Journal of Clinical Oncology, Vol 20, Issue 18
(September), 2002: 3891-3897
© 2002 American Society for Clinical Oncology
Alemtuzumab in Previously Treated Chronic Lymphocytic Leukemia Patients Who Also Had Received Fludarabine
By K. R. Rai,
C. E. Freter,
R. J. Mercier,
M. R. Cooper,
B. S. Mitchell,
E. A. Stadtmauer,
P. Santábarbara,
B. Wacker,
L. Brettman
From the Long Island Jewish Medical Center, New Hyde Park, NY; Georgetown University Medical Center, Lombardi Cancer Center, Washington, DC; Marshfield Clinic, Marshfield, WI; Wake Forest University Baptist Medical Center, Winston-Salem, and University of North Carolina at Chapel Hill, Chapel Hill, NC; University of Pennsylvania Medical Center, Philadelphia, PA; Ilex Oncology, San Antonio, TX; and Millennium Pharmaceuticals, Cambridge, MA.
This work was presented in part at the Forty-Second Annual Meeting of the American Society of Hematology, San Francisco, CA, December 1-5, 2000.Address reprint requests to K.R. Rai, Long Island Jewish Medical Center, New Hyde Park, New York, NY 11040; email: rai{at}lij.edu
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ABSTRACT
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PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens.
PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute–sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory.
RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to  38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to 42.0 months), and the median survival time was 35.8 months (range, 8.8 to 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies.
CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.
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INTRODUCTION
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THERE IS NO PROVEN and effective therapy for patients with chronic lymphocytic leukemia (CLL) who have active disease after prior therapies, including fludarabine. These patients have advanced-stage disease with a poor overall survival outlook.1 Efforts to identify agents that may benefit such patients are urgently needed. Monoclonal antibodies targeted against lymphocytes and able to bind and trigger cell lysis are candidate agents for this purpose. Alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom), a humanized monoclonal antibody,2 is directed against the CD52 antigen, which is expressed on most normal and malignant lymphocytes,3 but not on hematopoietic stem cells.4 We report here the results of a pilot phase II study of the therapeutic role of alemtuzumab in CLL patients with active disease who had previously received fludarabine as well as other chemotherapy regimens. The results reported here formed the basis on which a larger trial with alemtuzumab was eventually conducted.
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PATIENTS AND METHODS
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An open phase II trial was conducted at six study centers in the United States. The primary objectives were to assess the safety and efficacy of alemtuzumab in patients who had been previously treated with fludarabine. The study was conducted in accordance with good clinical practice, and all patients gave informed written consent before commencement.
Inclusion Criteria
Adults ( 18 years old) with a diagnosis of CLL (B-cell or T-cell prolymphocytic leukemia) whose prior treatment regimens had included fludarabine were eligible if they had not achieved either a complete or partial response (CR or PR), had relapsed less than 6 months after a response with fludarabine, or had not responded to treatment with any chemotherapy agent. Inclusion also required a World Health Organization performance status of 0 or 1 and a life expectancy of at least 12 weeks.
Exclusion Criteria
The exclusion criteria were as follows: (1) previous treatment with alemtuzumab; (2) a previous bone marrow or other organ transplant; (3) presence of an active infection; (4) presence of an active secondary malignancy; (5) CNS involvement; (6) proven or suspected human immunodeficiency virus infection; and (7) pregnancy or lactation.
Treatment
Alemtuzumab was diluted into 100 mL of 0.9% saline and administered intravenously over 2 hours. During the first week, patients were started at a lower dose of 10 mg daily until this dose was well tolerated, and then the dose was increased to the target dose of 30 mg, usually by the fourth or fifth day. Alemtuzumab was administered subsequently on a three-times-weekly schedule. Treatment was for a maximum of 16 weeks, provided that there was evidence of continuing clinical benefit on assessment after an initial 8-week period. Premedication was 50 mg of diphenhydramine and 650 mg of acetaminophen, 30 minutes before infusion. Antibiotic prophylaxis was optional. The use of corticosteroids was discouraged, although it was allowed on an as-needed basis for infusion-related reactions not controlled by premedication, at the investigator’s discretion, or as maintenance corticosteroids used as medication for other indications before study onset. If a patient experienced serious hematologic toxicity or a serious infection while receiving treatment, alemtuzumab was withheld until the problem was resolved.
