Original Article
Chlorambucil in Indolent Chronic Lymphocytic Leukemia
N Engl J Med 1998; 338:1506-1514May 21, 1998
- Abstract
Background
To determine whether chlorambucil treatment benefits patients with indolent chronic lymphocytic leukemia (CLL), we conducted two randomized trials in 1535 patients with previously untreated stage A CLL.
Methods
In the first trial, 609 patients were randomly assigned to receive either daily chlorambucil or no treatment; in the second trial, 926 patients were randomly assigned to receive either intermittent chlorambucil plus prednisone or no treatment. Median follow-up for the first and second trials exceeded 11 and 6 years, respectively. The end points were overall survival, response to treatment, and disease progression.
Results
Treatment of indolent CLL did not increase survival in either trial. In the treated group, as compared with the untreated group, the relative risk of death was 1.14 (95 percent confidence interval, 0.92 to 1.41; P=0.23) in the first trial and 0.96 (95 percent confidence interval, 0.75 to 1.23; P=0.74) in the second trial, with 76 percent and 69 percent of patients, respectively, having a response to therapy. Although chlorambucil slowed disease progression, there was no effect on overall survival. In the untreated group in the first trial, 49 percent of patients did not have progression to more advanced disease and did not need therapy after follow-up of more than 11 years; however, 27 percent of patients with stage A CLL died of causes related to the disease.
Conclusions
Chlorambucil does not prolong survival in patients with stage A CLL. Since deferring therapy until the disease progresses to stage B or C does not compromise survival, treatment of indolent CLL is unnecessary.
Media in This Article
Figure 3
Overall Survival in the Second Trial.Figure 2
Kaplan–Meier Estimates of Mortality Due to CLL-Related Causes, Second Cancers, and Unknown Causes in the First Trial.Article Activity
- Article
Many patients with chronic lymphocytic leukemia (CLL) have long lives and die of causes unrelated to the disease.1,2 Rai's classification3-5 and Binet's staging system6 have improved the identification of the indolent form of the disease (Table 1Table 1
Staging Systems Used for Chronic Lymphocytic Leukemia.), and both ways of staging CLL accurately identify patients with a good prognosis. Of all patients with CLL, 31 percent have Rai stage 0, whereas 63 percent have Binet stage A. Among patients with Rai stage 0, 59 percent are alive 10 years after the diagnosis, and among those with Binet's stage A the 10-year survival rate is 51 percent.1 There is no evidence that treatment of CLL with chlorambucil affects survival, but this alkylating agent can relieve symptoms in many patients.7-14 It is not clear whether therapy benefits patients with the indolent form of CLL. An early report from our group failed to show differences in survival between patients who were treated with chlorambucil immediately after the diagnosis of stage A CLL and those who were not treated.14 We now report the long-term results of the first trial and a second trial in which 926 previously untreated patients with stage A CLL were randomly assigned to either no treatment or a combination of chlorambucil and prednisone.
Methods
Patients and Treatments
Both trials included only previously untreated patients with stage A CLL. Patients with prolymphocytic leukemia, a second neoplasm other than basal-cell carcinoma, a positive Coombs' test, or in the second trial, contraindications to prednisone were excluded.
Thirty-one centers participated in the first trial and 46 in the second trial, and randomization was performed by telephone at a centralized location. The first trial enrolled 609 patients between 1980 and 1985 and randomly assigned 308 patients to no treatment and 301 patients to 0.1 mg of chlorambucil per kilogram of body weight per day. The second trial enrolled 926 patients between 1985 and 1990 and randomly assigned 466 patients to no treatment and 460 patients to 0.3 mg of chlorambucil per kilogram per day for five days every month and 40 mg of prednisone per square meter of body-surface area per day for five days every month. In the first trial, chlorambucil was administered until clinical resistance to the drug was observed. In the second trial, the planned duration of treatment was three years.
In the first trial, patients whose disease progressed from stage A to stage B were treated with daily chlorambucil if they were previously untreated, or with a combination of cyclophosphamide, vincristine, and prednisone (COP) if they were in the chlorambucil group. Patients enrolled in the second trial whose disease progressed to stage B were given intermittent chlorambucil plus prednisone if they were previously untreated or a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) if they were in the group treated with chlorambucil plus prednisone. Progression to stage C warranted COP for previously untreated patients in the first trial, CHOP for treated patients in the first trial and untreated patients in the second trial, or CHOP plus methotrexate for patients in the treated group in the second trial.
End Points
The primary end points were overall survival, mortality related to CLL, response to treatment, and disease progression. A clinical and hematologic response was defined as the absence of lymphadenopathy, a lymphocyte count of less than 4000 per cubic millimeter, a hemoglobin concentration of more than 100 g per liter, and a platelet count of more than 100,000 per cubic millimeter. Bone marrow biopsy or aspiration was recommended but not required for patients who had clinical and hematologic responses. A partial response was defined as a reduction of at least 75 percent in the initial lymphocyte count and at least 50 percent in each of the initially enlarged lymph nodes. Resistance to treatment or treatment failure was defined as the occurrence of any or all of the following: progression of disease to stage B or C, the lack of a reduction of at least 50 percent in the enlarged lymph nodes, or the lack of a reduction of at least 75 percent in the absolute lymphocyte count.
Causes of death were divided into those related to CLL and those unrelated to CLL; the latter category included only deaths that were unambiguously unrelated to CLL. Deaths related to second neoplasms were recorded separately and considered to be related to CLL. Since an increased number of such deaths was seen in the chlorambucil-treated group in the initial analysis of the first trial, the incidence of cancer was examined in the two trials. To evaluate the response, a follow-up examination was scheduled during the ninth month in the first trial and the sixth month in the second trial. Thereafter, a follow-up examination was scheduled every six months.
