Phase II study of 2-chlorodeoxyadenosine in combination with chlorambucil in previously untreated B-cell chronic lymphocytic leukemia.

The objective was to determine the safety and efficacy of adding a maximally tolerated dose of 2-chlorodeoxyadenosine (2-CdA) to standard chlorambucil (CLB) therapy in previously untreated B-cell chronic lymphocytic leukemia (CLL). Thirty patients with CLL (median age, 64 years) received two courses of 2-CdA given intravenously (2 mg/m2 daily for 7 days) added to biweekly administration of CLB at 30 mg/m2 given orally. The diagnosis of CLL, treatment indications, and response criteria were according to the National Cancer Institute established guidelines. Sixteen patients (53%) had advanced-stage disease, and four (13%) had trisomy 12 abnormality. The overall remission rate was 80%, including 20% complete remission (CR), 30% nodular partial remission (nPR), and 30% partial remission (PR). Minimal residual disease was detected phenotypically in two of five patients with CR and in eight of nine with nPR. Overall, CR, nPR, and PR rates were not influenced significantly by the presence of cytogenetic abnormalities or advanced clinical stage. With a median follow-up of 33 months, 58% of patients who had a response had relapse. Median time to progression in all 30 patients was 30 months, and time to progression and progression-free survival were not significantly different for the different response groups, clinical stages, or cytogenetic groups. Severe neutropenia and thrombocytopenia occurred in 33% and 7% of patients, respectively. Only two patients had documented bacterial infections, and four had herpetic infections. Concurrent combination chemotherapy with abbreviated doses of 2-CdA and standard-dose CLB is feasible and safe in previously untreated CLL. Antitumor activity may be superior to that of CLB alone given in conventional doses. Whether a different schedule of combining these two agents would result in improved outcome is being investigated.     

Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma

BACKGROUND: The combination of fludarabine, cyclophosphamide, and rituximab (FC-R) shows significant in vitro synergism and may improve patient outcome with little overlapping toxicity. METHODS: Between December 2000 and June 2005, 77 patients completed therapy after a median of 4 cycles of FC-R (fludarabine at a dose of 25 mg/m2 intravenously [i.v.] on Days 1-3, cyclophosphamide at a dose of 250 mg/m2 i.v. on Days 1-3, and rituximab at a dose of 375 mg/m2 on Day 1). The median age of the patients was 59 years, 65% were male; 31% had previously untreated disease; and 44% had chronic lymphocytic leukemia (CLL), 29% had follicular lymphoma, and 27% other indolent lymphoid malignancies. In addition to standard disease response criteria, patients underwent evaluation using flow cytometric and/or molecular studies. RESULTS: Objective responses (OR) and complete responses (CR) were observed in 83% and 42%, respectively, of evaluable patients (n=76), respectively. For patients with CLL, the respective OR and CR rates were 100% and 67% as firstline therapy, and 95% and 14% as salvage therapy. For patients with follicular lymphoma, the respective OR and CR rates were 100% and 86% as firstline therapy, and 87% and 67% as salvage therapy. Responders who had no detectable disease on flow cytometric and/or molecular studies experienced prolonged remissions with no recurrences reported at a median 25 months of follow-up. Peripheral stem cell collection using stem cell factor plus granulocyte-colony-stimulating factor was successful in 10 of 13 patients who underwent mobilization (77%). CONCLUSIONS: FC-R is highly active as initial or salvage therapy in patients with CLL or indolent non-Hodgkin lymphoma. Collection of autologous stem cells during molecular remission is feasible and may facilitate future exploration of high-dose therapy in these patients.     

