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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-03-0972.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Clinic I of Internal Medicine, University of
Cologne, Cologne, Germany; WiSP Research, Langenfeld, Germany; Medical
Clinic III Hematology, Oncology and Transfusion Medicine,
Universitätsklinikum Benjamin Franklin, Berlin, Germany; Center
of Internal Medicine, Robert-Bosch-Krankenhaus, Stuttgart, Germany;
Department of Medicine V, Hematology/Rheumatology/Oncology,
Ruprecht-Karls-University, Heidelberg, Germany; Medical Clinic,
Hematology/Oncology, Klinikum Erfurt GmbH, Erfurt, Germany; Department
of Medicine/Hematology and Oncology, Charité Campus Virchow
Klinikum, Berlin, Germany; and the German CLL Study Group, Munich,
Germany.
This multicenter phase 2 trial investigated safety and efficacy of
a new immunochemotherapeutic regimen combining rituximab (R) and
fludarabine (F) in patients with fludarabine- and anthracycline-naive chronic lymphocytic leukemia (CLL). The rationale for using R + F
includes single-agent efficacy of both drugs, in vitro synergism of R
and F, and no apparent overlapping toxicity. Of 31 eligible patients
with B-CLL enrolled, 20 were previously untreated and 11 relapsed.
Treatment consisted of fludarabine administered at standard doses (25 mg/m2/d; days 1-5, 29-33, 57-61, and 85-89) and rituximab
(375 mg/m2/d) given on days 57, 85, 113, and 151. Side
effects such as fever, chills, and exanthema were generally mild
(National Cancer Institute Common Toxicity Criteria [NCI-CTC]
grade 1/2 in 48% and grade 3 and/or 4 in 3% of
patients). Fever and chills were mainly associated with the first
rituximab infusion. Hematologic toxicity included neutropenia (grade 1 and/or 2 in 26%, grade 3 and/or 4 in 42%) and
thrombocytopenia (grade 1 and/or 2 in 19%, grade 3 and/or 4 in 9%). One patient died of cerebral bleeding during
prolonged thrombocytopenia after the second cycle of fludarabine. There were a total of 32 infections in 16 patients, none of which was fatal.
The overall response rate (complete remission [CR] and partial
remission [PR]) was 87% (27 of 31 evaluable patients). In 20 previously untreated patients, 17 (85%) responded. Ten of 31 patients
achieved CR (5 of 20 untreated; 5 of 11 pretreated; 9 of 21 Binet stage
B, 1 of 10 Binet stage C). The median duration of response was 75 weeks. We conclude that the combination of rituximab and fludarabine is
feasible and effective in patients with B-CLL.
(Blood. 2002;100:3115-3120) Recent advances in understanding the biology of
chronic lymphocytic leukemia (CLL) indicate that there are 2 variants
arising at different stages of B-cell differentiation. This variance is reflected by the mutational status of the immunoglobulin variable region (IgV) genes.1 In addition, by using fluorescence in situ hybridization technique, genomic aberrations can be diagnosed in
up to 80% of cases. Both the IgV mutation status and the
pattern of genomic aberrations have a high predictive value for disease progression and survival in patients with CLL.2,3
Therefore, therapeutic approaches are currently being reassessed with
emphasis on prognostic factor-directed therapy.
This development is accompanied by promising new treatment options. The
most convincing results were reported for a single-agent therapy using
the purine analog fludarabine. In pretreated patients the overall
response rates range from 50% to 60%. Approximately 80% of untreated
patients respond with a complete remission (CR) rate of
35%.4,5 Randomized trials demonstrated that fludarabine induces higher responses and more durable remissions compared with
chlorambucil; cyclophosphamide, hydroxydaunomycin, Oncovin (vincristine), and prednisone (CHOP); or cyclophosphamide, Adriamycin (doxorubicin), and prednisone (CAP).6,7 However,
the most relevant clinical end point, overall survival, was not
substantially different.6,7
Despite encouraging results with fludarabine or fludarabine
combinations, all patients ultimately relapse. Relapse is most probably
a result of residual tumor cells. Studies using minimal residual
disease (MRD) assays with lower sensitivity reported some MRD-negative
cases after fludarabine therapy.8,9 In contrast, a more
recent study comprising 16 newly diagnosed cases of CLL documented that
all patients in CR had polymerase chain reaction (PCR)-detectable
residual tumor cells.10 Thus, most likely all patients
with CLL treated with conventional chemotherapy have residual tumor
cells. Because a true CR is the major therapeutic goal in CLL, there is
a need for new therapeutic approaches with different mechanism of action.