Clinical evaluation was performed twice weekly for weeks 1 to 4 and weekly thereafter. Lymphocyte subset analysis by flow cytometry was encouraged (but not mandatory) at enrollment, at week 4, at the end of treatment, and at 1-month follow-up for the assessment of CD3 (total T cells), CD4 (T-helper cells), CD8 (T-suppressor cells), CD19 (total B cells), CD16 (natural killer cells), and CD52 (alemtuzumab antigen, which is a measure of total lymphocytes). Bone marrow examination was performed at baseline and every 8 weeks throughout the study. Blood chemistry was assessed at least weekly for the first 4 weeks and at least monthly thereafter. Investigators were encouraged to assess levels of anti-alemtuzumab antibodies (by immunoassay of serum samples collected before the alemtuzumab infusion) every 4 weeks during treatment and 28 days after treatment end, but this was not mandatory. The specificity of antibody positivity for alemtuzumab was confirmed by competitive assay with unlabeled alemtuzumab.
Response Evaluation
Efficacy analyses included Kaplan-Meier plots and quartiles for duration of response for overall patient survival and time to disease progression. An independent review panel (IRP), constituted by three experts in CLL who were not involved in this study, critically reviewed the demographic and response and toxicity data on all patients and determined response according to 1996 National Cancer Institute–sponsored Working Group criteria.5 The members of the IRP were S. Johnson, MD (Taunton and Somerset Hospital, Somerset, United Kingdom), M. Keating, MD (M.D. Anderson Cancer Center, Houston, TX), and E. Montserrat, MD (Hospital Clinic, Barcelona, Spain). The response results reported here are those assessed by the IRP.
Posttreatment Follow-Up
Patients were clinically re-evaluated at monthly intervals for 6 months and at 3-month intervals thereafter.
Statistical Considerations
The Gehan two-stage design was used6; 14 patients were enrolled initially, and when it was observed that at least one patient demonstrated a major response, the trial was expanded to enter 24 patients. Efficacy and toxicities were recorded on patients who had received at least one dose of alemtuzumab (intention-to-treat [ITT] population).
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RESULTS
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Demographics
Twenty-four patients with advanced disease were enrolled and treated (15 males and nine females); 23 had B-cell CLL and one had T-cell prolymphocytic leukemia. Disease status at enrollment is listed in Table 1. Table 2 provides details of prior treatments. All 24 patients had previously been treated with fludarabine, 13 had never had a beneficial response (CR or PR), four had relapsed within 6 months after an initial response with fludarabine therapy, and the remaining seven had not responded to other chemotherapy regimens given after fludarabine and were in a clinical relapse. Eight patients were refractory to both alkylating agents and fludarabine.
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Table 1. Disease Characteristics at Enrollment (ITT population; n = 24) With Alemtuzumab Therapy and Incidence of Response
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Response
Data on overall response to alemtuzumab, as determined by the IRP, are shown in Table 3. In Table 1 we provide these data according to disease characteristics at study entry and, in Table 2, according to response to prior treatments. Eight (33%) of 24 patients (95% confidence interval, 16% to 55%) achieved a major response (Table 3); all were PRs. Among the eight patients who were refractory to both alkylating agents and fludarabine, there were three who achieved a PR. Although the sample size was small, the overall response rate was higher in the intermediate-risk (four of six) than in the high-risk (three of 17) categories (Table 1).
Nine (37.5%) of 24 patients achieved complete resolution of disease in bone marrow, whereas blood absolute lymphocyte count was normalized in 15 (75%) of 20 patients (Table 4). Of the eight patients in PR, three had baseline splenomegaly; this resolved completely in two cases and improved by more than 50% in one case, whereas three patients had baseline hepatomegaly, which resolved in two cases. As shown in Tables 1 and 4, enlarged lymph nodes were seen at baseline in 22 patients. Follow-up data on lymph node size are missing for four patients. Overall, eight patients with lymph node enlargement at baseline had node sizes improve by more than 50%. Eleven patients entered the study with at least one node larger than 5 cm in diameter (bulky adenopathy), and three had a reduction of 50% in their nodal masses (Table 1).
