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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-07-1952.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Leukemia, The University of
Texas MD Anderson Cancer Center, Houston.
We explored the safety and efficacy of rituximab plus alemtuzumab
in patients with relapsed or refractory lymphoid malignancies. Forty-eight patients were treated and were assessable for response (32 with chronic lymphocytic leukemia [CLL], 9 with CLL/prolymphocytic leukemia [PLL], 1 with PLL, 4 with mantle cell leukemia/lymphoma, 2 with Richter transformation). The overall response rate was 52%
(complete remission, 8%; nodular partial response, 4%;
partial response, 40%). With a median follow-up of 6.5 months (range, 1-20 months), the median time to progression was 6 months (range, 1-20 months); median survival, 11 months (11+ months for responders vs 6 months for nonresponders). Most toxicities were grade 2 or lower and
infusion-related. Infections occurred in 52% of the patients.
Cytomegalovirus (CMV) antigenemia assays were positive in 27%
of the patients, but only 15% were symptomatic and required therapy.
The combination of rituximab and alemtuzumab is feasible, has an
acceptable safety profile, and has clinical activity with a short
course in a group of patients with poor prognoses.
(Blood. 2003;101:3413-3415) Rituximab and alemtuzumab are active in patients
with chronic lymphocytic leukemia (CLL) and non-Hodgkin
lymphoma (NHL).1-6 However, efficacy in some disease sites
(lymph nodes, spleen, liver) is limited, and the antibodies by
themselves are not curative. Combinations of monoclonal antibodies with
other active agents are therefore being explored.7-10
Although preliminary data show these combinations to be feasible and
safe, the impact on remission duration and survival remains undetermined.
We studied the safety and efficacy of rituximab plus alemtuzumab in
patients with relapsed or refractory lymphoproliferative disorders. The
rationale for combining the 2 monoclonal antibodies is their reported
single-agent activity and the possibility of synergistic effects based
on (1) coexpression of distinct antigens, (2) variable expression of
CD20 and CD52, (3) suboptimal efficacy of single-agent monoclonal
antibody therapy in patients with bulky organomegaly (alemtuzumab) and
bone marrow (rituximab), and (4) potential for induction of apoptosis
through intracellular signaling pathways.
Forty-eight patients with a diagnosis of relapsed or refractory
chronic lymphoid malignancies coexpressing CD20 and CD52 were treated
(Table 1). Prior exposure to rituximab or
alemtuzumab was permitted. Cytomegalo-virus (CMV) antigenemia was
tested before therapy was begun and weekly thereafter as long as the
patient was receiving therapy. An Eastern Cooperative Oncology
Group (ECOG) performance status of 2 or lower was required.
Acceptable organ function was defined by a serum creatinine level of 2 mg/dL or less and a serum total bilirubin level of 2 mg/dL or less. The study was approved by the institutional review board. All patients signed written informed consent prior to participation.
Patients received rituximab at a dose of 375 mg/m2 weekly
for 4 weeks.11 The first dose of rituximab was
divided into 100 mg/m2 given on day 1 and 275 mg/m2 given on day 2 to patients with a white blood cell
(WBC) count of 50 000/µL or higher.12 Alemtuzumab was
given at the loading-dose schedule of 3 mg, 10 mg, and 30 mg on 3 consecutive days during week 1 followed by a dose of 30 mg on days 3 and 5 of weeks 2 to 4 (Figure 1).
Patients could receive a second 28-day cycle depending on response and
toxicities. All patients received prophylactic trimethoprim/sulfamethoxazole and valacyclovir (or equivalent). Prophylactic antibiotics were continued for at least 2 months following
completion of therapy.
All patients were assessed for toxicity and response. Response criteria
were defined according to National Cancer Institute working group
(NCI-WG) criteria for CLL.13 Evaluation of
response in patients with NHL was done according to published
guidelines.14
Of the 48 patients, 7 (15%) received a second course and 4 (10%) did not complete at least one course. Reasons for premature discontinuation were progressive disease (2 patients), infectious complications (pneumonia; 1 patient), and anaphylactic reaction during
the loading doses of alemtuzumab (1 patient).
All patients were evaluable for response. Twenty-five patients
(52%) responded. Four patients (8%) achieved complete remission (CR),
2 (4%) a nodular partial response (PR), and 19 (40%) a PR. The
remaining 23 patients (48%) either had stable disease or progressed. Of 32 patients with CLL, 20 (63%) responded, and of 9 patients with
CLL/ prolymphocytic leukemia (PLL), 4 (44%) responded. Among the
patients who achieved CR, 2 had CLL, 1 had CLL/PLL, and 1 had PLL.
Partial responses occurred in 16 patients with CLL and 3 with CLL/PLL.
