatment consisting of 2-CdA (5 mg/m²), Ara-C (2 g/m²), mitoxantrone (MIT, 10 mg/m²) and granulocyte colony-stimulating factor (G-CSF) (CLAG-M) in refractory AML. In case of partial remission, a second CLAG-M was administered. Patients in complete remission (CR) received consolidation courses based on high-dose Ara-C and MIT with or without 2-CdA. Forty-three patients from five centers were registered: 25 primary resistant and 18 relapsed. CR was achieved in 21 (49%) patients, 20 (47%) were refractory and 2 (5%) died early. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS; 1 year) for the 42 patients as a whole and the 20 patients in CR were 43% and 73%, respectively. Disease-free survival (1 year) was 68.6%. None of the analyzed prognostic factors influenced the CR and OS probability significantly. We conclude that CLAG-M regimen has significant antileukemia activity in refractory AML, which seems to be better than the activity of many other regimens. The toxicity of the treatment is acceptable.     

Role of interferon-alpha administration after 2-deoxycoformycin in the treatment of hairy cell leukemia patients

BACKGROUND AND OBJECTIVE: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder which is treated effectively by interferon-alpha (IFN-alpha), deoxycoformycin (DCF) and 2-clorodeoxyadenosine (2-CdA). As a third of patients treated with DCF do not achieve a complete remission (CR) and many of them tend to relapse, we evaluated the potential role of IFN-alpha, randomly administered after DCF, in increasing the number of patients attaining CR and/or duration of CR. METHODS: From March 1997 to December 2000, 167 previously untreated HCL patients, from 37 Italian institutions, were enrolled in the study. A total of 138 males and 29 females, with a median age of 55 yr were included in the study. All patients received six courses of DCF 4 mg/m(2) i.v. every other week and then two additional courses once a month. Complete and partial responders were randomly assigned to receive or not receive IFN-alpha at a dose of 3 MU s.c. three times a week for 6 months. RESULTS: Of the 167 patients enrolled in the study, 145 (86.8%) obtained a CR or a partial remission (PR) and were therefore suitable for randomization. One hundred and thirty-five patients were successively randomized to receive IFN-alpha (63 cases; arm A) or not (72 cases; arm B). Progression of disease was observed in eight (arm A) and 12 (arm B) patients with a median time of 27.8 and 26.9 months, respectively. As far as the improvement in response was concerned, no significant difference in the two subgroups was observed. In fact, five patients in arm A and six patients in arm B showing a good PR at the end of DCF therapy, subsequently attained a late CR. CONCLUSIONS: From our data there does not appear to be any significant role for IFN-alpha in improving the proportion and the duration of CR in HCL patients previously treated with DCF.     

Long-term follow-up of hairy cell leukemia patients treated with 2-chlorodeoxyadenosine

BACKGROUND AND OBJECTIVES: The management of patients with hairy cell leukemia (HCL) has evolved significantly over the past two decades. In fact, both 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) induce complete response (CR) in the majority of the patients with HCL. However, fewer data exist on the long-term follow-up of patients who have undergone the characteristically brief exposure to 2-CdA therapy. Thus, it is important to evaluate such long-term outcome data in order to increase understanding of the efficacy of this agent in the management of HCL. DESIGN AND METHODS: We reviewed the long-term follow-up data of 23 HCL patients pretreated with a-interferon and then treated with 2-CdA administered as a single continuous IV infusion for 7 days at the dose of 0.1 mg/kg/day in our institute between January 1991 and February 1992. RESULTS: Of 23 patients, 19 (83%) achieved a CR and 4 (17%) a partial response (PR), with an overall response rate of 100%. After a median follow-up of 102 months (range: 96-108), there have been 9 (39%) relapses. In the PR subset 100% of patients relapsed within the first 45 months of follow-up. In the group of patients who obtained a CR, 26% relapsed; all these relapses occurred between 54 and 86 months. Overall, the median time to relapse was 54 months (range: 16-86). All relapsed patients were re-treated with 2-CdA at the dose of 0.15 mg/kg/day for 5 days in a 2-hour infusion, and 67% and 22% then obtained CR or PR, respectively. The median duration of this second response was 48 months (range: 22-80). All but one of these patients are still maintaining the second response to 2-CdA. The 9-year overall and the relapse-free survivals are 91% and 70%, respectively. INTERPRETATION AND CONCLUSIONS: In HCL patients a single dose of 2-CdA induces a long-term CR with a 9-year survival > 90%. Over 50% of patients appear to be clinically cured by this procedure, but the lack of a long-term plateau in the relapse-free survival curve means caution on this point is still warranted.     