Aggressive treatment such as high-dose chemotherapy followed by
autologous or allogeneic transplantation for selected younger high-risk
patients or combinations of fludarabine with other cytostatic agents
are currently under investigation. Different regimens using fludarabine
plus anthracylines and/or cyclophosphamide have been evaluated. In
untreated patients combining fludarabine (F; 30 mg/m2, days
1-3) and cyclophosphamide (C; 300 mg/m2 daily for 3 days)
increases the overall response rate to 88% and the CR rate to
35%.11 However, neutropenic fever or severe infections
occurred in up to 40% of patients treated.11-13 Thus, randomized clinical trials are currently being conducted to compare the
FC combination to fludarabine alone.
Monoclonal antibodies such as rituximab (anti-CD20) have attracted
substantial interest as a new class of effective reagents in the
treatment of malignant lymphoma.14 Rituximab is a
chimeric-humanized monoclonal antibody that has given response rates of
50% in relapsed or refractory low-grade non-Hodgkin lymphoma (NHL).
Treatment results with single-agent rituximab in patients with CLL
using conventional doses were inferior compared with follicular
lymphoma.15 This result might, at least in part, be due to
the lower density of CD20 antigen expression on CLL
cells.16,17 Pharmacokinetic studies revealed a
substantially lower pretreatment plasma level of rituximab in patients
with CLL compared with those with other low-grade
lymphoma.18 Patients with higher numbers of circulating CD20+ tumor cells were more likely to experience severe
side effects related to a massive release of cytokines.19
Severe acute reactions were generally more common during initial
infusion.19,20 These side effects can be controlled by a
"stepped-up" dosing of rituximab or the addition of
steroids.21
Experimental data indicate a potential superadditive effect of
combining rituximab with fludarabine because of modified BcL-2 expression.22 In addition rituximab can enhance the
sensitivity of tumor cells to chemotherapy-induced apoptosis and might
thus help to functionally overcome clinical drug resistance. A recent preclinical study demonstrated synergy between rituximab and
fludarabine.23 This synergistic effect might be due to the
down-regulation of Bcl-2 through inhibition of interleukin 10. Down-regulation of the anticomplement proteins CD55, CD46, and CD 59 might also contribute to this synergy.23-25
On the basis of the rationale of synergistic and potential
superadditive effects of fludarabine and rituximab, we conducted a
multicenter phase 2 trial, investigating the safety and efficacy of a
sequential application schedule in patients with fludarabine- and
anthracycline-naive CLL. Here, we report the clinical results of this
combined immunochemotherapy.
This prospective multicenter, open-label, phase 2 study was
conducted between August 1999 and February 2001 and involved 6 centers
in Germany. The study was carried out in accordance to the Declaration
of Helsinki (Hong Kong Amendment, 1989). The protocol met all
requirements of the European Good Clinical Practice Guidelines (July
1990) and received approval from the ethics committees of all
participating centers. All eligible patients gave written informed
consent. The first objective of this study was to determine whether the
combination of fludarabine and rituximab is feasible and well
tolerated. The second objective was to test the efficacy of this
combination treatment in CLL patients. The response rate (CR + PR)
was chosen as primary efficacy end point.