Statistical Analysis
Statistical analysis was carried out on an intention-to-treat basis. This analysis was based on findings on the reference date of the scheduled fifth interim analysis for the first trial (July 1, 1994) and the third interim analysis for the second trial (January 1, 1994). Survival analysis was based on Kaplan–Meier estimates,15 the log-rank test,16 and the Cox regression model.17 All P values are two-sided and adjusted for repeated analyses. To account for the five planned interim analyses, a threshold alpha level of 0.0158 was used in order to guarantee an overall type I error of 0.05.18
Results
Characteristics of the Patients
The median follow-up of survivors was 129 months (range, 6 to 169) in the first trial and 73 months (range, 6 to 106) in the second trial. Three patients in the first trial and six patients in the second were excluded from the analysis because of the lack of information after randomization. There were slightly higher blood lymphocyte counts and degrees of bone marrow infiltration in the daily-chlorambucil group in the first trial. There were no significant differences between the groups in either trial at the time of randomization (Table 2Table 2
Characteristics of the Patients at Randomization.).Survival
The First Trial
In the first trial, 344 deaths were reported (Figure 1Figure 1
Overall Survival in the First Trial.), 169 in the untreated group (5-year survival, 80 percent; 10-year survival, 54 percent) and 175 in the treated group (5-year survival, 76 percent; 10-year survival, 47 percent) (relative risk of death, 1.14 in the treated group as compared with the untreated group; 95 percent confidence interval, 0.92 to 1.41; P=0.23 by the log-rank test). In the untreated group, 54 of the 169 deaths were unrelated to CLL, 22 were caused by a second neoplasm, and no cause was found in 9. Death was considered to be related to CLL in 84 patients (due to disease progression in 41, infection in 36, iatrogenic causes in 2, thrombocytopenia in 1, and other causes in 4). In the treated group, 47 of the 175 deaths were unrelated to CLL, 28 were the consequence of a second cancer, and no cause was found in 6. Death was related to CLL in 94 patients (due to disease progression in 45, infection in 41, iatrogenic complications in 6, and autoimmune hemolytic anemia in 2). The distribution of deaths related to CLL was similar in the two groups (P=0.11 by the log-rank test) (Figure 2Figure 2Kaplan–Meier Estimates of Mortality Due to CLL-Related Causes, Second Cancers, and Unknown Causes in the First Trial.).Table 3Table 3
Incidence of Second Cancers in the Two Trials According to Treatment Assignment. shows the incidence of second neoplasms in the two groups. Forty-eight cancers were observed in the untreated group (median interval between entry into the trial and the occurrence of the second cancer, 67 months; range, 6 to 165), as compared with 66 in the treated group (median interval, 72 months; range, 2 to 141) (P=0.045 by the chi-square test). Skin, mammary, and colon cancers and acute leukemia predominated in the treated group. Five of the six cases of leukemia in the two groups were of myeloid origin. The two cases of acute leukemia in the untreated group occurred in patients who were switched to chlorambucil five and nine years before the diagnosis of acute leukemia. The same phenomenon was observed in six of the nine patients with skin cancer in the untreated group.The Second Trial
In the second trial, 247 deaths were recorded (Figure 3Figure 3
Overall Survival in the Second Trial.), 126 in the untreated group (five-year survival, 81 percent; seven-year survival, 69 percent) and 121 in the treated group (five-year survival, 81 percent; seven-year survival, 69 percent; relative risk of death, 0.96; 95 percent confidence interval, 0.75 to 1.23; P=0.74 by the log-rank test).In the untreated group, 25 of the 126 deaths were unrelated to CLL, 19 were caused by a second neoplasm, and no cause was identified in 17. Death was related to CLL in 65 patients (due to disease progression in 37, infection in 23, iatrogenic causes in 2, and thrombocytopenia in 3). In the treated group, 39 of the 121 deaths were unrelated to CLL, 18 were related to cancer, no cause was identified in 17, and 47 were related to CLL (due to disease progression in 20, infection in 24, and thrombocytopenia in 3). There was no significant difference in overall survival after the exclusion of deaths unrelated to CLL (P=0.16 by the log-rank test) (Figure 4Figure 4
Kaplan–Meier Estimates of Mortality Due to CLL-Related Causes, Second Cancers, and Unknown Causes in the Second Trial.).The median follow-up was five years less than that of the first trial. As shown in Table 3, there were 50 second neoplasms in the untreated group (median interval from entry into the trial to the occurrence of a second cancer, 42 months; range, 1 to 104), as compared with 42 in the treated group (median interval, 30 months; range, 1 to 100) (P=0.42 by the chi-square test).
Response to Treatment and Disease Progression
The First Trial
In the first trial, the response to treatment could be evaluated in 278 of the 293 patients in the treated group who were alive at nine months. Of these 278 patients, 125 had complete responses (45 percent), 86 (31 percent) had partial responses, and 67 (24 percent) had no response to treatment. Among patients with complete responses and partial responses, the respective seven-year survival rates were 78 percent and 69 percent, as compared with a rate of 50 percent for patients with no response to therapy. Rai stage 0, Binet stage A',19 and fewer areas with enlarged lymph nodes were selected by a Cox model (data not shown) as predictive of a therapeutic response.
The Second Trial
In the second trial, the response to treatment could be evaluated in 437 of the 453 patients in the treated group who were alive at six months. Of these 437 patients, 124 (28 percent) had complete responses, 179 (41 percent) had partial responses, and 134 patients (31 percent) had no response to treatment. Among patients with complete responses and partial responses, the respective seven-year survival rates were 84 percent and 77 percent, as compared with a rate of 58 percent for patients who had no response to therapy. Rai stage 0, Binet stage A', lower initial lymphocyte count, and fewer areas with enlarged lymph nodes were selected by a Cox model (data not shown) as predictive of a therapeutic response.
Both Trials
Figure 5AFigure 5
Patients without Progression to Stage B or C in the First Trial (Panel A) and the Second Trial (Panel B). and Figure 5B shows that in both trials disease progression occurred in significantly more patients in the untreated group than in the treated group. Progression to stage B occurred in 67 and 85 patients, respectively, in the untreated groups of the first and second trials, as compared with 38 and 41 patients in the treated groups of the two protocols. The survival of the untreated patients after progression to stage B (five-year survival, 56 percent in the first trial and 52 percent in the second trial) was similar to the survival of patients with stage B at presentation who received the same therapy in portions of the two trials devoted to the study of patients with stage B CLL.20,21 With respect to the proportion of patients with progression to stage C, there were no major differences between the untreated and treated groups in either trial. A minority of the untreated patients with progression to stage B (22 of 67 in the first trial and 22 of 85 in the second trial) were crossed over to therapy, whereas most of the untreated patients with progression to stage C (64 of 81 in the first trial and 67 of 84 in the second trial) were crossed over to therapy, and in some of these patients, CLL had previously evolved to stage B. Thus, the absence of a difference in the rate of progression to stage C might reflect resistance to chemotherapy in these patients.Modifications of the Therapeutic Schedule
The First Trial
Among the 308 patients who were assigned to receive no treatment in the first trial (Table 4Table 4
Additional Treatment Given and Stage at the Time of the Change in Treatment, According to Treatment Assignment in the First Trial.), 158 ultimately received treatment (110 received daily chlorambucil, 13 intermittent chlorambucil plus prednisone, 15 COP, 4 CHOP, 8 other combinations of chemotherapy, 6 corticosteroids, and 1 splenic irradiation, and 1 underwent splenectomy). Of these 158 patients, 97 were treated despite remaining in stage A, 44 because of progression to stage B, and 17 because of progression to stage C. In the group assigned to daily chlorambucil, 83 of the 301 patients were changed to another therapy (13 received chlorambucil plus prednisone, 24 COP, 20 CHOP, 22 other combinations of chemotherapy, and 4 corticosteroids). Treatment was changed in 28 patients even though they remained in stage A, in 14 because of progression to stage B, and in 41 because of progression to stage C.The Second Trial
Among the 466 patients assigned to receive no therapy in the second trial, 187 received treatment (137 received chlorambucil plus prednisone, 20 CHOP, 14 daily chlorambucil, 14 other combinations of chemotherapy, 1 corticosteroids, and 1 total irradiation). Of these, 107 were given treatment despite remaining in stage A, 63 because they had progression to stage B, and 17 because they had progression to stage C. Among the treated patients, 97 were changed to another treatment (37 to CHOP, 28 to daily chlorambucil, 24 to other combinations of chemotherapy, 6 to corticosteroids, 1 to splenectomy, and 1 to splenic irradiation). Treatment was changed in 53 patients even though they remained in stage A, in 18 because of progression to stage B, and in 26 because of progression to stage C. In both trials, the intention-to-treat analysis included all patients who were treated even though they remained in stage A.
Discussion
A major issue in the management of indolent CLL (stage A) is whether deferring treatment is a reasonable alternative to immediate therapy. Our two trials, with more than 11 and 6 years of follow-up on 1535 patients, addressed this question. We found that daily chlorambucil alone or intermittent treatment with chlorambucil and prednisone did not prolong survival in patients with indolent CLL. Since deferring therapy until the disease progressed to stage B or stage C did not compromise survival, initial therapy could have been appropriately postponed.
Given daily or intermittently, alone or combined with corticosteroids, chlorambucil is the most commonly used drug in CLL.8-11,22 Although one study reported12 that high doses of chlorambucil (15 mg per day until there was complete remission) were efficacious in advanced CLL, our results and previous reports from our group concerning stage A7 and stage B20 CLL, together with the results of Shustik et al.10 and Catovsky et al.,9 demonstrate that the early use of chlorambucil does not influence survival in CLL.