No responses occurred in patients with Richter transformation or mantle
cell leukemia/lymphoma. Among the 7 patients who received 2 courses, 4 (57%) responded, compared with 21 responses (57%) among
the 37 patients who completed 1 course only.
Almost all patients achieved a complete clearance of malignant cells in
the peripheral blood (Table 2). In
contrast, only 9 (36%) of 25 patients with CLL and 2 (25%) of 8 patients with CLL/PLL had a bone marrow CR. A 50% or greater decrease
from baseline lymphadenopathy and hepatosplenomegaly occurred in 24 (59%) of 41 patients with CLL and 10 (67%) of 15 patients with
CLL/PLL. No significant difference in response was noted
between patients with fludarabine-sensitive and fludarabine-refractory
disease. Nor was there any significant difference in response among
patients who had received prior therapy with monoclonal antibodies and those who had not.
With a median follow-up of 6.5 months (range, 1-20 months), the median time to progression was 6 months. The median overall survival was 11 months. Whereas the median survival was 6 months for nonresponders, at the time of writing median survival had not been reached for responding patients with 11+ months. The combination was well tolerated. Most nonhematologic toxicities were infusion-related. Frequently observed were fever (75%), rigors (67%), skin reactions (38%), constitutional symptoms (mainly fatigue; 33%), gastrointestinal symptoms including nausea and vomiting (27%), and dyspnea (25%). Almost all of the adverse events were grade 2 or lower according to NCI Common Toxicity Criteria. In general, alemtuzumab was associated with a higher frequency and severity of adverse events than rituximab. Myelosuppression was seen in up to two thirds of the patients but usually did not exceed grade 2. Twenty-five (52%) of the 48 patients experienced at least one
infectious episode (Table 3). A positive
CMV antigenemia test was observed in 13 patients (27%). However, only
7 patients (15%) were symptomatic, and 9 (19%) were treated.
Reactivation of CMV was not associated with organ disease. Fever of
unknown origin (FUO) was the most frequent febrile event (13%).
Although in only 2 of the patients could FUO be related to a positive
CMV antigenemia test, CMV should be suspected in any patient with
fever, negative bacterial cultures and chest radiograph, and no
response to broad-spectrum antibiotics. Pneumonia (fungal or bacterial)
was the most frequent organ manifestation of any type of
infection.
This is the first trial to combine rituximab and alemtuzumab in patients with relapsed or refractory lymphoid malignancies. We show that the combination is feasible and safe. Most adverse events were infusion-related and were comparable in severity and frequency to those observed with single-agent alemtuzumab. We did not observe a higher incidence of infections than would be expected with alemtuzumab alone. No fatal infections occurred in this study. In 27% of the patients the CMV antigenemia test turned positive. However, only 15% of the patients were symptomatic and required therapy, which is in agreement with data from other alemtuzumab studies.15 We report a response rate of 52%, including 8% complete responders. This response rate is higher than that observed with single-agent alemtuzumab.1 However, patients in this study have a wide range of diagnoses and it is difficult to draw any firm conclusions as to whether the combination of rituximab and alemtuzumab has any advantage over single-agent monoclonal antibody therapy. A familiar pattern emerges if one looks at response in distinct anatomic departments: almost complete clearance of malignant cells in the peripheral blood and a 40% to 70% response rate in bone marrow, lymph nodes, and spleen/liver. Although these responses are comparable to those achieved with the single-agent monoclonal antibody, they were achieved after only 4 weeks of therapy, whereas the median duration of therapy in the pivotal trial of alemtuzumab was 8 weeks.1 No difference in response was demonstrated between patients who received 2 courses of therapy and those who received 1 course only. Our results indicate feasibility, an acceptable safety profile, and clinical activity of the antibody combination in a group of patients with poor prognoses. Future studies should focus on histologically more homogenous populations of patients, explore different routes of administration (eg, subcutaneous) for alemtuzumab and prolonged treatment schedules,16 and further explore this antibody combination as treatment for residual disease following prior induction therapy.
We are grateful to Mary L. Williams and Susan Lerner for assistance with data collection and management.
Submitted July 2, 2002; accepted November 1, 2002.
Prepublished online as Blood First Edition Paper, January 9, 2003; DOI 10.1182/blood-2002-07-1952.
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: Stefan Faderl, Department of Leukemia, Box 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: sfaderl{at}mdanderson.org.
1.
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.
2002;99:3554-3561 2. Hainsworth JD. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma: interim follow-up of a multicenter phase II trial. Semin Oncol. 2002;29:25-29.
3.
O'Brien S, Kantarjian H, Thomas DA, et al.
Rituximab dose-escalation trial in chronic lymphocytic leukemia.
J Clin Oncol.
2001;19:2165-2170
4.
