Journal of Clinical Oncology, Vol 19, Issue 8
(April), 2001: 2165-2170
© 2001 American Society for Clinical Oncology
Rituximab Dose-Escalation Trial in Chronic Lymphocytic Leukemia
By Susan M. O’Brien,
Hagop Kantarjian,
Deborah A. Thomas,
Francis J. Giles,
Emil J. Freireich,
Jorge Cortes,
Susan Lerner,
Michael J. Keating
From the Leukemia Department, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Address reprint requests to: Susan M. O’Brien, MD, Leukemia Department, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030.
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ABSTRACT
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PURPOSE: To conduct a dose-escalation trial of rituximab in patients with chronic lymphocytic leukemia (CLL) to define the maximum-tolerated dose (MTD), to evaluate first-dose reactions in patients with high circulating lymphocyte counts, and to assess the efficacy at higher versus lower doses.
PATIENTS AND METHODS: Fifty patients with CLL (n = 40) or other mature B-cell lymphoid leukemias (n = 10) were treated with four weekly infusions of rituximab. The first dose was 375 mg/m2 for all patients; dose- escalation began with dose 2 but was held constant for each patient. Escalated doses were from 500 to 2,250 mg/m2.
RESULTS: Toxicity with the first dose (375 mg/m2) was noted in 94% of patients but was grade 1 or 2 in most, predominantly fever and chills. Six patients (12%) experienced severe toxicity with the first dose, including fever, chills, dyspnea, and hypoxia in all six patients, hypotension in five, and hypertension in one. Toxicity on subsequent doses was minimal until a dose of 2,250 mg/m2 was achieved. Eight (67%) of 12 patients had grade 2 toxicity, including fever, chills, nausea, and malaise, although no patient had grade 3 or 4 toxicity. Severe toxicity with the first dose was significantly more common in patients with other B-cell leukemias, occurring in five (50%) of 10 patients versus one (2%) of 40 patients with CLL (P < .001). The overall response rate was 40%; all responses in patients with CLL were partial remissions. Response rates were 36% in CLL and 60% in other B-cell lymphoid leukemias. Response was correlated with dose: 22% for patients treated at 500 to 825 mg/m2, 43% for those treated at 1,000 to 1,500 mg/m2, and 75% for those treated at the highest dose of 2,250 mg/m2 (P = .007). The median time to disease progression was 8 months. Myelosuppression and infections were uncommon.
CONCLUSION: Rituximab has significant activity in patients with CLL at the higher dose levels. Severe first-dose reactions were uncommon in patients with CLL, even with high circulating lymphocyte counts, but were frequent in patients with other mature B-cell leukemias in which CD20 surface expression is increased. Efficacy of rituximab was also significant in this group of patients.
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INTRODUCTION
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RITUXIMAB IS a chimeric humanized monoclonal antibody that binds to the surface antigen CD20. CD20 is present on human B lymphocytes as well as on the lymphocytes from most patients with mature B-cell lymphoma and leukemia.1 The pivotal trial which led to Food and Drug Administration approval of rituximab described 166 patients with relapsed low-grade lymphoma who received rituximab at 375 mg/m2 weekly for a total of four doses.2 The overall response rate was 48%, with a striking difference in response rates among histologic types. International Working Formulation A patients (tissue equivalent of chronic lymphocytic leukemia [CLL]) had a markedly inferior response rate of only 12% compared with patients with follicular lymphoma.3 Cells from these patients have significantly less CD20 surface expression than is seen in patients with follicular lymphoma, and this is also true for patients with CLL.4 Pharmacokinetic studies conducted during this trial showed markedly lower levels of rituximab antibody in the serum of patients with Working Formulation A disease.2
Both factors, namely less CD20 surface expression and lower serum levels of the antibody, were taken into consideration in the design of the current trial. Patients with CLL have a large circulating tumor burden, and rituximab given at 375 mg/m2 might produce a low response rate, as extrapolated from the low-grade lymphoma trial. Hence, the aim of this trial was to conduct a dose-escalation study with rituximab in patients with previously treated CLL. Because rituximab is a monoclonal antibody rather than a chemotherapeutic agent, it was recognized that a true maximum-tolerated dose (MTD) might not be achieved, and the trial was designed so that if significant toxicity was seen on subsequent doses, dose escalation would cease because significant toxicity on subsequent administration is uncommon with the standard 375 mg/m2 dose. Because most toxicities in the pivotal trial were observed with the first dose and because there was concern that toxicity might be greater in patients with a high circulating tumor burden, all patients received a first dose of 375 mg/m2.