In the absence of curative therapy, there are advantages to deferring treatment for patients with stage A CLL (63 percent of all patients with CLL have stage A disease). Postponing treatment avoids the side effects of cytotoxic therapy, including the infectious complications related to myelosuppression and the need for stringent follow-up. However, some patients who are concerned about their disease may want treatment, even in the absence of disease progression.
Although chlorambucil has been reported to induce secondary acute leukemia in patients treated for polycythemia vera23 and when used as an immunosuppressive agent,24-27 this complication has not been reported in patients with CLL. In our series there were six cases of acute leukemia among the 422 patients who received daily chlorambucil as initial or secondary treatment, as compared with no cases among the 145 patients who never received therapy (Table 3).
An unexpected finding that emerged from the early results of the first trial was the relatively high frequency of epithelial neoplasms in the group treated with chlorambucil. This was subsequently found in three successive interim analyses (33, 50, and 66 cancers in the treated group at the third, fourth, and fifth interim analyses, respectively, as compared with 19, 25, and 48 cancers in the untreated group). However, these differences are not significant (P=0.045), and they were not confirmed in the second trial. Nevertheless, we cannot rule out an oncogenic potential of chlorambucil because the total dose of chlorambucil differed in the two trials (3 mg per kilogram per month vs. 1.5 mg per kilogram when given intermittently), as did the duration of treatment (long-term continuous therapy vs. three years of therapy) and the timing of therapy (daily vs. intermittent).
Our results indicate that chlorambucil can delay disease progression, even though it does not affect survival. We cannot rule out the possibility that patients in the treated groups with progression to stage B had a poorer initial prognosis. However, the differences in survival nine years after randomization (Table 4) between untreated patients with progression to stage B and treated patients with progression to stage B (54 percent vs. 21 percent) suggest that early exposure to the drug selects for resistant clones, which are the cause of the poor prognosis of patients who have no response to early therapy.
Of the 308 patients in the first trial who were not treated, 49 percent remained in stage A and needed no therapy after follow-up of more than 11 years. However, 27 percent of the untreated patients in stage A died of causes related to the disease, and more than half began therapy because the disease began to progress.
Our results emphasize the need for both a better definition of stage A CLL and curative treatment for indolent CLL, particularly in young patients. There is evidence that purine analogues, particularly fludarabine, are the most effective agents for this disorder.28-30 Since these drugs have not been shown to improve overall survival, it is premature to recommend them for patients with stage A CLL, particularly in stage A', since survival in patients with stage A' disease is close to that of a sex-matched and age-matched normal population. However, young patients with stage A" CLL, whose five-year survival rate is 62 percent,7 may be candidates for treatment with these drugs.
We are indebted to Professor Jacques Benichou (Centre Hospitalier Universitaire de Rouen) for his invaluable help in revising the manuscript.
Source Information
From the Unité d'Immuno-Hématologie et d'Immunopathologie, Institut Pasteur, Paris (G.D.); Département d'Hématologie, Hôpital Pitié-Salpêtrière, Paris (K.M., J.-L.B.); Service des Maladies du Sang, Centre Hospitalier Régional–Hôpital Sud, Amiens (B. Desablens); Service des Maladies du Sang, Hôpital Claude Huriez, Lille (B.C.); Service des Maladies du Sang, Centre Hospitalier Universitaire–Hôpital Lapeyronie, Montpellier (M.N.); Service de Médecine G, Centre Hospitalier Régional–Hôpital Sud, Rennes (R.L.); Service Hématologie Clinique, Centre Hospitalier Universitaire de Caen, Caen (M.L.); Département d'Hématologie, Centre Hospitalier Universitaire–Hôpital Nord, Saint-Etienne (J.J.); Onco-Hématologie, Maladies Infectieuses, Centre Hospitalier Avignon–Hôpital Henri Duffaut, Avignon (G.L.); Département d'Hématologie et d'Oncologie Virale, Centre Hospitalier Universitaire–Hôpital Jean Bernard, Poitiers (B. Dreyfus); and Unité d'Hematologie Clinique, Hôtel-Dieu, Clermont-Ferrand (P.T.) — all in France.
Address reprint requests to Dr. Dighiero at Unité d'Immuno-Hématologie et d'Immunopathologie, Institut Pasteur, 28 rue du Dr. Roux, F-75724 Paris CEDEX 15, France.
Other authors were François-Louis Turpin, M.D. (Oncologie Médicale et Hématologie, Centre René Huguenin, St. Cloud, France), Gérard Tertian, M.D. (Laboratoire d'Hématologie, d'Immunologie, et de Cytogénétique, Hôpital Bicêtre, Le Kremlin Bicêtre, France), and Agnès Bichoffe, M.D. (Département de Médecine Interne, Centre Hospitalier Général de Montluçon, Montluçon, France).
Appendix
The following institutions (all in France unless otherwise specified) and members of the French Cooperative Group on Chronic Lymphocytic Leukemia were involved in the two trials: Centre Hospitalier Régional, Lille: P. Fenaux, P. Morel; Centre Henri Becquerel, Rouen: H. Piguet, M. Monconduit, F. Tilly; Hôpital Sud, Amiens: J.-F. Claisse; Hôpital Robert Debré, Reims: J.-C. Adjizian, G. Potron, B. Pignon; Centre Hospitalier Régional, Caen: X. Troussard, O. Reman; Groupe Hospitalier Pitié-Salpêtrière, Paris: H. Merle-Béral; Centre Hospitalier Régional, Tours: M. Reisenleiter, C. Linassier, J.-P. Lamagnère; Hôpital Nord, Saint-Etienne: C. Vasselom; Hôpital Sud, Rennes: D. Jacomy, B. Grosbois; Hôpital La Mileterie, Poitiers: F. Guilhot; Hôpital de la Source, Orléans: G. Vaugier; Hôpital de la Durance, Avignon: P. Souteyrand, G. Lepeu, A.-M. Touchais; Hôpital Mustapha, Algiers, Algeria: N. Boudjerra; Centre Hospitalier Régional, Limoges: M. Bordessoule; Hôtel-Dieu, Clermont-Ferrand: O. Tournilhac; Centre Départemental de Transfusion Sanguine, Pontoise: J. Facquet-Danis; Hôpital Edouard-Herriot, Lyons: C. Sebban; Centre Hospitalier, Meaux: C. Allard; Centre Hospitalier Régional, Montpellier: B. Murgue; Centre Hospitalier, Nîmes: J.-F. Schved, A. Arnaud; Hôpital Avicenne, Bobigny: P. Cassassus; Hôpital de Pontchaillou, Rennes: P.-Y. Le Prisé; Centre Hospitalier, Antibes: J.-F. Dor; Hôpital Antoine Béclère, Clamart: P. Solal-Celigny, G. Tchernia; Hôpital Beaujon, Clichy: J.-F. Bernard; Hôpital Saint-Joseph, Paris: J.-M. James; Centre Hospitalier, Vichy: A. Reigner; Centre Hospitalier, Chambéry: M. Blanc; Centre Hospitalier Régional, Nantes: M.-J. Rapp; Centre Hospitalier, Evreux: J.-P. Bourgeois; Hôpital Jean Verdier, Bondy: F. Lejeune; Centre Hospitalier, Chalon-sur-Saône: B. Salles; Centre Hospitalier de la Côte Basque, Bayonne: M. Renoux; Hôpital Jules Courmont, Lyons: B. Garin; Centre Hospitalier Maréchal Joffre, Perpignan: J. Camo; Hôpital Robert Boulin, Libourne: J. Ceccaldi; Centre Hospitalier, Corbeil: A. Devidas; Centre René Gauducheau, Nantes: A. Le Mevel-Le Pourhiet; Centre Hospitalier Régional, Brest: J. Brière; Centre Hospitalier, Saint-Germain en Laye: M. Janvier; Hôpital Saint-Louis, Paris: Y. Najean; and Hôpital Saint-Louis, Paris: C. Chastang and S. Chevret (statisticians), D. Meffre and C. Dumont (monitors).