As shown in Table 3, in the responding subpopulation (n = 8), the median time to response was 3.9 months (range, 1.6 to 5.3 months), and the median duration of response was 15.4 months (range, 4.6 to 38.0 months). The median time to disease progression for responders was 19.6 months (range, 7.7 to 42.0 months), compared with 7.1 months (range, 0.5 to 42.0 months) for the ITT group (Fig 1). The median survival time was 35.8 months (range, 8.8 to 47.1 months) in responders and 27.5 months (range, < 1 to 47.1 months) in the ITT group (Fig 2).
Median values for hematologic parameters, including hemoglobin, absolute neutrophil counts, and platelet counts were recorded. The results for the ITT group are shown in Fig 3 and for the responding subgroup in Fig 4. Values before transfusions were obtained in patients who continued to receive platelet or RBC transfusions. Platelet counts increased steadily, doubling over baseline values by week 12 and reaching a median of 200 x 109/L by week 24 in all patients and 320 x 109/L in patients with PRs. "B" symptoms, such as fever, night sweats, and weight loss, were present in five patients (20.8%) before initiation of alemtuzumab therapy and resolved in four patients by the end of the study.
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Fig 3. Median hematologic parameters during the course of alemtuzumab therapy: intention-to-treat population (n = 24).
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Three patients (12.5%) relapsed more than 1 year after responding to initial treatment and were re-treated. Two achieved a second PR, although one subsequently died as a result of Richter’s transformation.
Safety
Twenty-three patients reached the target level of 30 mg of alemtuzumab within four to seven doses. The most commonly reported adverse events (AEs) were infusion related, including fever (100%), rigors (92%), hypotension (67%), nausea (63%), and vomiting (54%). These acute events were mainly grades 1 and 2 and occurred predominantly in the first week of treatment and then decreased in incidence and severity. The most commonly reported severe events were grade 3 or 4 fevers, rigors, or vomiting, each reported in four patients (16.7%). Dyspnea was reported in five patients (20.8%; two grade 1, two grade 2, and one grade 3). Nine patients (37.5%) had to discontinue treatment as a result of AEs, including five cases of pneumonia and two of fever. Only one of these patients had achieved a PR.
Grade 3 or 4 neutropenia was noted at baseline in five patients (20.8%). Between weeks 3 and 4, the proportion of patients with grade 3 to 4 neutropenia increased to 59.1%, but by the 1-month follow-up period after the end of alemtuzumab therapy, all of these values had improved to close to baseline levels. Of the five patients who had grade 3 or 4 neutropenia before initiation of alemtuzumab treatment, all four patients with data available at follow-up had normalization of neutrophil counts. Grade 3 thrombocytopenia was present at baseline in 10 patients (41.7%). At the 1- and 2-month follow-up visits, the proportion of patients with grade 3 thrombocytopenia decreased to 20.0% and 7.1%, respectively.
Opportunistic infections (OIs) occurred on-study in 10 patients (41.7%), and these were most often (eight patients; 33.3%) pulmonary infections. Among the eight patients with an objective clinical response (all PRs), two developed OIs, compared with eight of 16 nonresponders. Five of the 10 patients with OIs received no prophylaxis against infections, whereas the remaining five received either trimethoprim/sulfamethoxazole (TMS) or acyclovir, but not both. The nature of infections among those who received no prophylaxis was Pneumocystis carinii pneumonia (PCP)—three proven cases and one clinically suspected—and one Candida/Aspergillus. Among the five patients who received some prophylaxis, one each receiving TMS developed Candida, disseminated herpes zoster, and invasive aspergillosis, and one each receiving prophylactic acyclovir developed Klebsiella pneumonia and suspected Legionella/mycobacterium/cytomegalovirus infection. All patients who developed PCP recovered after appropriate treatment.
Severe infections were reported in 8%, 6%, and 7% of patients in months 1, 2, and 3, respectively, during alemtuzumab therapy. Seven of eight patients reporting a major infection immediately after the study were among those who had not responded to alemtuzumab therapy. Five patients died, two as a result of infections and one each as a result of progressive disease, cerebral hemorrhage, and suicide during treatment or within 35 days of the last dose.
Concomitant Corticosteroid Use
Ten patients (41.7%) received varying, but relatively small, doses of systemic corticosteroids while on study to control chills, fever, and urticaria; for prophylaxis of reactions from platelet infusions; and, in four cases, to control previously existing hemolytic anemia. The duration of systemic corticosteroid treatment was less than 5 days in five patients.