Reduced-dose cladribine (2-CdA) plus mitoxantrone is effective in the treatment of mantle-cell and low-grade non-Hodgkin's lymphoma

Cladribine (2-chlorodeoxyadenosine) (2-CdA) has been shown to be effective in mantle-cell (MCL) and low-grade lymphomas (lgNHL). The aim of this multicentre study was to evaluate the rate and duration of remissions and to examine the toxicity of the combination of reduced-dose 2-CdA and mitoxantrone (CdM) in MCL and lgNHL as first-line therapy or for patients in their relapse. A total of 285 courses, median of five courses per patient, were administered to 62 evaluable patients (42 previously untreated, 20 relapsed) with 5 mg/m(2) 2-CdA per day given as an intermittent 2-h infusion over 3 consecutive days combined with 8 mg/m(2) mitoxantrone on days 1 and 2 for the untreated patients or 12 mg/m(2) mitoxantrone on day 1 for patients in their first relapse for a maximum of six cycles every four weeks. 32 follicular, 18 MCL, 9 lymphoplasmacytoid, 2 marginal zone and 1 unclassified low-grade B-cell lymphoma were involved in the study. 56 of the 62 patients responded to CdM resulting in an overall response rate of 90% (95% confidence interval (CI), 80-96%) with a complete remission (CR) rate of 44% (95% CI, 31-57%) and a median duration of remission of 25 months (range 6-42+). The overall survival rate at 48 months was 80%. For 42 previously untreated patients, the overall response rate was 88% (95% CI, 74-96%) with a CR rate of 38% (95% CI, 24-54%), whereas the response rate for the group of 20 previously treated patients was similar with a 95% overall response (95% CI, 75-100%) and a CR rate of 55% (95% CI, 32-77%). In MCL, CdM showed a high activity, achieving a response rate of 100% (95% CI, 81-100%) with a CR rate of 44% and a median duration of remission of 24 months (range 6-35+). Myelosuppression was the major toxicity with 23% grade 3 granulocytopenia and 50% grade 4. Thrombocytopenia was less commonly observed, with only 8% grades 3 and 4. These results demonstrate that the combination of reduced-dose 2-CdA and mitoxantrone is a highly active regimen in the treatment of low-grade lymphomas, and in particular of MCL.     

Combination chemotherapy with the M-2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone) for chronic lymphocytic leukemia (stages III and IV)

The M-2 protocol was administered every 5 weeks to 25 patients with stage III and IV chronic lymphocytic leukemia (CLL). Complete remission (CR; absence of all clinical and bone marrow evidence of leukemia including normal immune markers for monoclonal disease) and partial remission (PR; greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 X 10(6)/l) were achieved in 20 and 48%, respectively. A median number of 24 cycles of therapy was required to produce a CR. The median duration of unmaintained remission was 12 months. All CR patients are still surviving. The median survival of the PR patients and the overall groups is 21 months. To improve the CR rate and survival in patients with advanced CLL, more effective methods of determining residual leukemic cells and different treatment strategies will be needed.     

Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter's syndrome.

Approximately 3 to 5% of patients with chronic lymphocytic leukemia (CLL) develop an aggressive large cell non Hodgkin's lymphoma (NHL) known as Richter's syndrome (RS). RS has a poor prognosis and a response rate of < 10% with fludarabine-based or other cytotoxic combination regimens. The aim of this study was to evaluate the efficacy and toxicity of the hyperCVXD regimen in RS. Twenty-nine patients, median age 61 years (36-75) 23 males, were treated. Prior diagnosis was CLL in 26 patients, NHL in 2, and Prolymphocytic leukemia in 1. Treatment consisted of fractionated cyclophosphamide, vincristine, daunoXome and dexamethasone. Six patients (20%) died while receiving study therapy, 4 (14%) during the first cycle of whom 2 had started therapy with overt pneumonia. Grade 4 granulocytopenia occurred in all 95 cycles of therapy with a median time to recovery of 14 days. Twenty three (24%) cycles were complicated by fever, and 15 (15%) by pneumonia. Sepsis was documented in 8 (8%) cycles, and neuropathy in 5 (5%) of cycles. Twenty three patients had a platelet count < 100 x 10(9)/l prior to therapy: a greater than 50% decrease in platelet count over pre-therapy level occurred in 79% of first cycles, overt bleeding occurred in 4 (4%) of all cycles. Eleven of 29 (38%) patients achieved complete remission (CR), 4 of whom have relapsed after 5, 6, 9, and 12 months of remission. Two of 11 CR patients presented with RS without any prior CLL therapy. One patient had a partial remission. Thus the overall response rate was 12/29 (41%). Overall median survival was 10 months, 19 months in patients who achieved CR, 3 months in those who did not (p = 0.0008). A landmark analysis performed at 2 months from start of therapy comparing patients alive in CR versus patients alive but not in CR showed a median survival of 19 months versus 6 months, respectively (p 0.0017). In conclusion the hyper CVXD regimen has a relatively high response rate, significant toxicity and a moderate impact on survival in RS.     