- References
References
1
Dighiero G ,Travade P ,Chevret S , et al. B-cell chronic lymphocytic leukemia: present status and future directions. Blood 1991;78:1901-1914
Web of Science | Medline2
Rozman C ,Montserrat E . Chronic lymphocytic leukemia. N Engl J Med 1995;333:1052-1057[Erratum, N Engl J Med 1995;333:1515.]
Full Text | Web of Science | Medline3
Rai K ,Sawitsky A ,Cronkite EP ,Chanana AD ,Levy RN ,Pasternack BS . Clinical staging of chronic lymphocytic leukemia. Blood 1975;46:219-234
Web of Science | Medline4
Cheson BD ,Bennett JM ,Grever M , et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996;87:4990-4997
Web of Science | Medline5
International Workshop on Chronic Lymphocytic Leukemia
Web of Science | Medline6
Binet JL ,Auquier A ,Dighiero G , et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 1981;48:198-206
CrossRef | Web of Science | Medline7
The French Cooperative Group on Chronic Lymphocytic Leukemia
Web of Science | Medline8
Sawitsky A ,Rai KR ,Glidewell O ,Silver RT . Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood 1977;50:1049-1059
Web of Science | Medline9
Catovsky D ,Richards S ,Fooks J ,Hamblin TJ . CLL trials in the United Kingdom: MRC trials 1, 2 and 3. Leuk Lymphoma 1991;5:Suppl 4:105-111
CrossRef | Web of Science10
Shustik C ,Mick R ,Silver R ,Sawitsky A ,Rai K ,Shapiro L . Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol 1988;6:7-12
CrossRef | Web of Science | Medline11
Begleiter A ,Mowat M ,Israels LG ,Johnston JB . Chlorambucil in chronic lymphocytic leukemia: mechanisms of action. Leuk Lymphoma 1996;23:187-201
CrossRef | Web of Science | Medline12
Jaksic B ,Brugiatelli M . High dose continuous chlorambucil vs intermittent chlorambucil plus prednisone for treatment of B-CLL -- IGCI CLL-01 trial. Nouv Rev Fr Hematol 1988;30:437-442
Medline13
Jaksic B ,Brugiatelli M ,Krc I , et al. High dose chlorambucil versus Binet's modified cyclophosphamide, doxorubicin, vincristine, and prednisone regimen in the treatment of patients with advanced B-cell chronic lymphocytic leukemia: results of an international multicenter randomized trial: International Society of Chemo-Immunotherapy, Vienna. Cancer 1997;79:2107-2114
CrossRef | Web of Science | Medline14
Dighiero G ,Binet JL . Chronic lymphocytic leukemia. Hematol Cell Ther 1996;38:Suppl 2:S41-S63
Medline15
Kaplan E ,Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481
CrossRef | Web of Science16
Peto R ,Peto J . Asymptotically efficient rank invariant test procedures. J R Stat Soc [A] 1972;135:185-206
CrossRef | Web of Science17
Cox DR . Regression models and life-tables. J R Stat Soc [B] 1972;34:187-20218
Pocock SJ . Group sequential methods in the design and analysis of clinical trials. Biometrika 1977;64:191-199
CrossRef | Web of Science19
The French Cooperative Group on Chronic Lymphocytic Leukaemia
Web of Science | Medline20
The French Cooperative Group on Chronic Lymphocytic Leukaemia
Web of Science | Medline21
The French Cooperative Group on Chronic Lymphocytic Leukaemia
CrossRef | Web of Science | Medline22
Catovsky D ,Fooks J ,Richards S . The UK Medical Research Council CLL trials 1 and 2. Nouv Rev Fr Hematol 1988;30:423-427
Medline23
Berk PD ,Goldberg JD ,Silverstein MN , et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med 1981;304:441-447
Full Text | Web of Science | Medline24
Kauppi MJ ,Savolainen HA ,Anttila VJ ,Isomaki HA . Increased risk of leukaemia in patients with juvenile chronic arthritis treated with chlorambucil. Acta Paediatr 1996;85:248-250
CrossRef | Web of Science | Medline25
Dedrick RL ,Morrison PF . Carcinogenic potency of alkylating agents in rodents and humans. Cancer Res 1992;52:2464-2467
Web of Science | Medline26
Patapanian H ,Graham S ,Sambrook PN , et al. The oncogenicity of chlorambucil in rheumatoid arthritis. Br J Rheumatol 1988;27:44-47
CrossRef | Medline27
Palmer RG ,Denman AM . Malignancies induced by chlorambucil. Cancer Treat Rev 1984;11:121-129
CrossRef | Web of Science | Medline28
Keating MJ ,Kantarjian H ,Talpaz M , et al. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood 1989;74:19-25
Web of Science | Medline29
Johnson S ,Smith AG ,Loffler H , et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet 1996;347:1432-1438
Web of Science | Medline30
Rai KR ,Peterson B ,Elias L , et al. A randomized comparison of Fludarabine and Chlorambucil for patients with previously untreated chronic lymphocytic leukemia: a CALGB, SWOG, CTG/NCI-C and ECOG Inter-Group study. Blood 1996;88:Suppl 1:141a-141a abstract.
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Stefano Molica. (2011) Progress in the treatment of chronic lymphocytic leukemia: results of the German CLL8 trial. Expert Review of Anticancer Therapy 11:9, 1333-1340
CrossRef7
Samantha Jaglowski, Jeffrey A Jones. (2011) Choosing first-line therapy for chronic lymphocytic leukemia. Expert Review of Anticancer Therapy 11:9, 1379-1390
CrossRef8
Alessandra Ferrajoli, Michael J. Keating, Susan O'Brien, Jorge Cortes, Deborah A. Thomas. (2011) Experience with rituximab immunotherapy as an early intervention in patients with Rai stage 0 to II chronic lymphocytic leukemia. Cancer 117:14, 3182-3186
CrossRef9
W. G. Wierda, T. J. Kipps, J. Durig, L. Griskevicius, S. Stilgenbauer, J. Mayer, L. Smolej, G. Hess, R. Griniute, F. J. Hernandez-Ilizaliturri, S. Padmanabhan, M. Gorczyca, C.-N. Chang, G. Chan, I. Gupta, T. G. Nielsen, C. A. Russell, . (2011) Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 117:24, 6450-6458
CrossRef10
Thibaut Brugat, Florence Nguyen-Khac, Hélène Merle-Béral, Jozo Delic. (2011) Concomitant telomere shortening, acquisition of multiple chromosomal aberrations and in vitro resistance to apoptosis in a single case of progressive CLL. Leukemia Research 35:5, e37-e40
CrossRef11
Christopher R. Friese, Craig C. Earle, Lysa S. Magazu, Jennifer R. Brown, Bridget A. Neville, Nathanael D. Hevelone, Lisa C. Richardson, Gregory A. Abel. (2011) Timeliness and quality of diagnostic care for medicare recipients with chronic lymphocytic leukemia. Cancer 117:7, 1470-1477
CrossRef12
Paula Cramer, Michael Hallek. (2011) Prognostic factors in chronic lymphocytic leukemia—what do we need to know?. Nature Reviews Clinical Oncology 8:1, 38-47
CrossRef13
R. R. Furman. (2010) Prognostic Markers and Stratification of Chronic Lymphocytic Leukemia. Hematology 2010:1, 77-81
CrossRef14
B. D. Hock, J. L. McKenzie, L. McArthur, S. Tansley, K. G. Taylor, L. J. Fernyhough. (2010) CD38 as a prognostic marker in chronic lymphocytic leukaemia at a single New Zealand centre: patient survival in comparison to age- and sex-matched population data. Internal Medicine Journal 40:12, 842-849
CrossRef15
Valentin Goede, Barbara Eichhorst, Michael Hallek. 2010. Therapy of Chronic Lymphocytic Leukemia: Front-Line and Salvage. , 308-314.