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PATIENTS AND METHODS
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Study Group
Fifty patients with either CLL (n = 40) or other mature B-cell leukemias (n = 10) were entered onto the study after an informed consent was obtained according to institutional guidelines. All patients had a pretreatment evaluation including history and physical examination, complete blood counts, differential and platelet counts, liver and renal function studies, bone marrow aspiration and biopsy, and samples for immunophenotyping. Entry criteria required the following: (1) confirmation of the diagnosis, (2) normal renal (creatinine < 2.0 mg/100 mL) and hepatic (bilirubin < 2.0 mg/100 mL) function, and (3) a performance status  3 (Zubrod scale). Patients with CLL in Rai stages III to IV were eligible. Patients with stages 0 to II disease were eligible if they had evidence of active disease as indicated by an increase in symptoms related to leukemia including weight loss of  10% over a 6-month period, temperature of 38°C or greater without evidence of infection, extreme fatigue, massive or progressive hepatosplenomegaly, or massive or progressive lymphadenopathy.
Therapy
All patients received the first dose of rituximab 375 mg/m2 intravenously over 6 to 12 hours. Diphenhydramine and acetaminophen were given as premedication and the rituximab was started at a low infusion rate of 50 mg/h, which was subsequently escalated to a maximum of 400 mg/h. If symptoms ensued, including fever and chills, the infusion was interrupted, patients were treated symptomatically, and the infusion was resumed at a lower rate and re-escalated.
For doses 2 through 4, all patients received a fixed but higher dose of rituximab; the dose levels were 500, 650, 825, 1,000, 1,500, and 2,250 mg/m2. The same premedication and infusion-rate parameters were used for the subsequent doses. A total of four doses at weekly intervals were administered. The 3 + 3 rule of phase I trials was applied: if grade 3 or 4 toxicity was seen in none of three patients, escalate to the next dose level; if grade 3 or 4 toxicity was seen in one of three patients, enter three more patients at that dose level; if grade 3 or 4 toxicity was seen in two of three to six patients, MTD is defined.
Response Criteria
Response criteria were those defined by the National Cancer Institute Working Group.5 Complete remission required disappearance of all palpable disease, normalization of blood counts with neutrophils at more than 1.5 x 109/L, platelets at more than 100 x 109/L, hemoglobin at more than 11 g/dL, a bone marrow aspirate lymphocyte percentage of less than 30%, and no evidence of disease on bone marrow biopsy. A nodular partial remission required the same criteria as a complete response, but lymphoid nodules could be seen on bone marrow biopsy. Partial remission required 50% or more reduction in palpable disease as well as one or more of the following remaining features: a neutrophil count of 1.5 x 109/L or 50% improvement over baseline, a platelet count more than 100 x 109/L or 50% improvement over baseline, or a hemoglobin level of more than 11.0 g/dL or 50% improvement over baseline without transfusions. No bone marrow evaluation was required for determination of partial response. Responses in patients with other B-cell leukemias were assessed using the same criteria as for CLL.
Statistical Considerations
Associations between patient characteristics and response outcome were evaluated by  2 tests.6 The cutoff points for quantitative variables were those defining abnormal levels or others commonly used. Distributions of survival and time to progression were estimated by the method of Kaplan and Meier.7 Survival time was measured from first day of rituximab therapy until death; deaths from all causes were included. Time to progression was measured from the start of rituximab therapy until detection of relapse.