Patients with CLL as defined by the National Cancer Institute
(NCI)-sponsored working group, aged 18 to 75 years, with stages Binet
B or C, at first diagnosis or after treatment with chlorambucil, prednisone, or a combination of both, were enrolled into the study. More than 30% of all peripheral lymphocytic cells had to be
CD20+. An Eastern Cooperative Oncology Group (ECOG)
performance status of 0 to 3 was required with a life expectancy of at
least 3 months. Patients were excluded if they had received prior
treatment with fludarabine or anthracycline-containing regimens or had
a positive Coombs test. Other exclusion criteria were Richter syndrome,
previous treatment with murine antibodies, active opportunistic
infections, any other severe infection not controlled by medical or
surgical therapy, or major organ dysfunction. Patients who were
pregnant or lactating or those who had participated in other trials
during the past 12 weeks were also excluded.
Treatment plan
Patient monitoring
Definition of end points
Complete remission. CR criteria included no evidence of disease; absence of lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal blood count (neutrophils > 1.5 × 109/L, platelets > 100 × 109/L, hemoglobin > 11 g/dL, lymphocytes < 4.0 × 109/L); bone marrow biopsy with normal cellularity; and lymphocytes less than 30%. A CR not confirmed by bone marrow biopsy was designated as CRu. CR had to be maintained for at least 8 weeks. Partial remission. A PR was defined as change from stage C to stage A or B, change from stage B to A (Binet), or at least 50% reduction in blood lymphocytes and 50% reduction in lymphadenopathy and/or 50% reduction in splenomegaly and/or hepatomegaly, plus at least one of the following features: neutrophils more than 1.5 × 109/L or 50% improvement over baseline, platelets more than 100 × 109/L or 50% improvement over baseline, or hemoglobin more than 11.0 g/dL (not supported by transfusion) or 50% improvement over baseline. A PR had to be maintained for at least 8 weeks. Stable disease. Stable disease (SD) was defined as no change in stage (Binet) and no CR, PR, or progression. Progressive disease. Progressive disease (PD) was defined as change from stage A disease to stage B or C, or from stage B to C. At least one of the following also needed to be present: more than 50% increase in the size of at least 2 lymph nodes or new palpable lymph nodes; more than 50% increase of splenomegaly or hepatomegaly, transformation to a more aggressive histology, Richter syndrome, or prolymphocytic leukemia; and at least more than 50% increase in the absolute number of circulating lymphocytes. Event-related criteria. Progression-free survival was defined as the time from initiation of treatment until last follow-up, the time at which progression occurred according to the modified NCI criteria26 or further therapy for symptomatic CLL was required or death occurring from any cause. Duration of response is defined as progression-free survival in the subgroup of patients who achieved a complete or partial remission. Sample size determination A single-stage design according to the method of Fleming27 was selected, based on the following assumptions: (1) The experimental treatment under study in this trial would be considered as not sufficiently effective, if the true response rate (CR + PR) was lower than 60%; (2) the combination treatment with fludarabine/rituximab would be regarded as very promising for further investigation (eg, in a phase 3 comparative trial), if the true response rate exceeded 90%; (3) the probability of erroneously declaring the drug as sufficiently active for further investigation despite a true response rate of less than 60% (type I error) is set at 5%; (4) the probability of erroneously rejecting the therapy as not sufficiently active (< 60%) in case of a true promising response rate (> 90%) is 20% (type II error; power = 80%).Concerning feasibility and tolerability, a failure rate of up to 10% was considered to be acceptable. On the basis of 30 patients, an intolerability rate of more than 10% is ruled out with a probability of 80% (one-sided 80% confidence limit) if the combination treatment is found to be not feasible in all patients or all but one patient. Statistical analysis For the efficacy analysis, patients had to have received at least one cycle of therapy. All patients having received at least one application of study therapy were also evaluable for toxicity. Rate comparisons between patient subgroups were performed by using the Fisher exact test. Event-related data (survival and progression-free survival, response duration) were estimated by the product limit method.28 Prognostic subgroups were compared by using the log-rank test.29
A total of 34 patients were enrolled. One patient was found to have no B-CLL and was therefore withdrawn by the participating center before having received any trial medication. Two patients had been pretreated with fludarabine or other purine analogues and were thus excluded from the study. The remaining 31 patients were evaluable for toxicity and response. One patient developed a prolonged thrombocytopenia after the second cycle of fludarabine and was refractory to platelet transfusion. This patient died as a result of cerebral bleeding on day 69, without receiving further study medication. Demographic characteristics Table 1 shows the demographic characteristics of the 31 evaluable patients with B-CLL. Patients had a median age of 59 years (range, 30-70 years). More than half of the patients (51%) had a reduced performance status (ECOG Index > 0). The time from first diagnosis ranged from 1 to 10 years. At the time of study entry 21 patients had Binet stage B and 10 had Binet stage C. Fifty-two percent of the patients exhibited B symptoms. The median number of prior treatments in 11 pretreated patients was 1 (range, 0-2 treatments), consisting mainly of chlorambucil alone or in combination with prednisone. Cytologic and/or histologic examination of bone marrow samples was provided in the majority (87%) of cases. The infiltration pattern was predominantly diffuse (85%).