CrossRef16
Tadeusz Robak, Ewa Lech-Maranda, Pawel Robak. (2010) Rituximab plus fludarabine and cyclophosphamide or other agents in chronic lymphocytic leukemia. Expert Review of Anticancer Therapy 10:10, 1529-1543
CrossRef17
José Ángel Hernández, Marcos González, Jesús María Hernández. (2010) Leucemia linfática crónica. Medicina Clínica 135:4, 172-178
CrossRef18
Arnon P. Kater, Sanne H. Tonino. (2010) Standards for the Treatment of Relapsed Chronic Lymphocytic Leukemia: A Case-Based Study. Clinical Lymphoma, Myeloma & Leukemia 10:0, S34-S41
CrossRef19
Tom Butler, J.G. Gribben. (2010) Biologic and clinical significance of molecular profiling in Chronic Lymphocytic Leukemia. Blood Reviews 24:3, 135-141
CrossRef20
B. Eichhorst, M. Hallek, M. Dreyling, . (2010) Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 21:Supplement 5, v162-v164
CrossRef21
Thorsten Zenz, Daniel Mertens, Ralf Küppers, Hartmut Döhner, Stephan Stilgenbauer. (2010) From pathogenesis to treatment of chronic lymphocytic leukaemia. Nature Reviews Cancer
CrossRef22
D A MacIntyre, B Jiménez, E Jantus Lewintre, C Reinoso Martín, H Schäfer, C García Ballesteros, J Ramón Mayans, M Spraul, J García-Conde, A Pineda-Lucena. (2010) Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups. Leukemia 24:4, 788-797
CrossRef23
Eiman A. Al Zaabi, Louis A. Fernandez, Irene A. Sadek, D. Christie Riddell, Wenda L. Greer. (2010) Multiplex Ligation-Dependent Probe Amplification Versus Multiprobe Fluorescence in Situ Hybridization To Detect Genomic Aberrations in Chronic Lymphocytic Leukemia. The Journal of Molecular Diagnostics 12:2, 197-203
CrossRef24
Eduardo Mansilla, Gustavo H. Marin, Luis Nuñez, Hugo Drago, Flavio Sturla, Carol Mertz, Luis Rivera, Thomas Ichim, Neil Riordan, Clemente Raimondi. (2010) The Lysosomotropic Agent, Hydroxychloroquine, Delivered in a Biodegradable Nanoparticle System, Overcomes Drug Resistance of B-Chronic Lymphocytic Leukemia Cells In Vitro. Cancer Biotherapy & Radiopharmaceuticals 25:1, 97-103
CrossRef25
Nicole Lamanna. (2010) Challenges in the Frontline Treatment of Patients With Chronic Lymphocytic Leukemia. Current Hematologic Malignancy Reports 5:1, 45-51
CrossRef26
Tadeusz Robak, Krzysztof Jamroziak, Pawel Robak. (2009) Current and Emerging Treatments for Chronic Lymphocytic Leukaemia. Drugs 69:17, 2415-2449
CrossRef27
V Koljonen, H Kukko, E Pukkala, R Sankila, T Böhling, E Tukiainen, H Sihto, H Joensuu. (2009) Chronic lymphocytic leukaemia patients have a high risk of Merkel-cell polyomavirus DNA-positive Merkel-cell carcinoma. British Journal of Cancer 101:8, 1444-1447
CrossRef28
Sandra M. Camps, Sylvie Chevret, Vincent Lévy. (2009) How to use clinical vignettes in hematology—A pilot survey in the context of chronic lymphocytic leukemia. Leukemia Research 33:10, 1328-1334
CrossRef29
Lukas Smolej. (2009) Modern concepts in the treatment of chronic lymphocytic leukemia. Hematology 14:5, 249-254
CrossRef30
P. Abrisqueta, A. Pereira, C. Rozman, M. Aymerich, E. Gine, C. Moreno, A. Muntanola, M. Rozman, N. Villamor, K. Hodgson, E. Campo, F. Bosch, E. Montserrat. (2009) Improving survival in patients with chronic lymphocytic leukemia (1980-2008): the Hospital Clinic of Barcelona experience. Blood 114:10, 2044-2050
CrossRef31
Julio Delgado, Javier Briones, Jorge Sierra. (2009) Emerging therapies for patients with advanced chronic lymphocytic leukaemia. Blood Reviews 23:5, 217-224
CrossRef32
Tadeusz Robak. (2009) Ofatumumab for the treatment of chronic lymphocytic leukemia. Therapy 6:4, 577-587
CrossRef33
Tae Sung Park, June-Won Cheong, Jaewoo Song, Jong Rak Choi. (2009) Therapy-related myelodysplastic syndrome with der(17)t(12;17)(q13;p13) as a new recurrent cytogenetic abnormality after treatment for chronic lymphocytic leukemia. Leukemia Research 33:7, 1001-1004
CrossRef34
B. Eichhorst, M. Hallek, M. Dreyling, . (2009) Chronic lymphocytic leukemia: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up. Annals of Oncology 20:Supplement 4, iv102-iv104
CrossRef35
Tait D. Shanafelt, Deborah A. Bowen, Chaya Venkat, Susan L. Slager, Clive S. Zent, Neil E. Kay, Megan Reinalda, Han Tun, Jeff A. Sloan, Timothy G. Call. (2009) The physician–patient relationship and quality of life: Lessons from chronic lymphocytic leukemia. Leukemia Research 33:2, 263-270
CrossRef36
John C. Byrd, Bercedis L. Peterson, Kanti R. Rai, David Hurd, Raymond Hohl, Michael C. Perry, Jon Gockerman, Sreenivasa Nattam, Richard A. Larson. (2009) Fludarabine followed by alemtuzumab consolidation for previously untreated chronic lymphocytic leukemia: final report of Cancer and Leukemia Group B study 19901. Leukemia & Lymphoma 50:10, 1589-1596
CrossRef37
T. D. Shanafelt. (2009) Predicting clinical outcome in CLL: how and why. Hematology 2009:1, 421-429
CrossRef38
Raquel Castejón, Miguel Yebra, María-Jesús Citores, Mercedes Villarreal, José A. García-Marco, Juan A. Vargas. (2009) Drug induction apoptosis assay as predictive value of chemotherapy response in patients with B-cell chronic lymphocytic leukemia. Leukemia & Lymphoma 50:4, 593-603
CrossRef39
T. Zenz, A. Krober, K. Scherer, S. Habe, A. Buhler, A. Benner, T. Denzel, D. Winkler, J. Edelmann, C. Schwanen, H. Dohner, S. Stilgenbauer. (2008) Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood 112:8, 3322-3329
CrossRef40
Stefan Peinert, John F. Seymour. (2008) Indolent Lymphomas Other than Follicular and Marginal Zone Lymphomas. Hematology/Oncology Clinics of North America 22:5, 903-940
CrossRef41
Dighiero, Guillaume, . (2008) Monoclonal B-Cell Lymphocytosis — A Frequent Premalignant Condition. New England Journal of Medicine 359:6, 638-640
Full Text42
Tadeusz Robak. (2008) Alemtuzumab for B-cell chronic lymphocytic leukemia. Expert Review of Anticancer Therapy 8:7, 1033-1051
CrossRef43
M. Hallek, B. D. Cheson, D. Catovsky, F. Caligaris-Cappio, G. Dighiero, H. Dohner, P. Hillmen, M. J. Keating, E. Montserrat, K. R. Rai, T. J. Kipps. (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111:12, 5446-5456
CrossRef44
G Dighiero, TJ Hamblin. (2008) Chronic lymphocytic leukaemia. The Lancet 371:9617, 1017-1029
CrossRef45
Carolina Pavlovsky, Laura Pardo, Miguel A. Pavlovsky, Claudia Corrado, Sandra Sapia, Pablo Mountford, Mariela Monreal, Isolda Fernandez, Gustavo Milone, Astrid Pavlovsky, Mariana Juni, Santiago Pavlovsky. (2008) Is assessment of surface CD38 expression worthwhile as a prognostic factor in chronic lymphocytic leukemia patients?. Hematology 13:1, 24-27
CrossRef46
Renee C. Tschumper, Susan M. Geyer, Megan E. Campbell, Neil E. Kay, Tait D. Shanafelt, Clive S. Zent, Grzegorz S. Nowakowski, Timothy G. Call, Gordon W. Dewald, Diane F. Jelinek. (2008) Immunoglobulin diversity gene usage predicts unfavorable outcome in a subset of chronic lymphocytic leukemia patients. Journal of Clinical Investigation 118:1, 306-315
CrossRef47
Tom Butler, John G Gribben. (2008) Biologic prognostic markers and their application in clinical trials and management of chronic lymphocytic leukaemia patients. Expert Opinion on Medical Diagnostics 2:1, 101-112
CrossRef48
Dennis Carney. (2008) Peripheral blood lymphocytosis–what is the threshold for further investigation?. Leukemia & Lymphoma 49:9, 1659-1661
CrossRef49
Christine Fernandez, Christine Fernandez, Véronique Leblond, Johnny Moretto. 2008. Traitement des leucémies. , 655-670.