Alemtuzumab was minimally immunogenic on testing for anti-alemtuzumab antibodies. Of 53 samples obtained from 10 patients, 52 were negative, whereas a single sample from one patient had a low titer of the antibody after 7 weeks of treatment.
Lymphocyte Subset Analysis
Lymphocyte subset analysis by flow cytometry was performed before the start of alemtuzumab in 19 patients. These analyses were repeated in varying numbers (13 to 15) of patients at 4 weeks, at the end of alemtuzumab therapy, and again 28 days after this therapy. The results are listed in Table 5. As shown, there was a profound decrease in B cells (CD19+), T cells (CD3+, CD4+, and CD8+), and natural killer cells (CD16+) at week 4 and at the end of treatment, but there was evidence that recovery of T cells had commenced in some patients at the end of treatment, and this recovery seemed to continue when patients were tested again 28 days later. At that time, there also was evidence of a re-emergence of B cells and of CD52+ lymphocytes in some patients.
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DISCUSSION
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Before the initiation in 1998 of the pivotal study of alemtuzumab in previously treated CLL patients,7 two phase II pilot studies had been conducted in such patients. The results of one study, performed in Europe, have already been published,8 and here we report on the second study, performed in the United States. Although the overall results of response rates were similar to those in the European study, the patient population differed somewhat in these two studies. All 24 patients in our trial had previously received fludarabine (as well as other chemotherapy regimens), whereas only three of 29 patients in the European trial had received prior fludarabine. Seventy-one percent of patients in our trial had either not responded to fludarabine or had responded initially but had experienced a recurrence of the disease within 6 months. The remaining 29% of cases had been fludarabine sensitive (on the basis of a prior response) but had relapsed and not responded to subsequent chemotherapy regimens.
The toxicity of alemtuzumab has two main aspects: acute infusion-related events and increased vulnerability to infection because of cytopenias. A lower initial dose (10 mg) was used to decrease first-dose infusion-related effects. Despite this, four patients experienced grade 3 or 4 infusion-related fever, rigors, or vomiting, and one patient had grade 3 dyspnea. This problem has been addressed in the subsequently performed pivotal trial by starting treatment at an even lower alemtuzumab dose of 3 mg.7 In this study, CD8+ and CD4+ T-cell counts reached a nadir 4 weeks into treatment and then began to recover slowly, so that by 1 month from the end of alemtuzumab therapy, their median numbers were 240 and 210/mm3, respectively (Table 5).
The degree of profound and prompt panlymphocytopenia (B cells and T cells) that we and Osterborg et al8 observed was not anticipated, and, therefore, neither was the ensuing high incidence of OIs. As was noted previously, a routine prophylaxis against OIs (such as Pneumocystis pneumonia and viral infections) was not provided in our study on a mandatory basis. Prophylaxis, when used, was effective in this study, with viral problems arising in the absence of acyclovir and bacterial complications, predominantly PCP, arising in the absence of TMS.
The objective response rate (33% PRs) in previously treated CLL patients, including those treated with fludarabine, obtained in our study is identical to the 33% overall response rate in the pivotal trial7 and is only slightly less than the 41% observed in the European study (in which only three of 29 patients had received prior fludarabine). The median duration of response in our trial was 15.4 months (range, 4.6 to 38.0 months), which is similar to 12 months (range, 6 to 25 months) in the European study.
As detailed in Table 4, independent of achievement of a PR by the criteria recommended in the National Cancer Institute guidelines to assess an overall response,5 a marked reduction in the tumor burden was observed in each of five sites that CLL is known to frequently infiltrate. Lymphocytosis in the blood was cleared completely in 75%, and splenomegaly was resolved in 38% and hepatomegaly in 50% of cases. Complete clearance of lymphocytic infiltration in the bone marrow is seldom achievable with any of the currently available treatments, even in previously untreated CLL patients. In our study, with use of alemtuzumab in this population of previously heavily treated patients with active disease, 37% achieved a total elimination of lymphocytic infiltration, and an additional 21% had 50% clearance. As detailed in Table 1, shrinkage in the size of enlarged lymph nodes by 50% was more frequent (four of six such cases) when the nodes were not very bulky (> 2 but < 5 cm in diameter) than in cases (three of 11) with bulky nodes (> 5 cm in diameter). It is noteworthy that the subsequently performed pivotal study,7 as well as the European study,8 also reported similar findings.