Adverse events Adverse events were graded according to the NCI Common Toxicity Criteria Grading System (version 2.0, April 1999). Table 2 shows the hematologic toxicity during treatment. Severe anemia (grade 3 and/or 4) was observed in 10% of patients, severe leukopenia in 25%, neutropenia in 42%, and thrombopenia in 9%, respectively. The overall figures for leucocytes, lymphocytes, and platelets during treatment are shown in Figure 2. The most frequent nonhematologic side effects were infections (52%) and infusion-related symptoms such as chills (39%), fever (32%), and erythema (26%) (Table 3). Importantly, only one grade 3 fever was encountered. A total of 32 infections were observed in 16 patients (Table 4). Most of the infections were respiratory (10 of 32) and herpes virus infections (7 of 32). However, only 4 infections were fever of unknown origin (grade 3 and/or 4). More than 60% of the 167 adverse events reported were judged as nontreatment-related by the treating physician (data not shown).
Response Responses are listed in Table 5. The overall response rate was 87%, based on 31 evaluable patients. The combined CR/CRu rate was 33%. In addition, 55% of patients achieved a PR. One patient had SD, and 2 (7%) had refractory disease. There were no statistically significant differences in the subgroup analysis between untreated and pretreated patients. In addition, there were no substantial differences between Binet stage B and C patients, respectively, although there were fewer CRs in Binet C patients (11%) compared with Binet B patients (43%). The analysis of duration of response (Figure 3) is rather preliminary, due to a median follow-up duration of only 54 weeks. Currently, the median duration of response amounts to 75 weeks.
The following findings emerge from the present study: (1) The combined chemoimmunotherapy consisting of 4 cycles of fludarabine and 4 cycles of rituximab is very effective in patients with B-CLL. The overall response rate in the present phase 2 study involving 31 patients was 87% with a CR rate of 33% (CR and CRu) and a PR rate of 55%. The overall response rate was similar in previously treated (90%) and untreated patients (85%). There was no substantial difference in the overall response between patients in stage Binet B or C, although there were more CRs in Binet B patients (43%) compared with Binet C patients (11%). (2) This new treatment regimen is feasible and can be administered safely on an outpatient basis. Toxicity was moderate with no increased risk of severe infection. There were only 4 patients (13%) with grade 3 or 4 (World Health Organization [WHO]) infections, none of which was fatal. Grade 3 and/or 4 hematologic toxicity was observed for neutropenia (42% of patients), anemia (10%), and thrombocytopenia (9%), respectively. Other side effects included chills (39%), fever (32%), and erythema (26%). The overall response rate of 87% in our study compares favorably to those reported from the most effective chemotherapy combinations in patients with CLL.11-13 However, the response rates observed in the present trial were achieved with 4 courses of fludarabine, whereas 6 cycles were generally used in single-agent fludarabine or fludarabine/cyclophosphamide trials. Thus, the total fludarabine dose is lower in the present trial compared with most trials in which fludarabine is involved. This low dose might, at least in part, explain the mild side effects observed in the present trial. In addition, only very moderate dose reduction or deviation from the planned time schedule was necessary (data not shown). There were only minor acute side effects and also no event of hemolytic anemia in the present trial. The incidence of autoimmune hemolytic anemia in patients with CLL treated with fludarabine alone ranges between 11% and 21%.30-32 The temporary B-cell depletion caused by rituximab might prevent the development of fludarabine-associated autoimmune hemolytic anemia. This hypothesis is supported by the findings of others who observed effective treatment of acute immune hemolytic anemia with rituximab.33,34 Thus, the combined