CrossRef50
Michele Roullet, Rachel Sargent, Theresa Pasha, Isabela Cajiao, Rebecca Elstrom, Treasa Smith, Stephen Liebhaber, Paul Zhang, Adam Bagg. (2007) ZAP70 Expression Assessed by Immunohistochemistry on Peripheral Blood: A Simple Prognostic Assay for Patients With Chronic Lymphocytic Leukemia. Applied Immunohistochemistry & Molecular Morphology 15:4, 471-476
CrossRef51
Christoph Plass, John C. Byrd, Aparna Raval, Stephan M. Tanner, Albert de la Chapelle. (2007) Molecular profiling of chronic lymphocytic leukaemia: genetics meets epigenetics to identify predisposing genes. British Journal of Haematology 139:5, 744-752
CrossRef52
Rebecca L. Auer, John Gribben, Finbarr E. Cotter. (2007) Emerging therapy for chronic lymphocytic leukaemia. British Journal of Haematology 139:5, 635-644
CrossRef53
Tadeusz Robak. (2007) Recent progress in the management of chronic lymphocytic leukemia. Cancer Treatment Reviews 33:8, 710-728
CrossRef54
Paolo Ghia, Andrés J.M. Ferreri, Federico Caligaris-Cappio. (2007) Chronic lymphocytic leukemia. Critical Reviews in Oncology/Hematology 64:3, 234-246
CrossRef55
A. P. Kater, M. H. J. van Oers, T. J. Kipps. (2007) Cellular immune therapy for chronic lymphocytic leukemia. Blood 110:8, 2811-2818
CrossRef56
Tait D. Shanafelt, Deborah Bowen, Chaya Venkat, Susan L. Slager, Clive S. Zent, Neil E. Kay, Megan Reinalda, Jeff A. Sloan, Timothy G. Call. (2007) Quality of life in chronic lymphocytic leukemia: an international survey of 1482 patients. British Journal of Haematology 139:2, 255-264
CrossRef57
Claire Dearden. 2007. Chronic Lymphocytic Leukaemia. .
CrossRef58
Deepa Sampath, William Plunkett. (2007) The role of DNA repair in chronic lymphocytic leukemia pathogenesis and chemotherapy resistance. Current Oncology Reports 9:5, 361-367
CrossRef59
Eva Giné, Carol Moreno, Jordi Esteve, Emili Montserrat. (2007) The role of stem-cell transplantation in chronic lympocytic leukemia risk-adapted therapy. Best Practice & Research Clinical Haematology 20:3, 529-543
CrossRef60
Thorsten Zenz, Hartmut Döhner, Stephan Stilgenbauer. (2007) Genetics and risk-stratified approach to therapy in chronic lymphocytic leukemia. Best Practice & Research Clinical Haematology 20:3, 439-453
CrossRef61
N E Kay, S M O'Brien, A R Pettitt, S Stilgenbauer. (2007) The role of prognostic factors in assessing ‘high-risk’ subgroups of patients with chronic lymphocytic leukemia. Leukemia 21:9, 1885-1891
CrossRef62
Tomer T. Levin, Yuelin Li, John Riskind, Kanti Rai. (2007) Depression, anxiety and quality of life in a chronic lymphocytic leukemia cohort. General Hospital Psychiatry 29:3, 251-256
CrossRef63
I Ricca, A Rocci, D Drandi, R Francese, M Compagno, C Lobetti Bodoni, F De Marco, M Astolfi, L Monitillo, S Vallet, R Calvi, F Ficara, P Omedè, R Rosato, A Gallamini, C Marinone, L Bergui, M Boccadoro, C Tarella, M Ladetto. (2007) Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients. Leukemia
CrossRef64
Chadi Nabhan, Steven Coutré, Peter Hillmen. (2007) Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime?. British Journal of Haematology 136:3, 379-392
CrossRef65
T. D. Shanafelt, N. E. Kay. (2007) Comprehensive Management of the CLL Patient: A Holistic Approach. Hematology 2007:1, 324-331
CrossRef66
Giovanni Del Poeta, Maria Ilaria Del Principe, Francesco Buccisano, Luca Maurillo, Pasquale Niscola, Adriano Venditti, Sergio Amadori. (2006) Role of immunochemotherapy in the treatment of chronic lymphocytic leukemia. Expert Review of Anticancer Therapy 6:12, 1787-1800
CrossRef67
Stefan Faderl, William Wierda, Michael J. Keating. (2006) New aspects of the treatment of chronic lymphocytic leukemia. Current Hematologic Malignancy Reports 1:4, 251-257
CrossRef68
K. W. L. Yee, S. M. O'Brien. (2006) Chronic Lymphocytic Leukemia: Diagnosis and Treatment. Mayo Clinic Proceedings 81:8, 1105-1129
CrossRef69
Jozef Hatok, Peter Račay, Jan Hudeček, Dušan Dobrota. (2006) Genes of multidrug resistance in haematological malignancies. Biologia 61:3, 247-256
CrossRef70
Peter Hillmen. (2006) Beyond Detectable Minimal Residual Disease in Chronic Lymphocytic Leukemia. Seminars in Oncology 33, 23-28
CrossRef71
Nicole Lamanna, Mark A. Weiss. (2006) Purine Analogue-Based Chemotherapy Regimens for Second-Line Therapy in Patients With Chronic Lymphocytic Leukemia. Seminars in Hematology 43, S44-S49
CrossRef72
Neil E. Kay. (2006) Purine Analogue-Based Chemotherapy Regimens for Patients With Previously Untreated B-Chronic Lymphocytic Leukemia. Seminars in Hematology 43, S50-S54
CrossRef73
Nicole Lamanna. (2006) Advances in the treatment of chronic lymphocytic leukemia. Current Hematologic Malignancy Reports 1:1, 43-48
CrossRef74
Clive S. Zent, Timothy G. Call, William J. Hogan, Tait D. Shanafelt, Neil E. Kay. (2006) Update on risk-stratified management for chronic lymphocytic leukemia. Leukemia & Lymphoma 47:9, 1738-1746
CrossRef75
Vincenzo Callea, Maura Brugiatelli, Caterina Stelitano, Massimo Gentile, Francesco Nobile, Fortunato Morabito. (2006) Incidence of second neoplasia in patients with B-cell chronic lymphocytic leukemia treated with chlorambucil maintenance chemotherapy. Leukemia & Lymphoma 47:11, 2314-2320
CrossRef76
R. Cailliod, C. Quantin, P. M. Carli, V. Jooste, G. Teuff, Binquet C., M. Maynadie. (2005) A Population-based Assessment of the Prognostic Value of the CD19 Positive Lymphocyte Count in B-cell Chronic Lymphocytic Leukemia using Cox and Markov Models. European Journal of Epidemiology 20:12, 993-1001
CrossRef77
M A Hussein, H Gundacker, D R Head, L Elias, K A Foon, D H Boldt, S M Dobin, S R Dakhil, G T Budd, F R Appelbaum. (2005) Cyclophosphamide followed by fludarabine for untreated chronic lymphocytic leukemia: a phase II SWOG TRIAL 9706. Leukemia 19:11, 1880-1886