Our results (Table 2) suggest that the likelihood of an objective beneficial response is greater when alemtuzumab is used in patients who have not been previously heavily treated. When the number of prior regimens was only one or two, five of 10 patients achieved a PR with alemtuzumab, in contrast to only one of eight who had received four or more prior therapeutic regimens.
Our data on a limited number of patients indicated that immunogenicity with alemtuzumab is not common; indeed, only one patient sample had a low titer of antibodies. Because of a persistent and profound lymphocytopenia in the blood of patients tested at week 4, at the end of treatment, and again 28 days later, the probability of negative findings being due to Campath-1H blocking on the lymphocyte surface is extremely low. Furthermore, it has been shown that some investigators have successfully re-treated patients with alemtuzumab,9,10 while maintenance therapy for prolonged periods has also been shown in a few patients to remain effective for up to 3 months.11
The results at major disease sites with clearance of malignant cells from blood and bone marrow are encouraging, because alemtuzumab may allow harvesting of uncontaminated peripheral-blood stem cells and open the way for further treatment by autologous peripheral-blood stem-cell transplantation. This has already been performed for a small number of patients with CLL after alemtuzumab treatment.12 In these studies, the absence of malignant cells was confirmed by flow cytometry. After treatment of 29 patients with alemtuzumab, seven patients proceeded to autologous transplantation after alemtuzumab therapy,12 six were reported as alive at 10 months after transplantation, and none had required further therapy. This study demonstrated that peripheral-blood stem-cell transplantation is feasible in patients who still have detectable residual disease after alemtuzumab and that it often results in an improvement in the quality of remission.
A pivotal trial of alemtuzumab,7 initiated in 1998 (4 years after the completion of the study reported here) in fludarabine-failing CLL patients, led to the approval of this agent for the treatment of such patients by the United States Food and Drug Administration. The results and experience gained from our study provided critical information that aided in the design and the eventual success of the pivotal trial. First, alemtuzumab therapy was initiated at a first dose of 3 mg, before the 10-mg dose, and was then increased to the target dose of 30 mg. Each dose increase took place only when the patient was able to tolerate the previous dose. This step led to a reduction in the incidence of severe AEs related to alemtuzumab infusions. Second, the pivotal trial7 required a mandatory prophylaxis regimen with TMS and famciclovir; this contributed to a marked reduction in the incidence of OIs treated with alemtuzumab. Current recommendations are TMS, one tablet twice daily, three times a week; and famciclovir, 250 mg twice daily, or equivalents administered starting on day 0 of treatment and continuing throughout the course and for a minimum of 2 months after treatment is completed.
In summary, the results of this study have shown alemtuzumab to be an important and effective treatment for those previously heavily treated CLL patients who also have received fludarabine therapy. We believe that our study provides a critical historical perspective in the story of the emergence of a new humanized monoclonal antibody in the treatment of CLL.
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ACKNOWLEDGMENTS
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Supported by the Chemotherapy Foundation and the Edward Brodsky Fund (to K.R.R.).
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REFERENCES
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1. Keating M, O’Brien S, Plunkett W, et al: Results of first salvage therapy for patients refractory to a Fludara regimen in chronic lymphocytic leukemia. Leuk Lymphoma (in press)
2. Riechmann L, Clark M, Waldmann H, et al: Reshaping human antibodies for therapy. Nature 332: 323-327, 1988[CrossRef][Medline]
3. Dyer MSJ, Hale G, Marcus R, et al: Remission induction in patients with lymphoid malignancies using unconjugated Campath-1H monoclonal antibodies. Leuk Lymphoma 2: 179-193, 1990
4. Gilleece MH, Dexter TM: Effect of Campath-1H antibody on human hematopoietic progenitors in vitro. Blood 82: 807-812, 1993[Abstract/Free Full Text]
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. Gehan EA: The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. J Chronic Dis 13: 346-363, 1961[CrossRef][Medline]
7. Keating MJ, Flinn I, Jain V, et al: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 99: 3554-3561, 2002[Abstract/Free Full Text]
8. Osterborg A, Dyer MJ, Bunjes D, et al: Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia: European study group of CAMPATH-1H treatment in chronic lymphocytic leukemia. J Clin Oncol 15: 1567-1574, 1997[Abstract]
9. Bowen AL, Zomas A, Emmett E, et al: Subcutaneous CAMPATH-1H in fludarabine-resistant/relapsed chronic lymphocytic and B-prolymphocytic leukaemia. Br J Haematol 96: 617-619, 1997[CrossRef][Medline]
10. Pangalis GA, Dimopoulou MN, Angelopoulou MK, et al: Campath-1H in B-chronic lymphocytic leukemia: Report on a patient treated thrice in a 3 year period. Med Oncol 17: 70-73, 2000[Medline]
11. Rai KR, Janson D, Driscoll N, et al: Varying modes of maintenance therapy with Campath-1H in chronic lymphocytic leukemia. Proc Am Soc Clin Oncol 21: 275a, 2002 (abstr 1099)
12. Kennedy S, Rawstron A, Evans P, et al: Campath-1H therapy in 29 patients with refractory CLL: ‘True’ complete remission is an attainable goal. Blood 94: 603a, 1999 (abstr)
Submitted June 20, 2001;
accepted June 4, 2002.