Fludarabine and mitoxantrone for patients with chronic lymphocytic leukemia

BACKGROUND: The objective of the current study was to assess the efficacy of combination therapy with fludarabine and mitoxantrone in patients with B-cell chronic lymphocytic leukemia (CLL). METHODS: Eighty-eight patients were treated with fludarabine 30 mg/m(2) intravenously daily for 3 days and mitoxantrone 10 mg/m(2) on Day 1 (FN). Patients were divided into four groups based on expected response to single-agent fludarabine. These four groups included previously untreated patients, patients who previously were treated with alkylating agents, patients who were successfully treated with alkylating agents and fludarabine but who developed recurrent disease, and patients whose disease was refractory to fludarabine with or without alkylating agents. RESULTS: The overall response rate was 66%. The response rates were 83% in previously untreated patients, 87% in patients previously treated with alkylating agents, 50% in patients whose disease was not refractory to fludarabine at the start of therapy, and 25% in patients whose disease was refractory to fludarabine. The complete remission (CR) rate was 20% for previously untreated patients, which was not significantly different from the CR rate for a group of historical control patients who were treated with single-agent fludarabine. The median follow-up was 8 years for surviving patients. The median progression free survival was 24 months for all patients and 34 months for previously untreated patients. The median overall survival was 40 months, and the median survival of previously untreated patients was 88 months. The most common toxicities were myelosuppression and infection. Eleven patients (12.5%) developed a second malignancy after a median of 62 months. CONCLUSIONS: The FN regimen did not have a significant advantage over fludarabine alone in the treatment of patients with CLL.     

Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies.

BACKGROUND: This randomized study compared the efficacy and safety of fludarabine-mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m(2) i.v.), days 1-5, plus mitoxantrone (10 mg/m(2) i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m(2) i.v. infusion), doxorubicin (25 mg/m(2) i.v.) and vindesine (3 mg/m(2) i.v.) on day 1, and prednisone (50 mg/m(2)) on days 1-5. RESULTS: FM therapy resulted in superior remission rates (OR 81% versus 64%, CR 49% versus 17%; P = 0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications. CONCLUSION: FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome.     

Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with cladribine: a phase II study.

PURPOSE: As chemotherapy has not been extensively studied in patients with lymphoma of the mucosa-associated lymphoid tissue (MALT), we initiated a prospective study to evaluate the activity of the nucleoside analog cladribine (2-chlorodeoxyadenosine [2-CdA]) in this disease. PATIENTS AND METHODS: Patients with histologically verified MALT-type lymphoma were enrolled. 2-CdA was administered at a dose of 0.12 mg/kg body weight on 5 consecutive days, as a 2-hour infusion. Cycles were repeated every 4 weeks for a maximum of six cycles. RESULTS: Nineteen patients with gastric and seven patients with extragastric MALT lymphoma were enrolled. All patients were chemotherapy-naive, and two had been locally irradiated before systemic relapse of the lymphoma. A total of 102 cycles was administered to our patients (median number of cycles per patient, four). All 25 assessable patients responded to treatment: 21 patients (84%) achieved complete remission (CR) and four patients achieved partial remission. All patients (100%) with gastric presentation, but only three patients (43%) with extragastric presentation, achieved CR. Toxicities were moderate and mainly hematologic and required dose reduction and/or premature discontinuation of therapy in only three cases. Two patients died from vascular events, one shortly after the first cycle because of myocardial infarction and the other from stroke 3 months after the second course. Three patients relapsed after 13, 18, and 22 months and one patient showed progressive disease after 15 months. At present, 24 patients are alive at a median follow-up time of 32 months. CONCLUSION: Our data demonstrate that 2-CdA is highly effective in inducing CR in 84% of patients with MALT-type lymphoma.     