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RESULTS
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Study Group
Patient characteristics are listed in Table 1. The diagnosis was CLL in 40 patients, mantle-cell leukemia in four patients, marginal zone leukemia in four patients, and prolymphocytic leukemia (PLL) in two patients. All patients with CLL had received prior therapy. Two patients with marginal zone leukemia had received no prior therapy. Fifty-three percent of the patients with CLL had disease that was refractory to fludarabine, 43% had disease refractory to alkylating agents, and 33% had disease refractory to both. Median patient age was 66 years (range, 44 to 87 years). The majority of the patients (80%) had advanced-stage disease. Median hematologic parameters are listed in Table 1; the highest WBC count was 334 x 109/L.
First-Dose Toxicity
Forty-eight patients (94%) had side effects with the first dose of rituximab ( Table 2). Most toxicities were grades 1 or 2 and consisted of fever and chills. Mild dyspnea and asymptomatic blood pressure reductions were also noted in a minority of patients, as was nausea. Severe (grades 3 to 4) toxicity was seen in six patients (12%). Disease characteristics and side effects in these patients are listed in Table 3. All six patients developed fever, chills, dyspnea, and hypoxia; five patients had significant hypotension, and one had severe hypertension. Although three of the six patients had very high WBC counts, all three had mantle-cell leukemia. The patient with the highest WBC count (334 x 109/L) had CLL and had only minor toxicity with the first dose. Patients with other diagnoses and WBC counts significantly lower than the median also experienced severe toxicity. Thus, severe toxicity occurred in five (50%) of 10 patients with other diagnoses versus in one (2%) of 40 patients with CLL (P < .001).
In the six patients with severe toxicities, the rituximab infusion was discontinued and symptomatic treatment with fluids, steroids, further acetaminophen, and diphenhydramine was given. None continued therapy on the same day, but only one patient required a 24-hour admission to the intensive care unit (ICU). This was a 68-year-old woman with mantle-cell leukemia who had failed six prior regimens. The patient was RBC- and platelet transfusion–dependent and had a performance status of 3. She started treatment with a WBC count of 200 x 109/L. During treatment, her blood pressure decreased to 71/34, and oxygen saturation dropped to 88% on room air. Therapy was discontinued and she was admitted to the ICU. A chest x-ray showed noncardiogenic pulmonary edema. After treatment the patient was asymptomatic and transferred out of the ICU the next day. This is the only patient who had any evidence of tumor lysis, which was quite mild. On day 3, the WBC count was 41 x 109/L, creatinine had increased from 0.9 mg/dL to 1.5 mg/dL, and phosphorus peaked at 5.9 mg/dL. The WBC decreased to 19.8 x 109/L on day 5 but had increased to 91 x 109/L on day 8 when a second dose of rituximab 375 mg/m2 was given. Approximately 5 hours into the infusion, the blood pressure decreased to 86/46 at the same time the temperature was 389 axillary. The patient was again admitted to the ICU for less than 24 hours; no further rituximab was administered.
Retreatment with rituximab was attempted in four of the five other patients. The patient with CLL refused further therapy. The first patient with blastic mantle-cell leukemia was a 77-year-old man who had failed three prior regimens and had a performance status of 3. He was also receiving chronic prednisone treatment. He began therapy with a WBC count of 229 x 109/L and had a severe reaction after three fourths of the dose was administered. He was treated symptomatically and discharged home. Four days later he was hospitalized with progressive nodular pneumonia consistent with a fungal etiology. He received doses 2 and 3 at the escalated dose of 2,250 mg/m2 with minimal side effects. Fever recurred unrelated to rituximab, and blood revealed 50 cytomegalovirus-positive cells. The patient died of progressive pneumonia before receiving the fourth dose. The third patient with mantle-cell leukemia had the prescribed dose escalation to 2,250 mg/m2 and tolerated it well. The fourth patient with mantle-cell leukemia, who started with a WBC count of 35 x 109/L, received 4 weeks of treatment at 375 mg/m2 without dose escalation or subsequent problems. The patient with PLL received a second dose of 375 mg/m2 without problems, and the dose was then escalated to the target of 1,500 mg/m2, which was also tolerated well.