Fludarabine treatment in B-cell chronic lymphocytic leukemia: response, toxicity and survival analysis in 47 cases

BACKGROUND AND OBJECTIVE: Fludarabine monophosphate (FAMP) is a purine analog with specific therapeutic activity in B-cell chronic lymphocytic leukemia (CLL). Its current use as front-line therapy of CLL is still a matter of debate both because of the controversial results of the clinical trials so far reported and because of the toxicity profile of the drug. In order to contribute to clarifying the possible role of FAMP, we report a retrospective analysis of the results obtained with the purine analog in CLL patients in different phases of the disease. DESIGN AND METHODS: Forty-seven patients affected by advanced CLL, 36% untreated, 31.9% relapsed and 31.9% resistant, were treated with FAMP 25 mg/m2/day, either for 4 days every 3 weeks in 29 cases, or for 5 days every 4 weeks in 18.The median number of FAMP cycles was 6 (range 2-11). Response was defined according to total tumor mass (TTM) score reduction and toxicity was expressed according to WHO grading criteria. The median follow-up of the series was 13 months from the beginning of FAMP therapy. RESULTS: Out of 47 evaluable patients the response rate was 74.4%, with 34% complete response (CR). The overall response rate was 94%, 80% and 46.6% in untreated, relapsed and resistant cases, respectively; a significantly higher number of responses was associated with no previous treatment and number of FAMP cycles. Fifty-three percent of all cases and 58.8% of untreated ones did not experience any toxicity. Treatment-related side effects were mainly autoimmune phenomena in untreated patients and infectious complications in treated ones. One heavily pre-treated patient died because of neurologic complications. Median time to re-treatment was18 months (range 1-30) and was influenced by age and previous treatment. The overall median survival was 35.7 months with a significantly higher proportion of surviving cases among RAI 0-II stages, responders and patients receiving more than 5 FAMP cycles. INTERPRETATION AND CONCLUSIONS: The present report confirms the high efficacy of FAMP in previously pre-treated cases with acceptable toxicity and encourages its use as front-line treatment provided that the results of randomized trials demonstrate its superiority over conventional chemotherapy. The possible development of autoimmune phenomena should, however, be considered seriously.     

Cladribine decreases the level of angiogenic factors in patients with chronic lymphocytic leukemia

We investigated the serum concentration of basic fibroblast growth factor (bFGF) and transforming growth factor beta1 (TGFbeta1), using an enzyme linked immunosorbent assay (ELISA) in a group of 18 chronic lymphocytic leukemia (CLL) patients, before and after a successful treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA) and 16 healthy volunteers. The serum level of bFGF was found to be significantly lower in the control group (median 0.15 pg/ml, range 0.0-15.7 pg/ml), when compared to the untreated CLL patients (median 41.4 pg/ml, range 2.1-292.6 pg/ml) (p=0.0002). After a successful 2-CdA treatment we observed a significantly lower level of this cytokine (median 10.55 pg/ml, range 0.4-140.4 pg/ml) (p=0.0019) in the same patients. However, the level of bFGF in this group was still higher than in the control group (p=0.003). The levels of TGFbeta1 were higher in the group of untreated CLL patients (median 31.36 ng/ml, range 14.36-75.71 ng/ml) than in the control group (median 28.35 ng/ml, range 10.85-70.10 ng/ml) (p=0.029). After the 2-CdA treatment serum concentration of this cytokine decreased significantly (median 20.34 ng/ml, range 3.02-43.85 ng/ml) (p=0.031) with similar levels present to that of the healthy control group (p=0.3). In conclusion, we have shown that the serum concentration of bFGF and TGFbeta1 in CLL patients were significantly reduced after 2-CdA chemotherapy that resulted in remission. The level of these factors might correlate with the activity of the disease.     

The role of 2-chlorodeoxyadenosine in the treatment of patients with refractory angioimmunoblastic lymphadenopathy with dysproteinemia

Treatment of patients with angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD) often constitutes a challenge for the clinical haematologist. Single-agent and combination chemotherapy have failed to increase the response rate or survival of patients with AILD. A total of seven patients with refractory or relapsed AILD were treated with 2-chlorodeoxyadenosine (2-CdA) for variable number of cycles. The overall response rate was 57% with two patients (28.5%) achieving complete and sustained response. 2-Chlorodeoxyadenosine appears to be an active agent for patients with previously treated AILD. Phase II studies evaluating the efficacy of this agent as front-line treatment for AILD are justified, especially in the absence of any effective therapy for this disorder.