chemoimmunotherapy might actually reduce treatment-related side effects because of the nonoverlapping toxicity profile. Promising results of combination regimens with rituximab and cytotoxic drugs have been reported earlier in patients with advanced-stage low-grade B-cell NHL. In a nonrandomized study, the response rate was 95% with CR in 55%.35 In addition, 7 of 7 patients with follicular histology and complete remission were rendered bcl-2 negative. A more recent prospective phase 3 study randomly assigned 399 elderly patients with diffuse large B-cell lymphoma.36 Patients received either 8 cycles of CHOP or 8 cycles of CHOP plus rituximab (R-CHOP). The CR rate was significantly higher in the R-CHOP group (76% versus 63%, P = .005). With a median follow-up of 2 years, event-free and overall survival times were also substantially higher in the R-CHOP group: at 2 years, 70% of patients treated with R-CHOP were alive as compared with 57% of those treated with CHOP alone. Disease progression during treatment was observed in 22% of patients in the CHOP group and 9% of patients in the R-CHOP group. Recent trials with rituximab in patients with CLL have suggested a dose-response relationship whereby most cases responded at higher doses.37 These trials used up to 4 times the conventional dose of rituximab. However, the costs associated with rituximab at very high doses are substantial. In addition, patients with CLL with high peripheral tumor cell load are at risk of developing severe infusion-related side effects and thrombocytopenia when treated with rituximab alone.15,19,20 The promising results reported from this phase 2 trial are in line with those of Byrd et al,38 who conducted a randomized phase 2 trial of sequential versus concurrent rituximab in patients receiving fludarabine.38 Patients received either 6 cycles of fludarabine (25 mg/m2 days 1-5) followed 2 months later by rituximab (375 mg/m2 × 4) or concurrent rituximab at standard dose (375 mg/m2 at days 1 and 4 of fludarabine cycle 1 and on day 1 of fludarabine cycles 2-6). CR rate and overall response of 104 patients randomized were superior in the concurrent application arm. Investigators at the M.D. Anderson Center performed a retrospective analysis in patients with CLL that compared fludarabine (82 patients); fludarabine plus cyclophosphamide (53 patients); or fludarabine, cyclophosphamide, and rituximab (135 patients).39 Response rates were 85%, 91%, and 95%, respectively, with more CRs in the FCR combination (35%, 43%, and 63%). They also observed complete molecular remission as measured by PCR for immunoglobulin heavy-chain rearrangement in 56% of those patients who achieved CR. By using a more sensitive newly developed real-time ASO PCR technique with individual primers, we quantitatively analyzed 7 patients. Interestingly, one pretreated patient achieved complete molecular remission after rituximab and fludarabine.40 In summary, the results of a combined immunochemotherapy of rituximab and fludarabine demonstrate low toxicity and good efficacy in both pretreated and untreated patients with CLL. A randomized clinical trial in which this combination is being compared with fludarabine alone is warranted for patients with previously untreated CLL.
Submitted April 16, 2002; accepted June 11, 2002.
Prepublished online as Blood First Edition Paper, July 12, 2002; DOI 10.1182/blood-2002-03-0972.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Holger Schulz, Department I of Internal Medicine, University of Cologne, Cologne, 50924, Germany; e-mail: a.engert{at}uni-koeln.de.
1. Damle RN, Fais F, Ghiotto F, et al. Chronic lymphocytic leukemia: a proliferation of B cells at two distinct stages of differentiation. Curr Top Microbiol Immunol. 2000;252:285-292[Medline] [Order article via Infotrieve].
2.
Dohner H, Stilgenbauer S, Benner A, et al.
Genomic aberrations and survival in chronic lymphocytic leukemia.
N Engl J Med.
2000;343:1910-1916
3.
Damle RN, Wasil T, Fais F, et al.
Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.
Blood.
1999;94:1840-1847
4.
O'Brien S, Kantarjian H, Beran M, et al.
Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment.
Blood.
1993;82:1695-1700
5.
Keating MJ, O'Brien S, Kantarjian H, et al.
Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent.
Blood.
1993;81:2878-2884
6.
Rai KR, Peterson BL, Appelbaum FR, et al.
Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.
N Engl J Med.
2000;343:1750-1757 7. 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. The French Cooperative Group on CLL. Lancet. 1996;347:1432-1438[Medline] [Order article via Infotrieve].
8.
Esteve J, Villamor N, Colomer D, et al.
Hematopoietic stem cell transplantation in chronic lymphocytic leukemia: a report of 12 patients from a single institution.
Ann Oncol.
1998;9:167-172
9.
Robertson LE, Huh YO, Butler JJ, et al.
Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis.
Blood.
1992;80:29-36 10. Clavio M, Miglino M, Spriano M, et al. First line Fludarabine treatment of symptomatic chronic lymphoproliferative diseases: clinical results and molecular analysis of minimal residual disease. Eur J Haematol. 1998;61:197-203[Medline] [Order article via Infotrieve].
11.
O'Brien SM, Kantarjian HM, Cortes J, et al.
Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia.
J Clin Oncol.
2001;19:1414-1420
12.
Flinn IW, Byrd JC, Morrison C, et al.
Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies.
Blood.
2000;96:71-75 13. Hallek M, Schmitt B, Wilhelm M, et al. Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group. Br J Haematol. 2001;114:342-348[CrossRef][Medline] [Order article via Infotrieve]. 14. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825-2833[Abstract].
15.
Huhn D, von Schilling C, Wilhelm M, et al.
Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.
Blood.
2001;98:1326-1331 16. Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Catovsky D. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol. 1998;51:364-369[Abstract]. 17. Molica S, Levato D, Dattilo A, Mannella A. Clinico-prognostic relevance of quantitative immunophenotyping in B-cell chronic lymphocytic leukemia with emphasis on the expression of CD20 antigen and surface immunoglobulins. Eur J Haematol. 1998;60:47-52[Medline] [Order article via Infotrieve].
18.
Berinstein NL, Grillo-Lopez AJ, White CA, et al.
Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.
Ann Oncol.
1998;9:995-1001
19.
Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A.
Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8).
Blood.
1999;94:2217-2224
20.
Byrd JC, Waselenko JK, Maneatis TJ, et al.
Rituximab therapy in hematologic malignancy patients with circulating blood tumor cells: association with increased infusion-related side effects and rapid blood tumor clearance.
J Clin Oncol.
1999;17:791-795
21.
O'Brien SM, Kantarjian H, Thomas DA, et al.
Rituximab dose-escalation trial in chronic lymphocytic leukemia.
J Clin Oncol.
2001;19:2165-2170
22.
Alas S, Bonavida B.
Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs.
Cancer Res.
2001;61:5137-5144 23. Di Gaetano N, Xiao Y, Erba E, et al. Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol. 2001;114:800-809[CrossRef][Medline] [Order article via Infotrieve]. 24. Alas S, Bonavida B, Emmanouilides C. Potentiation of fludarabine cytotoxicity on non-Hodgkin's lymphoma by pentoxifylline and rituximab. Anticancer Res. 2000;20:2961-2966[Medline] [Order article via Infotrieve].
25.
Alas S, Emmanouilides C, Bonavida B.
Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis.
Clin Cancer Res.
2001;7:709-723
26.
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 27. Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982;38:143-151[CrossRef][Medline] [Order article via Infotrieve]. 28. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481[CrossRef]. 29. Peto R, Peto J. Asymptotically efficient rank invariation test procedures. J R Stat Soc A. 1972;135:185-206. 30. Weiss RB, Freiman J, Kweder SL, Diehl LF, Byrd JC. Hemolytic anemia after fludarabine therapy for chronic lymphocytic leukemia. J Clin Oncol. 1998;16:1885-1889[Abstract]. 31. Myint H, Copplestone JA, Orchard J, et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol. 1995;91:341-344[Medline] [Order article via Infotrieve]. 32. Di Raimondo F, Giustolisi R, Cacciola E, et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia patients treated with fludarabine. Leuk Lymphoma. 1993;11:63-68[Medline] [Order article via Infotrieve].