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia.

PURPOSE: The efficacy, toxicity, and tolerability of chemoimmunotherapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) were evaluated in previously treated patients with chronic lymphocytic leukemia (CLL). The purpose of this study was to improve the complete remission (CR) rate for previously treated patients and evaluate the quality of bone marrow response. PATIENTS AND METHODS: One hundred seventy-seven previously treated patients with CLL were evaluated. Treatment consisted of rituximab 375 mg/m(2) day 1 of course 1 and 500 mg/m(2) day 1 of courses 2 to 6; fludarabine 25 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6; and cyclophosphamide 250 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6. Courses were repeated every 4 weeks. RESULTS: CR was achieved in 25% of 177 patients, and nodular partial remission and partial remission were achieved in 16% and 32% of patients, respectively; the overall response rate was 73%. Twelve (32%) of 37 complete responders tested achieved molecular remission in bone marrow. Univariate and multivariate analyses were used to identify pretreatment patient characteristics associated with CR and overall remission, longer time to progression, and overall survival. CONCLUSION: The FCR regimen was an active and well-tolerated treatment for previously treated patients with CLL. Myelosuppression was the most common toxicity. FCR induced the highest CR rate reported in a clinical trial of previously treated patients with CLL. Furthermore, molecular remissions were achieved in a third of patients achieving CR.     

Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia.

PURPOSE: Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities. RESULTS: Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity. CONCLUSION: CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.     

Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia.

PURPOSE: To assess the efficacy of combination therapy with fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) based on data suggesting in vitro synergistic activity of the two agents. PATIENTS AND METHODS: A total of 128 patients with CLL were treated with fludarabine 30 mg/m(2) intravenously daily for 3 days and cyclophosphamide at either 500 mg/m(2) daily for 3 days (n = 11), 350 mg/m(2)/d for 3 days (n = 26), or 300 mg/m(2) daily for 3 days (n = 91). The cyclophosphamide dose was decreased because of myelosuppression in the early part of the study. Patients were divided into four groups based on the expectation for response to single-agent fludarabine, including previously untreated patients, patients previously treated with alkylating agents, patients successfully treated with alkylating agents and fludarabine but relapsing, and patients refractory to fludarabine with or without alkylating agents. RESULTS: Fludarabine and cyclophosphamide produced > or = 80% response rates in all patients not refractory to fludarabine at the start of therapy as well as a 38% response rate in patients who were refractory to fludarabine. The complete remission (CR) rate was 35% in previously untreated patients, which was not significantly different from the CR rate in historical control patients treated with single-agent fludarabine. However, residual disease assessed by flow cytometry occurred in only 8% of previously untreated patients achieving CR, and median time to progression has not been reached after a median follow-up of 41 months. The main complication of therapy was related to myelosuppression and infection. Neutropenia to less than 500 x 10(9)/L was noted in 48% of patients who received cyclophosphamide 300 mg/m(2). Pneumonia or sepsis occurred in 25% of patients, and fever of unknown origin occurred in another 25%. Pneumonia or sepsis were significantly more frequent in patients who were refractory to fludarabine at the start of combination chemotherapy. CONCLUSION: Fludarabine and cyclophosphamide seem to have a significant advantage over single-agent fludarabine in the salvage setting. Although the CR rate was not increased in previously untreated patients, residual disease detected by flow cytometry was rare and remission durations seemed to be prolonged in this subset. Myelosuppression and infection remain the most significant complications of therapy in CLL.     

Cladribine in the treatment of chronic lymphocytic leukemia.