Toxicity With Dose Escalation
Toxicity with subsequent doses is listed in Table 4. At doses of 500 mg/m2 to 1,500 mg/m2, only three of 35 patients had toxicities that were grade 1, including an asymptomatic reduction in the blood pressure, nausea, and malaise. Significant side effects were seen at the 2,250 mg/m2 dose level at which eight (67%) of 12 patients had grade 1 to 2 toxicity, including fever, chills, nausea, and malaise. Dose escalation was discontinued at this dose level, but no grade 3 or 4 toxicity was seen during the highest dose. Fever and chills were seen mainly with the first dose at the 2,250 mg/m2 level, but malaise and nausea occurred even during doses 3 and 4. The median absolute lymphocyte count of patients at the time they received the 2,250 mg/m2 dose of rituximab was 19 x 109/L (range, 0.7 to 74 x 109/L). There was no correlation with this count and whether patients had grade 1 or 2 toxicity. Toxicity (grade 1 to 2) was noted in four patients at the time they received the second dose of 2,250 mg/m2, although the median absolute lymphocyte count was only 2.2 x 109/L (range, 0.9 to 26 x 109/L).
Response
The overall response rate combining all dose levels was 40%; the number of responses at each dose level are listed in Table 5. Among patients with CLL, the response rate was 36%, and all responses were partial responses. One complete response was observed in a patient with PLL, and a nodular partial response occurred in a patient with marginal zone leukemia. When the response rates at low doses (500 to 825 mg/m2), intermediate doses (1,000 to 1,500 mg/m2), and at the highest dose (2,250 mg/m2) were examined, there was a significant dose response, as listed in Table 5; the respective response rates were 23%, 44%, and 80% (P = .007). If the analysis is confined only to patients with CLL, the respective response rates are 22%, 43% and 75% (P = .03). Rituximab had little effect on the bone marrow from patients with CLL, except at the highest dose level. In patients that responded to treatment, the median percentage of marrow lymphocytes was 67% (range, 27% to 93%) before treatment and 49% (range, 25% to 97%) after therapy. Patients treated at doses below 2,250 mg/m2 had median pre- and posttreatment marrow lymphocyte percentage of 73% and 64%, respectively. The corresponding values in responders receiving 2,250 mg/m2 were 65% and 34%, respectively.
Response in patients with diagnoses other than CLL are listed in Table 6. In two patients with mantle-cell leukemia the disease failed to respond to rituximab, but neither patient with mantle-cell leukemia was able to complete 4 weeks of therapy; the first patient died of progressive pneumonia, the second patient had severe toxicity with the second dose. In a third patient with mantle-cell leukemia, a complete response in the peripheral blood was achieved, but enlarging adenopathy also occurred. Lymph node biopsy revealed metastatic squamous cell carcinoma, and this patient was considered not assessable for response. Thus, among assessable patients who completed all four doses, response was noted in six of seven patients (response rate, 86%). Two patients did not receive escalated doses because of severe toxicity seen with the first dose and completed all four infusions at 375 mg/m2. Both patients achieved a response but were not included in the overall response rate because they did not receive the targeted dose of rituximab.
Analysis of Prognostic Factors
Multiple parameters were examined for response to rituximab including age, ß2 microglobulin, splenomegaly, hepatomegaly, WBC count, lymph node size, number of lymph node sites, Rai stage, and fludarabine status. There was no correlation between lymph node size and response to therapy, but bulky adenopathy was uncommon in this patient population, with only three patients having lymph node measurements of more than 5 cm. There was a trend for an improved response rate among patients with Rai stages I and II versus those with stages III and IV disease (60% v 35%, respectively; P =. 06). Sensitivity to fludarabine was the only factor that correlated significantly with response to rituximab. Response was seen in nine of 16 patients with disease sensitive to fludarabine and in four of 20 with disease refractory to fludarabine (response rates, 56% v 20%, respectively; P = .02). Distribution of patients with fludarabine sensitive and fludarabine refractory disease among the dose levels was similar with nine (56%) of 16 fludarabine-sensitive cases treated at lower doses versus 13 (65%) of 20 fludarabine-refractory cases (P = .59).