CrossRef78
Nicole Lamanna. (2005) Advances in the treatment of chronic lymphocytic leukemia. Current Oncology Reports 7:5, 333-338
CrossRef79
Agnes Kapou, Manolis A. Fousteris, Sotiris S. Nikolaropoulos, Maria Zervou, Simona G. Grdadolnik, Panagiotis Zoumpoulakis, Ioanna Kyrikou, Thomas Mavromoustakos. (2005) 2D NMR and conformational analysis of a prototype anti-tumour steroidal ester. Journal of Pharmaceutical and Biomedical Analysis 38:3, 428-434
CrossRef80
Stefano Molica, Francesca R Mauro, Vincenzo Callea, Massimo Gentile, Diana Giannarelli, Manuela Lopez, Francesco Lauria, Bruno Rotoli, Marco Montanaro, Agostino Cortelezzi, Vincenzo Liso, Franco Mandelli, Robin Foa, on behalf of the GIMEMA CLL Study G. (2005) A gender-based score system predicts the clinical outcome of patients with early B-cell chronic lymphocytic leukemia. Leukemia & Lymphoma 46:4, 553-560
CrossRef81
Tadeusz Robak. (2005) Therapy of Chronic Lymphocytic Leukaemia with Purine Nucleoside Analogues. Drugs & Aging 22:12, 983-1012
CrossRef82
Stefano Molica. (2005) Second neoplasms in chronic lymphocytic leukemia: incidence and pathogenesis with emphasis on the role of different therapies. Leukemia & Lymphoma 46:1, 49-54
CrossRef83
Evaggelia S. Arsenou, Manolis A. Fousteris, Anna I. Koutsourea, Athanasios Papageorgiou, Venetia Karayianni, Eleftheria Mioglou, Zafiria Iakovidou, Dionysios Mourelatos, Sotiris S. Nikolaropoulos. (2004) The allylic 7-ketone at the steroidal skeleton is crucial for the antileukemic potency of chlorambucil??s active metabolite steroidal esters. Anti-Cancer Drugs 15:10, 983-990
CrossRef84
Clive S. Zent, Neil E. Kay. (2004) Advances in the understanding of biology and prognosis in chronic lymphocytic leukemia. Current Oncology Reports 6:5, 348-354
CrossRef85
Rassenti, Laura Z., Huynh, Lang, Toy, Tracy L., Chen, Liguang, Keating, Michael J., Gribben, John G., Neuberg, Donna S., Flinn, Ian W., Rai, Kanti R., Byrd, John C., Kay, Neil E., Greaves, Andrew, Weiss, Arthur, Kipps, Thomas J., . (2004) ZAP-70 Compared with Immunoglobulin Heavy-Chain Gene Mutation Status as a Predictor of Disease Progression in Chronic Lymphocytic Leukemia. New England Journal of Medicine 351:9, 893-901
Full Text86
Guillaume Dighiero. (2004) Perspectives in chronic lymphocytic leukemia biology and management. Hematology/Oncology Clinics of North America 18:4, 927-943
CrossRef87
A. Gaiger, D. Heintel, U. Jager. (2004) Novel molecular diagnostic and therapeutic targets in chronic lymphocytic leukaemia. European Journal of Clinical Investigation 34:s2, 25-30
CrossRef88
Karen WL Yee, Susan M O’Brien, Francis J Giles. (2004) An update on the management of chronic lymphocytic leukaemia. Expert Opinion on Pharmacotherapy 5:7, 1535-1554
CrossRef89
Apostolia M. Tsimberidou, Michael J. Keating, Francis J. Giles, William G. Wierda, Alessandra Ferrajoli, Susan Lerner, Miloslav Beran, Michael Andreeff, Hagop M. Kantarjian, Susan O'Brien. (2004) Fludarabine and mitoxantrone for patients with chronic lymphocytic leukemia. Cancer 100:12, 2583-2591
CrossRef90
Nicolás Manito, Edgardo Kaplinsky, Josep Roca, Alberto Fernandez de Sevilla, Eduardo Castells, Enrique Esplugas. (2004) Heart transplantation and chronic lymphocytic leukemia: a successful case at 2 years of follow-up. The Journal of Heart and Lung Transplantation 23:6, 777-779
CrossRef91
D. Oscier, C. Fegan, P. Hillmen, T. Illidge, S. Johnson, P. Maguire, E. Matutes, D. Milligan. (2004) Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. British Journal of Haematology 125:3, 294-317
CrossRef92
Jan Maxwell Nørgaard, Lene Hyldahl Olesen, Peter Hokland. (2004) Changing picture of cellular drug resistance in human leukemia. Critical Reviews in Oncology/Hematology 50:1, 39-49
CrossRef93
T. D. Shanafelt, T. G. Call. (2004) Current Approach to Diagnosis and Management of Chronic Lymphocytic Leukemia. Mayo Clinic Proceedings 79:3, 388-398
CrossRef94
ANNETTE NICOLLE, STEPHEN J PROCTOR, GEOFFREY P SUMMERFIELD. (2004) High Dose Chlorambucil in the Treatment of Lymphoid Malignancies. Leukemia & Lymphoma 45:2, 271-275
CrossRef95
Mouhammed J Kyasa, Linda Hazlett, Rudolph S Parrish, Steven A Schichman, Clive S Zent. (2004) Veterans with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) have a Markedly Increased Rate of Second Malignancy, which is the Most Common Cause of Death. Leukemia & Lymphoma 45:3, 507-513
CrossRef96
MARTIN M OKEN, SANDRA LEE, NEIL E KAY, WILLIAM KNOSPE, PETER A CASSILETH. (2004) Pentostatin, Chlorambucil and Prednisone Therapy for B-Chronic Lymphocytic Leukemia: A Phase I/II Study by the Eastern Cooperative Oncology Group Study E1488. Leukemia & Lymphoma 45:1, 79-84
CrossRef97
Olivier Guipaud, Ludovic Deriano, Hélène Salin, Laurent Vallat, Laure Sabatier, Hélène Merle-Béral, Jozo Delic. (2003) B-cell chronic lymphocytic leukaemia: a polymorphic family unified by genomic features. The Lancet Oncology 4:8, 505-514
CrossRef98
Alberto Redaelli, Jennifer M Stephens, Benjamin L Laskin, Chris L Pashos, Marc F Botteman. (2003) The burden and outcomes associated with four leukemias: AML, ALL, CLL and CML. Expert Review of Anticancer Therapy 3:3, 311-329
CrossRef99
Françoise Vuillier, Guillaume Dighiero. (2003) Monocyte-derived Dendritic Cells in Chronic Lymphocytic Leukemia. Leukemia & Lymphoma 44:8, 1267-1273
CrossRef100
Gerassimos A. Pangalis, Theodoros P. Vassilakopoulos, Maria N. Dimopoulou, Marina P. Siakantaris, Flora N. Kontopidou, Maria K. Angelopoulou. (2002) B-chronic lymphocytic leukemia: practical aspects. Hematological Oncology 20:3, 103-146
CrossRef101
Leslie Andritsos, Hanna Khoury. (2002) Chronic lymphocytic leukemia. Current Treatment Options in Oncology 3:3, 225-231
CrossRef102