33.
Zecca M, De Stefano P, Nobili B, Locatelli F.
Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated, pure red cell aplasia and hemolytic anemia.
Blood.
2001;97:3995-3997 34. Quartier P, Brethon B, Philippet P, et al. Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet. 2001;358:1511-1513[CrossRef][Medline] [Order article via Infotrieve]. 35. Czuczman MS. CHOP plus rituximab chemoimmunotherapy of indolent B-cell lymphoma. Semin Oncol. 1999;26:88-96[Medline] [Order article via Infotrieve]. 36. Coiffier B, Ferme C, Hermine O, et al. Rituximab plus CHOP (R-CHOP) in the treatment of elderly patients with diffuse large B-cell lymphoma. An update of the GELA study. Blood. 2001;98:A3025.
37.
Byrd JC, Murphy T, Howard RS, et al.
Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity.
J Clin Oncol.
2001;19:2153-2164 38. Byrd JC, Peterson BL, Park K, et al. Concurrent rituximab and fludarabine has a higher complete response rate than sequential treatment in untreated chronic lymphocytic leukemia (CLL) patients: results from CALGB 9712. Blood. 2001;98:772a. 39. Wierda W, O'Brian S, Albitar M, et al. Combined fludarabine, cyclophosphamide, and rituximab achieve a high complete remission rate as initial treatment for chronic lymphocytic leukemia. Blood. 2001;98:771a. 40. Pfitzner T, Engert A, Wittor H, et al. A real-time PCR assay for the quantification of residual malignant cells in B cell chronic lymphatic leukemia. Leukemia. 2000;14:754-766[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  S. P. Treon, A. R. Branagan, L. Ioakimidis, J. D. Soumerai, C. J. Patterson, B. Turnbull, P. Wasi, C. Emmanouilides, S. R. Frankel, A. Lister, et al. Long-term outcomes to fludarabine and rituximab in Waldenstrom macroglobulinemia Blood, April 16, 2009; 113(16): 3673 - 3678. [Abstract] [Full Text] [PDF]
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 K. A. Foon, M. Boyiadzis, S. R. Land, S. Marks, A. Raptis, L. Pietragallo, D. Meisner, A. Laman, M. Sulecki, A. Butchko, et al. Chemoimmunotherapy With Low-Dose Fludarabine and Cyclophosphamide and High Dose Rituximab in Previously Untreated Patients With Chronic Lymphocytic Leukemia J. Clin. Oncol., February 1, 2009; 27(4): 498 - 503. [Abstract] [Full Text] [PDF]
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J. M. Flynn and J. C. Byrd Have We Forgotten the Purpose of Phase III Studies? J. Clin. Oncol., December 10, 2007; 25(35): 5553 - 5555. [Full Text] [PDF]
|
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 G. Ungerechts, C. Springfeld, M. E. Frenzke, J. Lampe, P. B. Johnston, W. B. Parker, E. J. Sorscher, and R. Cattaneo Lymphoma Chemovirotherapy: CD20-Targeted and Convertase-Armed Measles Virus Can Synergize with Fludarabine Cancer Res., November 15, 2007; 67(22): 10939 - 10947. [Abstract] [Full Text] [PDF]
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 K. W. L. Yee and S. M. O'Brien Chronic Lymphocytic Leukemia: Diagnosis and Treatment Mayo Clin. Proc., August 1, 2006; 81(8): 1105 - 1129. [Abstract] [Full Text] [PDF]
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F. Ravandi, J. L. Jorgensen, S. M. O'Brien, S. Verstovsek, C. A. Koller, S. Faderl, F. J. Giles, A. Ferrajoli, W. G. Wierda, S. Odinga, et al. Eradication of minimal residual disease in hairy cell leukemia Blood, June 15, 2006; 107(12): 4658 - 4662. [Abstract] [Full Text] [PDF]
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E. Montserrat, C. Moreno, J. Esteve, A. Urbano-Ispizua, E. Gine, and F. Bosch How I treat refractory CLL Blood, February 15, 2006; 107(4): 1276 - 1283. [Abstract] [Full Text] [PDF]