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a nucleoside analog with substituted halogen atom at position 2 in its purine ring that makes it resistant to deamination by adenosine deaminase (ADA). 2-CdA is the drug of choice in the treatment of hairy cell leukemia, but it is also highly active in other low grade lymphoid malignancies including chronic lymphocytic leukemia (CLL). The results of the studies presented so far have shown that 2-CdA gives similar complete response (CR) rate and overall response (OR) rate to fludarabine but the influence of both agents on survival times of the patients with CLL is still uncertain. CR rate induced with 2-CdA is significantly higher than in the patients treated with conventional chemotherapy. In refractory or relapsed patients 2-CdA induces 31 to 68% of overall responses including CR in 4 to 31%. In previously untreated patients overall remission rates of about 56-82% have been achieved with 2-CdA alone. When 2-CdA was used as primary therapy the CR rate was also significantly higher and ranged from 10% to 47%. Patients who received 2-CdA as their initial therapy and experienced a response lasting at least a year may be successfully treated subsequently with the same agent. A second response has been achieved in 35 to 100% patients treated with this agent for the second time. Despite the fact that 2-CdA gives higher CR and OR rates than conventional chemotherapy, it has not been established whether it has any influence on survival time. However, cross resistance between 2-CdA and FAMP in CLL patients is evident in the majority of studies. Bone marrow suppression with anemia neutropenia and thrombocytopenia are the dose limiting factors for 2-CdA use. These side effects are pronounced in heavily pretreated patients and after multiple courses of therapy. Treatment with this agent also leads to the decrease of the CD4+/CD8+ ratio for an extensive period of time exceeding 12, even up to 24 months. In consequence, infections including opportunistic type, are frequently observed. We suggest, that in patients with CLL, 2-CdA should be used as second line treatment rather than the first line therapy until the final results of ongoing randomized clinical trials are available.     

Fludarabine and epirubicin in the treatment of chronic lymphocytic leukaemia: A German multicenter phase II study

Purpose: Fludarabine has been reported to be the most effective single-agent in previously treated chronic lymphocytic leukaemia (CLL). Based on the in vitro synergism of fludarabine with anthracyclines and on results showing a higher efficacy of CHOP against COP we attempted to improve treatment results with a combination of fludarabine and an anthracycline.Patients and methods: The aim of the multicenter study was to evaluate the rate and duration of remissions and investigate the toxic and immunosuppressive effects of fludarabine and epirubicin in the treatment of CLL in Binet stages B and C as first-line therapy or in first relapse. Thirty-eight patients were treated with fludarabine 25 mg/m2 on days 1–5 and epirubicin 25 mg/m2 on days 4 and 5.Results: The overall response rate (OR) was 82% (95% confidence interval (95% CI): 66%–92%) with a CR rate of 32% (95% CI: 18%–49%). For the 25 previously untreated patients the OR was 92% (95% CI: 74%–99%) including 40% CRs (95% CI: 21%–61%). Granulocytopenia grade 3 occurred in 23% of all evaluable cycles, and grade 4 in 17%. The median remission duration was 19 months (range 6–37 months).Conclusion: The results show that the combination of fludarabine and epirubicin is tolerable and highly effective in the treatment of CLL. With the addition of epirubicin to fludarabine, it appears possible to achieve a higher response rate and a more rapid response, especially of nodal manifestations. This regimen can be administered in an outpatient facility except for the first cycle because of the risk of a tumour lysis. The possible benefit of the combination presented here in the treatment of CLL in comparison to single-agent fludarabine treatment is presently under study in a prospective randomised multicenter study.     

Combination chemotherapy with cisplatin and etoposide associated with radiotherapy in the treatment of small-cell lung cancer

Summary A total of 52 consecutive, previously untreated patients with small-cell lung cancer (SCLC) were scheduled to receive six cycles of a combination of etoposide (75 mg/m² per day) and cisplatin (20 mg/m² per day), each cycle given over 5 consecutive days. In all, 28 patients had extensive disease (ED) and 24, limited disease (LD). After three cycles of chemotherapy, all responding patients were given chest radiotherapy (RT) (45 Gy in two split courses and 30 Gy in LD and ED, respectively); only patients with LD who achieved complete remission (CR) after three cycles of chemotherapy were given prophylactic brain irradiation (30 Gy). In the 51 evaluable patients, the overall response rate was 90%, with a 31% CR and a 59% partial remission (PR) rate. In LD and ED patients, 57% and 11% CR rates and 30% and 82% PR rates were noted, respectively. Myelosuppression was the most frequently observed toxicity. The median duration of response was 12 months in LD (range, 3–41+months) and 7 months (range, 2–12 months) in ED; the median survival was 15 months in LD and 9.3 months in ED, respectively. In all 30% of LD patients are alive and well at a minimal follow-up of 18 months. This trial confirms the activity of the cisplatinetoposide combination in SCLC.Bursar, Italian Association for Cancer Research (AIRC)     