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 5. Feuring-Buske M, Kneba M, Unterhalt M, et al. IDEC-C2B8 (rituximab) anti-CD20 antibody treatment in relapsed advanced-stage follicular lymphomas: results of a phase-II study of the German Low-Grade Lymphoma Study Group. Ann Hematol. 2000;79:493-500[CrossRef][Medline] [Order article via Infotrieve]. 6. Lundin J, Österborg A, Brittinger G, et al. CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: a phase II multicenter study. J Clin Oncol. 1998;16:3257-3263[Abstract].
7.
Czuczman MS, Grillo-López AJ, White CA, et al.
Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy.
J Clin Oncol.
1999;17:268-276
8.
Kennedy B, Rawstron A, Carter C, et al.
Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia.
Blood.
2002;99:2245-2247 9. 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. 10. Wierda W, O'Brien S, Albitar M, et al. Combined fludarabine, cyclophosphamide, and rituximab achieves a high complete remission rate as initial treatment for chronic lymphocytic leukemia. Blood. 2001;98:771a.
11.
Huhn D, von Schilling C, Wilhelm M, et al.
Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.
Blood
2001;98:1326-1331
12.
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
13.
Cheson B, Bennett J, Grever M, et al.
NCI-sponsored working group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment.
Blood.
1996;87:4990-4997
14.
Cheson B, Horning SJ, Coiffier B, et al.
Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas.
J Clin Oncol.
1999;17:1244-1253 15. Cao TM, Nguyen DD, Dugan K, Starcher SA, Fechter RL, Coutre SE. Incidence of cytomegalovirus (CMV) viremia during Campath-1H therapy for relapsed/refractory chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (PLL). Blood. 2001;98:366a.
16.
Lundin J, Kimby E, Bjorkholm M, et al.
Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL).
Blood.
2002;100:768-773
© 2003 by The American Society of Hematology.
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  K Hodby and P A Fields Management of lymphoma in pregnancy Obstet Med, June 1, 2009; 2(2): 46 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Dimopoulos, M. A. Gertz, E. Kastritis, R. Garcia-Sanz, E. K. Kimby, V. LeBlond, J.-P. Fermand, G. Merlini, P. Morel, E. Morra, et al. Update on Treatment Recommendations From the Fourth International Workshop on Waldenstrom's Macroglobulinemia J. Clin. Oncol., January 1, 2009; 27(1): 120 - 126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Brenner, A. Gondos, and D. Pulte Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century Blood, May 15, 2008; 111(10): 4916 - 4921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Hillmen, A. B. Skotnicki, T. Robak, B. Jaksic, A. Dmoszynska, J. Wu, C. Sirard, and J. Mayer Alemtuzumab Compared With Chlorambucil As First-Line Therapy for Chronic Lymphocytic Leukemia J. Clin. Oncol., December 10, 2007; 25(35): 5616 - 5623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Morrison Management of Infectious Complications in Patients with Chronic Lymphocytic Leukemia Hematology, January 1, 2007; 2007(1): 332 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Faderl, A. Ferrajoli, W. G. Wierda, S. O'Brien, F. Ravandi-Kashani, L. Fayad, D. Thomas, H. Kantarjian, M. L. Browning RN, and M. J. Keating MB The Combination of Alemtuzumab [Continuous Intravenous Infusion (civ) Followed by Subcutaneous Injection (sc)] Plus Rituximab Has Activity in Patients (pts) with Relapsed Chronic Lymphocytic Leukemia (CLL). Blood (ASH Annual Meeting Abstracts), November 16, 2006; 108(11): 2827 - 2827. [Abstract] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. C. Wade Viral Infections in Patients with Hematological Malignancies Hematology, January 1, 2006; 2006(1): 368 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Abbott Chronic Lymphocytic Leukemia: Recent Advances in Diagnosis and Treatment Oncologist, January 1, 2006; 11(1): 21 - 30. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Ravandi and S. O'Brien Chronic Lymphoid Leukemias Other Than Chronic Lymphocytic Leukemia: Diagnosis and Treatment Mayo Clin. Proc., December 1, 2005; 80(12): 1660 - 1674. [Abstract] [PDF]
|
|
|
|
|
|
S. Faderl, A. Ferrajoli, W. Wierda, F. Ravandi, S. O'Brien, G. Garcia-Manero, D. A. Thomas, M. L. Browning, and M. J. Keating Continuous Infusion/Subcutaneous Alemtuzumab (Campath-1H) Plus Rituximab Is Active for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL). Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 2963 - 2963. [Abstract]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 R. R. Razonable Epidemiology of cytomegalovirus disease in solid organ and hematopoietic stem cell transplant recipients Am. J. Health Syst. Pharm., April 15, 2005; 62(suppl_1): S7 - S13. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. C. Byrd, S. Stilgenbauer, and I. W. Flinn Chronic Lymphocytic Leukemia Hematology, January 1, 2004; 2004(1): 163 - 183. [Abstract] [Full Text] [PDF]
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Abstract
Introduction