Myelosuppression/Infection
Myelosuppression was uncommon in this heavily pretreated population. Neutropenia measured as less than 109/L was seen in 27% of the patients, and severe neutropenia (< 0.5 x 109/L) was seen in 11%. Ten percent of patients had their platelet count drop by more than 50% during treatment. Sepsis or fever of unknown origin occurred in 10% of patients. One patient was a 77-year-old woman who developed urosepsis with Escherichia coli, three patients developed neutropenic fever with negative cultures, and one patient had nonneutropenic fever with negative cultures 5 days after the third dose of rituximab. The only patient with pneumonia had that infection present at the start of therapy.
Minor infections were seen in 10% of patients and included bronchitis, gastroenteritis, urinary tract infection, and a local infection at the catheter site. One patient developed herpes zoster.
Remission Duration and Survival
Median time to progression in patients whose disease responded was 8 months; the longest ongoing remission is 15+ months ( Fig 1). The median survival time has not been reached; the estimated 1-year survival rate is 80% ( Fig 2). Only one patient died during therapy; this patient had pneumonia and refractory mantle-cell leukemia when treatment started. Subsequent deaths have been related to disease progression.
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DISCUSSION
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Rituximab seems to have significant activity in CLL, but there is a dose-response relationship whereby most cases respond at the higher doses. An alternate approach to dose escalation is being examined by Byrd et al8; patients with CLL in this study received rituximab at a dose of 375 mg/m2 three times a week (ie, three times the standard weekly dose), with a total duration of therapy of 4 weeks. The overall response rate of 50% with this dose schema is similar to the results in our trial and suggests that higher doses are more effective against CLL. Pharmacokinetic studies may provide further information on designing the best dose/schedule in the setting of CLL. An important aim of our study was to determine whether rituximab had any significant activity in the setting of CLL; clearly, a response rate of 40% was encouraging. However, the cost associated with administration of such high doses is prohibitive. Potential synergy between chemotherapeutic agents and rituximab may be achieved with standard doses of the antibody. The finding that rituximab has activity in CLL lays the groundwork for use of this agent in combination with chemotherapy.
Although no true MTD was defined with this antibody, defining an MTD with a biologic agent might be difficult. Thus, dose escalation stopped when significant toxicities were seen on the subsequent doses because this was uncommon in patients in the lymphoma trial receiving all doses at 375 mg/m2. No patient treated at the highest dose of 2,250 mg/m2 had severe toxicity, but moderate side effects were common. All patients in this trial received 375 mg/m2 of rituximab for the first infusion to minimize potential side effects associated with a high circulating tumor burden. The incidence of grade 3 to 4 toxicity was low in patients with CLL (one of 40 patients). Nevertheless, recent data using rituximab in patients with previously untreated CLL suggest that severe first infusion reactions may be more common in this population.9 Whether prohibitive toxicity with higher doses as administered in this trial would occur without a previous does of 375 mg/m2 is unknown.
Although there was no correlation between lymph node size and response to therapy as seen in the lymphoma trial, bulky adenopathy in our study was uncommon. A disappointing finding was that in cases refractory to fludarabine-based therapy, response rates were lower with rituximab; there is no standard of care for patients in this group, and their disease responds poorly to multiagent chemotherapies. Although the presumed mechanisms of action of chemotherapy and monoclonal antibodies may be different, it is possible that a common final pathway that triggers apoptosis in the leukemic cells is defective, and thus, cross-resistance to multiple agents might result. Only 10 patients with other mature B-cell leukemias were treated, but the findings in this subset were of interest.
These cases responded well to the antibody, and, interestingly, two patients treated at the standard dose of 375 mg/m2 both achieved remissions. However, our data suggests that toxicity may be significantly greater in these patients, possibly because of increased levels of surface CD20 expression compared with that seen in patients with CLL. Three patients had very high WBC counts at the time of therapy, which may have resulted in brisk binding of the antibody and release of cytokines because of the high circulating tumor burden.
In conclusion, rituximab has significant activity in the treatment of CLL and seems to be more efficacious at higher doses. Incorporation of this monoclonal antibody earlier in treatment, possibly in combination with chemotherapy, requires future investigation.
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REFERENCES
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1.