Simultaneous low-dose radiation and low-dose chemotherapy in the treatment of advanced Hodgkin's disease

Simultaneous combination chemotherapy (CT) (BCNU 40 mg/m2, procarbazine 50 mg/m2, prednisone 40 mg/m2, and vincristine 1.4 mg/m2) with low-dose radiation therapy [(RT) 2000 rad] delivered to all areas of tumor involvement aside from the bone marrow was given to 28 patients with advanced Hodgkin's disease. Upon completion of RT and CT, the BCNU and procarbazine was increased by 100% until a total of six cycles of CT (with and without RT) were given. Eleven patients had received prior CT and had not achieved complete remission (CR) or had relapse from CT-induced CR within 1 year. Seventeen others had not had prior CT (7 had prior RT). Among the previously treated patients, one patient died in autopsy-proven CR during treatment. The other 10 patients achieved CR. Eight had relapsed at 4-36 months (median time to relapse, 6 months). Five patients died of Hodgkin's disease, three others died of status asthmaticus and pneumonia, radiation pneumonitis, and acute nonlymphocytic leukemia, respectively. Three patients are still alive (2 in continuous CR) at 28, 89, and 90 months. Among the previously untreated patients, four died during treatment, one of acute myocardial infarction, two of liver failure, and one of radiation pneumonitis. Twelve of the other 13 patients achieved CR. One of the CR died of pneumonia and sepsis 3 months after completion of treatment; two other patients relapsed at 10 and 15 months. Nine remain in continuous CR at 42-89 months of follow-up, (median follow-up, 81 months). Of 107 tumor areas treated with RT, in-field relapse occurred in two areas (1.9%). Hematologic tolerance to this treatment was good in both groups of patients. Radiation pneumonitis occurred in 50% of the patients whose lungs were irradiated, and it was fatal in two. By design or for other reasons, the median and mean doses of BCNU and procarbazine given to previously treated patients were 62% and 65.2%, respectively. In untreated patients, the median and mean doses of these two agents were 66.6% and 61.4%, respectively. There were no differences in dosage of these two agents between patients who remain alive in CR and those who relapsed and died. The potential of similar programs of radiation and chemotherapy is discussed.     

Cladribine in the Treatment of Chronic Lymphocytic Leukemia

Cladribine (2-chlorodeoxyadenosine, 2-CdA) is a nucleoside analog with substituted halogen atom at position 2 in its purine ring that makes it resistant to deamination by adenosine deaminase (ADA). 2-CdA is the drug of choice in the treatment of hairy cell leukemia, but it is also highly active in other low grade lymphoid malignancies including chronic lymphocytic leukemia (CLL). The results of the studies presented so far have shown that 2-CdA gives similar complete response (CR) rate and overall response (OR) rate to fludarabine but the influence of both agents on survival times of the patients with CLL is still uncertain. CR rate induced with 2-CdA is significantly higher than in the patients treated with conventional chemotherapy. In refractory or relapsed patients 2-CdA induces 31 to 68% of overall responses including CR in 4 to 31%. In previously untreated patients overall remission rates of about 56-82% have been achieved with 2-CdA alone. When 2-CdA was used as primary therapy the CR rate was also significantly higher and ranged from 10% to 47%. Patients who received 2-CdA as their initial therapy and experienced a response lasting at least a year may be successfully treated subsequently with the same agent. A second response has been achieved in 35 to 100% patients treated with this agent for the second time. Despite the fact that 2-CdA gives higher CR and OR rates than conventional chemotherapy, it has not been established whether it has any influence on survival time. However, cross resistance between 2-CdA and FAMP in CLL patients is evident in the majority of studies. Bone marrow suppression with anemia neutropenia and thrombocytopenia are the dose limiting factors for 2-CdA use. These side effects are pronounced in heavily pretreated patients and after multiple courses of therapy. Treatment with this agent also leads to the decrease of the CD4+/CD8+ ratio for an extensive period of time exceeding 12, even up to 24 months. In consequence, infections including opportunistic type, are frequently observed. We suggest, that in patients with CLL, 2-CdA should be used as second line treatment rather than the first line therapy until the final results of ongoing randomized clinical trials are available.     