Jeremy G. Perkins, Joseph M. Flynn, Robin S. Howard, John C. Byrd. (2002) Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma. Cancer 94:7, 2033-2039
CrossRef103
Tadeusz Robak. (2002) The Role of Nucleoside Analogues in the Treatment of Chronic Lymphocytic Leukemia-Lessons Learned from Prospective Randomized Trials. Leukemia & Lymphoma 43:3, 537-548
CrossRef104
J.A. Silverman, E. Franssen, R. Buckstein, K.R. Imrie. (2002) The Development of Marked Elevation in White Blood Cell Count Does Not Predict Inferior Outcome in Chronic Lymphocytic Leukemia. Leukemia & Lymphoma 43:6, 1245-1251
CrossRef105
Stephane Cheze, Michel Leporrier. (2002) Chronic Lymphocytic Leukemia. American Journal of Cancer 1:2, 127-143
CrossRef106
Francoise Vuillier, Karim Maloum, Elaine K. Thomas, Colette Jouanne, Guillaume Dighiero, Daniel Scott-Algara. (2001) Functional monocyte-derived dendritic cells can be generated in chronic lymphocytic leukaemia. British Journal of Haematology 115:4, 831-844
CrossRef107
M.J Keating. (2001) Progress in CLL, chemotherapy, antibodies and transplantation. Biomedicine & Pharmacotherapy 55:9-10, 524-528
CrossRef108
Stefano Molica, Gaetano Vitelli, Domenico Levato, Diana Giannarelli, Giuseppe Maria Gandolfo. (2001) Elevated serum levels of soluble CD44 can identify a subgroup of patients with early B-cell chronic lymphocytic leukemia who are at high risk of disease progression. Cancer 92:4, 713-719
CrossRef109
Vincent Levy, Raphaël Porcher, Fabrice Delabarre, Michel Leporrier, Bruno Cazin, Sylvie Chevret. (2001) Evaluating treatment strategies in chronic lymphocytic leukemia. Journal of Clinical Epidemiology 54:7, 747-754
CrossRef110
Mark A. Weiss. (2001) Novel treatment strategies in chronic lymphocytic leukemia. Current Oncology Reports 3:3, 217-222
CrossRef111
William G Wierda, Susan O’Brien. (2001) Immunotherapy of chronic lymphocytic leukemia. Expert Review of Anticancer Therapy 1:1, 73-83
CrossRef112
S Bolam, DG Oscier. 2001. Tumours of the Immune System. .
CrossRef113
Tadeusz Robak, Jerzy Z. Błonski, Marek Kasznicki. (2001) Does Intensive Treatment with High Dose Chlorambucil and Prednisone as First Line and Cladribine as Second Line Influence the Survival of the Patients with Chronic Lymphocytic Leukemia?. Leukemia & Lymphoma 41:5-6, 545-557
CrossRef114
Daniel Heintel, Ilse Schwarzinger, Claudia Chizzali-Bonfadin, Renate Thalhammer, Josef Schwarzmeier, Monika Fritzer-Szekeres, Ansgar Weltermann, Ingrid Simonitsch, Klaus Lechner, Ulrich Jaeger. (2001) Association of CD38 Antigen Expression with Other Prognostic Parameters in Early Stages of Chronic Lymphocytic Leukemia. Leukemia & Lymphoma 42:6, 1315-1321
CrossRef115
H. Mossafa, C. Fourcade, M. Pulic, L. Jary, S. Cheze, S. Szpiro-tapia, X. Troussard. (2001) Chronic Lymphocytic Leukemia Associated with Myelodysplastic Syndrome and/or Chronic Myeloid Leukemia: Evidence for Independent Clonal Chromosomal Evolution. Leukemia & Lymphoma 41:3-4, 337-341
CrossRef116
Eric Van Den Neste, Andre Delannoy, Walter Feremans, Augustin Ferrant, Lucienne Michaux. (2001) Second Primary Tumors and Immune Phenomena After Fludarabine or 2-Chloro-2′-Deoxy adenosine Treatment. Leukemia & Lymphoma 40:5-6, 541-550
CrossRef117
Terry J. Hamblin. (2001) Achieving Optimal Outcomes in Chronic Lymphocytic Leukaemia. Drugs 61:5, 593-611
CrossRef118
Dighiero, Guillaume, , Binet, Jacques-Louis, . (2000) When and How to Treat Chronic Lymphocytic Leukemia. New England Journal of Medicine 343:24, 1799-1801
Full Text119
Rai, Kanti R., Peterson, Bercedis L., Appelbaum, Frederick R., Kolitz, Jonathan, Elias, Laurence, Shepherd, Lois, Hines, John, Threatte, Gregory A., Larson, Richard A., Cheson, Bruce D., Schiffer, Charles A., . (2000) Fludarabine Compared with Chlorambucil as Primary Therapy for Chronic Lymphocytic Leukemia. New England Journal of Medicine 343:24, 1750-1757
Full Text120
Konradin Metze, Ana M. Lobo, Irene Lorand-Metze. (2000) Nucleolus organizer regions (AgNORs) and total tumor mass are independent prognostic parameters for treatment-free period in chronic lymphocytic leukemia. International Journal of Cancer 89:5, 440-443
CrossRef121
Michael J. Keating, Susan O'Brien. (2000) Conventional Management of Chronic Lymphocytic Leukemia. Reviews in Clinical and Experimental Hematology 4:2, 118-133
CrossRef122
Didier Decaudin, Celia Salanoubat, Patrice Carde. (2000) Is Mantle Cell Lymphoma A Sex-Related Disease?. Leukemia & Lymphoma 37:1-2, 181-184
CrossRef123
Nelson Kalil, Bruce D. Cheson. (2000) Management of Chronic Lymphocytic Leukaemia. Drugs & Aging 16:1, 9-27
CrossRef124
Stefano Molica, Gaetano Vitelli, Domenico Levato, Giuseppe Maria Gandolfo, Vincenzo Liso. (1999) Increased serum levels of vascular endothelial growth factor predict risk of progression in early B-cell chronic lymphocytic leukaemia. British Journal of Haematology 107:3, 605-610
CrossRef125
V. Mateo, L. Lagneaux, D. Bron, G. Biron, M. Armant, G. Delespesse, M. Sarfati. (1999) CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia. Nature Medicine 5:11, 1277-1284
CrossRef126
Andrew G. Bosanquet, Stephen A. Johnson, Sue M. Richards. (1999) Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay. British Journal of Haematology 106:1, 71-77
CrossRef127
William G. Wierda, Thomas J. Kipps. (1999) Chronic lymphocytic leukemia. Current Opinion in Hematology 6:4, 253
CrossRef128
Jacques Gardais. (1999) Is there still a place for clinical staging in chronic lymphocytic leukaemia?. Leukemia Research 23:6, 589-592
CrossRef129
O. Hermine. (1999) Hématologie. La Revue de Médecine Interne 20:1, 74-80
CrossRef130
(1998) Secondary Acute Leukemia in Chronic Lymphocytic Leukemia. New England Journal of Medicine 339:13, 924-924
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