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|
W. G. Wierda
Current and Investigational Therapies for Patients with CLL
Hematology,
January 1, 2006;
2006(1):
285 - 294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
E. T. Wong
Management of Central Nervous System Lymphomas Using Monoclonal Antibodies: Challenges and Opportunities
Clin. Cancer Res.,
October 1, 2005;
11(19):
7151s - 7157s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
W. Wierda, S. O'Brien, S. Wen, S. Faderl, G. Garcia-Manero, D. Thomas, K.-A. Do, J. Cortes, C. Koller, M. Beran, et al.
Chemoimmunotherapy With Fludarabine, Cyclophosphamide, and Rituximab for Relapsed and Refractory Chronic Lymphocytic Leukemia
J. Clin. Oncol.,
June 20, 2005;
23(18):
4070 - 4078.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Moreton, B. Kennedy, G. Lucas, M. Leach, S. M.B. Rassam, A. Haynes, J. Tighe, D. Oscier, C. Fegan, A. Rawstron, et al.
Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival
J. Clin. Oncol.,
May 1, 2005;
23(13):
2971 - 2979.
[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]
|
|
|
|
|
|
|
T. S. Lin, I. W. Flinn, R. Modali, T. A. Lehman, J. Webb, S. Waymer, M. E. Moran, M. S. Lucas, S. S. Farag, and J. C. Byrd
FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia
Blood,
January 1, 2005;
105(1):
289 - 291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Hale, P. Rebello, L. R. Brettman, C. Fegan, B. Kennedy, E. Kimby, M. Leach, J. Lundin, H. Mellstedt, P. Moreton, et al.
Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration
Blood,
August 15, 2004;
104(4):
948 - 955.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Rawstron, B. Kennedy, P. Moreton, A. J. Dickinson, M. J. Cullen, S. J. Richards, A. S. Jack, and P. Hillmen
Early prediction of outcome and response to alemtuzumab therapy in chronic lymphocytic leukemia
Blood,
March 15, 2004;
103(6):
2027 - 2031.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. L. Basquiera, A. R. Berretta, J. J. Garcia, and E. D. Palazzo
Coronary ischemia related to alemtuzumab therapy
Ann. Onc.,
March 1, 2004;
15(3):
539 - 540.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. R. Muller, G. Tsakou, F. Grunebach, S. M. Schmidt, and P. Brossart
Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells
Blood,
March 1, 2004;
103(5):
1763 - 1769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. M. Ghobrial, L. A. Otteman, W. L. White, D. A. Rizzieri, S. Weitman, and D. M. Vaughn
An EBV-Positive Lymphoproliferative Disorder after Therapy with Alemtuzumab
N. Engl. J. Med.,
December 25, 2003;
349(26):
2570 - 2572.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Coleman, D. M. Goldenberg, A. B. Siegel, J. C. Ketas, M. Ashe, J. M. Fiore, and J. P. Leonard
Epratuzumab: Targeting B-Cell Malignancies through CD22
Clin. Cancer Res.,
September 1, 2003;
9(10):
3991s - 3994s.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Kumar, T. K. Kimlinger, J. A. Lust, K. Donovan, and T. E. Witzig
Expression of CD52 on plasma cells in plasma cell proliferative disorders
Blood,
August 1, 2003;
102(3):
1075 - 1077.
[Abstract]
[Full Text]
[PDF]
|
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TOP
ABSTRACT
INTRODUCTION