Evaluation of intensive postremission chemotherapy for adults with acute nonlymphocytic leukemia using high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide

In order to test the toxicity and efficacy of intensive postremission therapy with high-dose cytosine arabinoside with L-asparaginase and amsacrine with etoposide in adults with acute nonlymphocytic leukemia (ANL), 100 adults (ages 19 to 75) with previously untreated ANL were entered into a study using six sequential cycles of chemotherapy. Cycles 1 (induction), 3, and 5 included conventional doses of daunomycin, cytosine arabinoside, 6-thioguanine, vincristine (VCR), and prednisone. Cycle 2 was cytosine arabinoside 3 g/m2 intravenously (IV) every 12 hours for four doses, followed by L-asparaginase 10,000 U intramuscularly (IM) at hour 42; this combination was repeated 1 week later. Cycle 4 included amsacrine 120 mg/m2/d and etoposide 100 mg/m2/d, both IV for five days, and cycle 6 was three monthly courses of VCR on day 1, and prednisone, mercaptopurine, and methotrexate each for five days. Seventy-four patients (74%) achieved complete remission (CR) (51 with cycle 1 and 23 after cycle 2). The overall disease-free survival (DFS) for patients achieving CR is 27% at 3 years by Kaplan-Meier analysis, while for patients achieving CR with cycle 1 it is 34%. The actuarial probability of being free from relapse at 3 years for patients achieving CR is 34%. Sixteen of the 74 CR patients (22%) died in CR while continuing to receive intensive chemotherapy, including 12 (18%) who succumbed to infection (nine bacterial, three fungal). After a median follow-up of 20 months, 36 patients have relapsed and 21 remain alive in CR. Intensive consolidation with high-dose cytosine arabinoside, amsacrine, and etoposide can modestly prolong DFS compared with historical controls. However, relapse continued to be a major problem and, in addition, with more aggressive consolidation therapy, infection during marrow aplasia resulted in a significant number of deaths.     

含氟达拉滨的联合化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞性淋巴瘤

目的：评价以氟达拉滨为主的化疗方案治疗慢性淋巴细胞白血病／小淋巴细胞淋巴瘤（CLI／SLL）的疗效和不良反应。方法：采用氟达拉滨为主的化疗方案，FC方案：氟达拉滨＋环磷酰胺；FMD方案：氟达拉滨＋米托蒽醌＋地塞米松；FMC方案：氟达拉滨＋米托蒽醌＋环磷酰胺，共治疗18例CLL／SLL患者，其中初发9例，复发、难治9例。结果：18例患者平均完成4．2个周期，完全缓解（CR）率61．1％，部分缓解（PR）率22．2％，总的有效（OR）率83．3％。初发组CR率66．7％。PR率33．3％，OR率100％；复发、难治组CR率55．6％，PR率11．1％，OR率66．7％，两组CR、OR率无显著性差异（P〉0．05）。FC方案和FMD方案治疗组CR、OR率无显著性差异（P〉0．05）。主要不良反应为骨髓抑制和免疫功能抑制，27．8％的患者出现Ⅲ～Ⅳ级粒细胞减少，22．2％的患者出现Ⅲ～Ⅳ级血小板减少。5例患者出现感染、发热，其中1例死亡。其它毒性包括恶心、呕吐，轻度肝肾功能损害，自身免疫性溶血性贫血。中位随访时间24月（1～40月），2年生存率88．9％，2年PFS率81．8％。初发组2年生存率100％，2年PFS率100％；难治组2年生存率83．3％，2年PFS率66．7％，两组无显著性差异（P〉0．05）。结论：氟达拉滨为主的联合化疗方案对CIL／SLL疗效好，同时患者对其耐受性亦较佳。     

Consolidation therapy with high-dose cyclophosphamide improves the quality of response in patients with chronic lymphocytic leukemia treated with fludarabine as induction therapy.