Zhou L-J, Tedder TF: CD20 Workshop panel report, in Schlossman SF, Boumsell L, Gilks W, et al (eds): Leucocyte Typing V. White Cell Differentiation Antigens. Oxford, United Kingdom, Oxford University, 1995, pp 511-514
2.
McLaughlin P, Grillo-Lopez A, 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 16: 2825-2833, 1998[Abstract]
3.
The Non-Hodgkin’s Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49: 2112-2135, 1982[Medline]
4.
Almasri NM, Duque RE, Iturraspe J, et al: Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia. Am J Hematol 40: 259-263, 1992[Medline]
5.
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 87: 4990-4997, 1996[Free Full Text]
6.
Mantel N: Evaluation of survival data and two new rank order statistics arising to consideration. Canc Chemother Rep 50: 163-170, 1966
7.
Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
8.
Byrd JC, Grever MR, Davis B, et al: Phase I/II study of thrice weekly rituximab in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): A feasible and active regimen. Blood 94: 3114, 1999 (abstr)[Abstract/Free Full Text]
9.
Keating MJ, O’Brien S, Lerner S, et al: Combination chemo-antibody therapy with fludarabine (F), cyclophosphamide (C) and rituximab (R) achieves a high CR rate in previously untreated chronic lymphocytic leukemia (CLL). Blood 96: 514a, 2000 (abstr)
Submitted March 17, 2000;
accepted March 2, 2001.
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|
|
M. L. Sorror, M. B. Maris, B. M. Sandmaier, B. E. Storer, M. J. Stuart, U. Hegenbart, E. Agura, T. R. Chauncey, J. Leis, M. Pulsipher, et al.
Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Advanced Chronic Lymphocytic Leukemia
J. Clin. Oncol.,
June 1, 2005;
23(16):
3819 - 3829.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P Levene, G. Singh, and C. Palmieri
Therapeutic monoclonal antibodies in oncology
J R Soc Med,
April 1, 2005;
98(4):
146 - 152.
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. F. Khouri, R. M. Saliba, C. Hosing, G.-J. Okoroji, S. Acholonu, P. Anderlini, D. Couriel, M. De Lima, M. L. Donato, L. Fayad, et al.
Concurrent Administration of High-Dose Rituximab Before and After Autologous Stem-Cell Transplantation for Relapsed Aggressive B-Cell Non-Hodgkin's Lymphomas
J. Clin. Oncol.,
April 1, 2005;
23(10):
2240 - 2247.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Hamaguchi, J. Uchida, D. W. Cain, G. M. Venturi, J. C. Poe, K. M. Haas, and T. F. Tedder
The Peritoneal Cavity Provides a Protective Niche for B1 and Conventional B Lymphocytes during Anti-CD20 Immunotherapy in Mice
J. Immunol.,
April 1, 2005;
174(7):
4389 - 4399.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
J. C. Byrd, G. Marcucci, M. R. Parthun, J. J. Xiao, R. B. Klisovic, M. Moran, T. S. Lin, S. Liu, A. R. Sklenar, M. E. Davis, et al.
A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia
Blood,
February 1, 2005;
105(3):
959 - 967.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
J. G. Gribben
Salvage Therapy for CLL and the Role of Stem Cell Transplantation
Hematology,
January 1, 2005;
2005(1):
292 - 298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
C. P. Mavragani, P. G. Vlachoyiannopoulos, N. Kosmas, I. Boletis, A. G. Tzioufas, and M. Voulgarelis
A case of reversible posterior leucoencephalopathy syndrome after rituximab infusion
Rheumatology,
November 1, 2004;
43(11):
1450 - 1451.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Enting, A. Demopoulos, L. M. DeAngelis, and L. E. Abrey
Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide
Neurology,
September 14, 2004;
63(5):
901 - 903.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. J. Olszewski and M. L. Grossbard
Empowering Targeted Therapy: Lessons from Rituximab
Sci. Signal.,
July 13, 2004;
2004(241):
pe30 - pe30.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ghielmini, S.-F. H. Schmitz, S. B. Cogliatti, G. Pichert, J. Hummerjohann, U. Waltzer, M. F. Fey, D. C. Betticher, G. Martinelli, F. Peccatori, et al.
Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule
Blood,
June 15, 2004;
103(12):
4416 - 4423.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. von Bergwelt-Baildon, B. Maecker, J. Schultze, and J. G. Gribben
CD40 activation: potential for specific immunotherapy in B-CLL
Ann. Onc.,
June 1, 2004;
15(6):
853 - 857.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Kennedy, P. V. Beum, M. D. Solga, D. J. DiLillo, M. A. Lindorfer, C. E. Hess, J. J. Densmore, M. E. Williams, and R. P. Taylor
Rituximab Infusion Promotes Rapid Complement Depletion and Acute CD20 Loss in Chronic Lymphocytic Leukemia
J. Immunol.,
March 1, 2004;
172(5):
3280 - 3288.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Mone, P. Huang, H. Pelicano, C. M. Cheney, J. M. Green, J. Y. Tso, A. J. Johnson, S. Jefferson, T. S. Lin, and J. C. Byrd
Hu1D10 induces apoptosis concurrent with activation of the AKT survival pathway in human chronic lymphocytic leukemia cells
Blood,
March 1, 2004;
103(5):
1846 - 1854.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Farag, I. W. Flinn, R. Modali, T. A. Lehman, D. Young, and J. C. Byrd
Fc{gamma}RIIIa and Fc{gamma}RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia
Blood,
February 15, 2004;
103(4):
1472 - 1474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Byrd, S. Stilgenbauer, and I. W. Flinn
Chronic Lymphocytic Leukemia
Hematology,
January 1, 2004;
2004(1):
163 - 183.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Thomas, S. O'Brien, C. Bueso-Ramos, S. Faderl, M. J. Keating, F. J. Giles, J. Cortes, and H. M. Kantarjian
Rituximab in relapsed or refractory hairy cell leukemia
Blood,
December 1, 2003;
102(12):
3906 - 3911.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Castagna, B. Sarina, A. Santoro, J. C. Byrd, K. Rai, and R. A. Larson
Fludarabine plus rituximab for untreated B-cell chronic lymphocytic leukemia
Blood,
September 15, 2003;
102(6):
2309 - 2310.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Byrd, D. M. Lucas, A. P. Mone, J. B. Kitner, J. J. Drabick, and M. R. Grever
KRN5500: a novel therapeutic agent with in vitro activity against human B-cell chronic lymphocytic leukemia cells mediates cytotoxicity via the intrinsic pathway of apoptosis
Blood,
June 1, 2003;
101(11):
4547 - 4550.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Mangel, R. Buckstein, K. Imrie, D. Spaner, E. Franssen, P. Pavlin, A. Boudreau, N. Pennell, D. Combs, and N. L. Berinstein
Pharmacokinetic study of patients with follicular or mantle cell lymphoma treated with rituximab as 'in vivo purge' and consolidative immunotherapy following autologous stem cell transplantation
Ann. Onc.,
May 1, 2003;
14(5):
758 - 765.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Hainsworth, S. Litchy, J. H. Barton, G. A. Houston, R. C. Hermann, J. E. Bradof, and F. A. Greco
Single-Agent Rituximab as First-Line and Maintenance Treatment for Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network
J. Clin. Oncol.,
May 1, 2003;
21(9):
1746 - 1751.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Mavromatis and B. D. Cheson
Monoclonal Antibody Therapy of Chronic Lymphocytic Leukemia
J. Clin. Oncol.,
May 1, 2003;
21(9):
1874 - 1881.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Faderl, D. A. Thomas, S. O'Brien, G. Garcia-Manero, H. M. Kantarjian, F. J. Giles, C. Koller, A. Ferrajoli, S. Verstovsek, B. Pro, et al.
Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies
Blood,
May 1, 2003;
101(9):
3413 - 3415.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Bannerji, S. Kitada, I. W. Flinn, M. Pearson, D. Young, J. C. Reed, and J. C. Byrd
Apoptotic-Regulatory and Complement-Protecting Protein Expression in Chronic Lymphocytic Leukemia: Relationship to In Vivo Rituximab Resistance
J. Clin. Oncol.,
April 15, 2003;
21(8):
1466 - 1471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Boye, T. Elter, and A. Engert
An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab
Ann. Onc.,
April 1, 2003;
14(4):
520 - 535.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Manches, G. Lui, L. Chaperot, R. Gressin, J.-P. Molens, M.-C. Jacob, J.-J. Sotto, D. Leroux, J.-C. Bensa, and J. Plumas
In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas
Blood,
February 1, 2003;
101(3):
949 - 954.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Keating, N. Chiorazzi, B. Messmer, R. N. Damle, S. L. Allen, K. R. Rai, M. Ferrarini, and T. J. Kipps
Biology and Treatment of Chronic Lymphocytic Leukemia
Hematology,
January 1, 2003;
2003(1):
153 - 175.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. N. O'Brien, N. M.A. Blijlevens, T. H. Mahfouz, and E. J. Anaissie
Infections in Patients with Hematological Cancer: Recent Developments
Hematology,
January 1, 2003;
2003(1):
438 - 472.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Byrd, B. L. Peterson, V. A. Morrison, K. Park, R. Jacobson, E. Hoke, J. W. Vardiman, K. Rai, C. A. Schiffer, and R. A. Larson
Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712)
Blood,
January 1, 2003;
101(1):
6 - 14.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Schulz, S. K. Klein, U. Rehwald, M. Reiser, A. Hinke, W.-U. Knauf, W.-E. Aulitzky, M. Hensel, M. Herold, D. Huhn, et al.
Phase 2 study of a combined immunochemotherapy using rituximab and fludarabine in patients with chronic lymphocytic leukemia
Blood,
October 16, 2002;
100(9):
3115 - 3120.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. D. Hainsworth, S. Litchy, H. A. Burris III, D. C. Scullin Jr, S. W. Corso, D. A. Yardley, L. Morrissey, and F. A. Greco
Rituximab as First-Line and Maintenance Therapy for Patients With Indolent Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
October 15, 2002;
20(20):
4261 - 4267.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. McLaughlin
Progress and Promise in the Treatment of Indolent Lymphomas
Oncologist,
June 1, 2002;
7(3):
217 - 225.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Keating, I. Flinn, V. Jain, J.-L. Binet, P. Hillmen, J. Byrd, M. Albitar, L. Brettman, P. Santabarbara, B. Wacker, et al.
Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study
Blood,
May 15, 2002;
99(10):
3554 - 3561.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Dimopoulos, C. Zervas, A. Zomas, C. Kiamouris, N. A. Viniou, V. Grigoraki, C. Karkantaris, C. Mitsouli, D. Gika, J. Christakis, et al.
Treatment of Waldenstrom's Macroglobulinemia With Rituximab
J. Clin. Oncol.,
May 1, 2002;
20(9):
2327 - 2333.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Byrd, S. Kitada, I. W. Flinn, J. L. Aron, M. Pearson, D. Lucas, and J. C. Reed
The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction
Blood,
February 1, 2002;
99(3):
1038 - 1043.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. E. Kay, T. J. Hamblin, D. F. Jelinek, G. W. Dewald, J. C. Byrd, S. Farag, M. Lucas, and T. Lin
Chronic Lymphocytic Leukemia
Hematology,
January 1, 2002;
2002(1):
193 - 213.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
I. F. Khouri, R. M. Saliba, S. A. Giralt, M.-S. Lee, G.-J. Okoroji, F. B. Hagemeister, M. Korbling, A. Younes, C. Ippoliti, J. L. Gajewski, et al.
Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality
Blood,
December 15, 2001;
98(13):
3595 - 3599.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. D. Cheson
Some Like It Hot!
J. Clin. Oncol.,
October 1, 2001;
19(19):
3908 - 3911.
[Full Text]
|
|
|
|
|
|
|
K. R. Rai, H. Dohner, M. J. Keating, and E. Montserrat
Chronic Lymphocytic Leukemia: Case-Based Session
Hematology,
January 1, 2001;
2001(1):
140 - 156.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