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J. C. Byrd, J. G. Gribben, B. L. Peterson, M. R. Grever, G. Lozanski, D. M. Lucas, B. Lampson, R. A. Larson, M. A. Caligiuri, and N. A. Heerema Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy J. Clin. Oncol., January 20, 2006; 24(3): 437 - 443. [Abstract] [Full Text] [PDF]
|
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 B. L. Abbott Chronic Lymphocytic Leukemia: Recent Advances in Diagnosis and Treatment Oncologist, January 1, 2006; 11(1): 21 - 30. [Abstract] [Full Text] [PDF]
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 R. Marasca, R. Maffei, M. Morselli, P. Zucchini, I. Castelli, S. Martinelli, M. Fontana, S. Ravanetti, M. Curotti, G. Leonardi, et al. Immunoglobulin Mutational Status Detected through Single-Round Amplification of Partial VH Region Represents a Good Prognostic Marker for Clinical Outcome in Chronic Lymphocytic Leukemia J. Mol. Diagn., November 1, 2005; 7(5): 566 - 574. [Abstract] [Full Text] [PDF]
|
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T. Elter, P. Borchmann, H. Schulz, M. Reiser, S. Trelle, R. Schnell, M. Jensen, P. Staib, T. Schinkothe, H. Stutzer, et al. Fludarabine in Combination With Alemtuzumab Is Effective and Feasible in Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia: Results of a Phase II Trial J. Clin. Oncol., October 1, 2005; 23(28): 7024 - 7031. [Abstract] [Full Text] [PDF]
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W. G. Wierda, T. J. Kipps, and M. J. Keating Novel Immune-Based Treatment Strategies for Chronic Lymphocytic Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6325 - 6332. [Abstract] [Full Text] [PDF]
|
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T. S. Lin, M. R. Grever, and J. C. Byrd Changing the Way We Think About Chronic Lymphocytic Leukemia J. Clin. Oncol., June 20, 2005; 23(18): 4009 - 4012. [Full Text] [PDF]
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M.S. Czuczman, A. Koryzna, A. Mohr, C. Stewart, K. Donohue, L. Blumenson, Z.P. Bernstein, P. McCarthy, A. Alam, F. Hernandez-Ilizaliturri, et al. Rituximab in Combination With Fludarabine Chemotherapy in Low-Grade or Follicular Lymphoma J. Clin. Oncol., February 1, 2005; 23(4): 694 - 704. [Abstract] [Full Text] [PDF]
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 M. Hallek and On Behalf Of The German CLL Study Group Chronic Lymphocytic Leukemia (CLL): First-Line Treatment Hematology, January 1, 2005; 2005(1): 285 - 291. [Abstract] [Full Text] [PDF]
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M. Ghielmini Multimodality Therapies and Optimal Schedule of Antibodies: Rituximab in Lymphoma as an Example Hematology, January 1, 2005; 2005(1): 321 - 328. [Abstract] [Full Text] [PDF]
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J. C. Byrd, K. Rai, B. L. Peterson, F. R. Appelbaum, V. A. Morrison, J. E. Kolitz, L. Shepherd, J. D. Hines, C. A. Schiffer, and R. A. Larson Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011 Blood, January 1, 2005; 105(1): 49 - 53. [Abstract] [Full Text] [PDF]
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T. D. Shanafelt and T. G. Call Current Approach to Diagnosis and Management of Chronic Lymphocytic Leukemia Mayo Clin. Proc., March 1, 2004; 79(3): 388 - 398. [Abstract] [PDF]
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T. D. Shanafelt, S. M. Geyer, and N. E. Kay Prognosis at diagnosis: integrating molecular biologic insights into clinical practice for patients with CLL Blood, February 15, 2004; 103(4): 1202 - 1210. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
2-microglobulin, serum
thymidinkinase, urine analysis, and Coombs test. Results of physical
examination, laboratory tests, and adverse events were recorded every 2 weeks throughout the treatment period.