Fludarabine is the most active agent in the treatment of chronic lymphocytic leukemia (CLL). Despite this activity only a minority of patients treated with fludarabine achieve a complete response. We evaluated a new treatment program of sequential therapy with fludarabine followed by high-dose cyclophosphamide in previously untreated patients with CLL. This report details the results in 25 patients with previously untreated CLL. Patients received fludarabine (25 mg/m2/day x 5 days every 4 weeks for six cycles) as induction followed by consolidation with high-dose cyclophosphamide at one of three dose levels 1.5 g/m2, 2.25 g/m2, or 3 g/m2 administered every 2 weeks for three doses. High-dose cyclophosphamide was given with G-CSF support (5 microg/kg/day days 3-12). Complete response (CR) required a normal physical examination, normal CBC, a normal bone marrow evaluation including no residual lymphoid nodules on biopsy. A nodular response was defined as a complete response with the exception of an occasional residual nodule seen on bone marrow biopsy. Flow cytometric analysis for CD5:CD19 dual staining and kappa/lambda clonal excess was performed in all patients as a sensitive measure of minimal residual disease (MRD). Selected patients had patient/tumor-specific oligonucleotides generated that were subsequently used in a polymerase chain reaction as an extremely sensitive measure of MRD. There were no treatment-related deaths and no patient encountered unacceptable toxicity. After completion of this sequential regimen 76% (95% confidence interval: 59-93%) of patients had a major response: eight (32%) achieved a CR, four (16%) a nodular response, seven (28%) a PR, and six patients (24%) failed. Four patients withdrew from study during induction with fludarabine and did not receive at least one cycle of cyclophosphamide. Of the 21 patients who received consolidation with cyclophosphamide 10 (48%) had an improved quality of response when compared to that achieved with fludarabine. Two patients (8%) had no disease detectable by flow cytometry ('flow cytometric' CR) after six cycles of fludarabine. This improved to nine patients (36%) after high-dose cyclophosphamide. Following consolidation with high-dose cyclophosphamide three patients (12%) tested negative by PCR. All of these patients had morphologic evidence of residual disease after six cycles of fludarabine. Consolidation with high-dose cyclophosphamide increased the fraction of patients achieving a nodular response or CR three-fold (16% to 48%). This appears to be clinically relevant because with a median follow-up of 52 (range 34-78) months the projected 6-year survival for patients achieving a CR or NR is 91% compared to 41% for all others (P = 0.012). We conclude that sequential therapy with fludarabine followed by high-dose cyclophosphamide in previously untreated patients with CLL is safe and can improve the quality of response in a large proportion of patients compared to therapy with fludarabine alone.     

FND与CHOP方案治疗进展期惰性淋巴瘤的疗效比较

目的比较FND(氟达拉滨 米托蒽醌 地塞米松)与CHOP方案治疗进展期惰性淋巴瘤的疗效与安全性。方法临床观察的终点包括缓解率(总有效率OR和完全缓解率CR),无失败生存(FFS),总体生存(OS)及毒性。40例病人随机分组,FND和CHOP组各20例。两种治疗方案均为每28天1次,共3个疗程,之后,二组病人均采用CHOP方案巩固3个疗程。FND方案为氟达拉滨25mg/m2,ivd1~5;米托蒽醌10mg/m2,ivd1;地塞米松20mg/d,ivd1~5。CHOP方案为环磷酰胺600mg/m2,ivd1;阿霉素25mg/m2,ivd1;长春新碱1.4mg/m2,ivd1和强的松50mg/m2,pod1~5。结果FND方案的完全缓解率和总有效率显著优于CHOP(OR83%vs40%,CR50%vs15%;P<0.01)。FND组的中位FFS是32个月,而CHOP组仅为15个月。两种治疗方案的耐受性均较好,只有少量的感染并发症发生。结论FND方案的完全缓解率、总有效率均显著优于CHOP,并可有效改善预后。