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Routine clinical use of alemtuzumab in patients with heavily pretreated B-cell chronic lymphocytic leukemia†‡
A nation-wide retrospective study in Austria
Article first published online: 19 OCT 2006
Copyright © 2006 American Cancer Society
Volume 107, Issue 10, pages 2408–2416, 15 November 2006
How to Cite
Fiegl, M., Falkner, A., Hopfinger, G., Brugger, S., Zabernigg, A., Bauer, F., Haslbauer, F., Demirtas, D., Grossschmidt, P., Tatzreiter, G., Gastl, G., Greil, R. and The Austrian Collaborative Study Group on Alemtuzumab in Chronic Lymphocytic Leukemia (2006), Routine clinical use of alemtuzumab in patients with heavily pretreated B-cell chronic lymphocytic leukemia. Cancer, 107: 2408–2416. doi: 10.1002/cncr.22263
Preliminary data from this study were presented in part at the 47th Annual Meeting of the American Society of Hematology, Atlanta, Georgia, December 10–13, 2005.
Additional contributors to this work included the following (Austrian centers): F. X. Schmid (Bregenz); A. Lang (Feldkirch); C. Ludescher, J. Kantner, R. Stauder, J. Büchel, J. Auberger, and M. Steurer (Innsbruck); A. Sahanic (Natters); L. Köck (Lienz); V. Faber and P. Mayer (Salzburg); G. Lobmair (Ried); D. Voskova (Linz); J. Schwarzmeier, M. Shehata, D. Heintel, and U. Jäger (Vienna); G. Jager (Graz); W. Lin (Villach); and H. Weiss (St. Veit).
- Issue published online: 8 NOV 2006
- Article first published online: 19 OCT 2006
- Manuscript Accepted: 22 AUG 2006
- Manuscript Revised: 16 AUG 2006
- Manuscript Received: 13 JUL 2006
- Schering Vienna GmbH
- chronic lymphocytic leukemia;
- monoclonal antibody;
In previous studies, alemtuzumab demonstrated considerable activity in patients with previously treated B-cell chronic lymphocytic leukemia (CLL), including fludarabine-refractory disease. In this retrospective study, the authors evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced, previously treated CLL who received treatment in the routine clinical setting.
Data were collected from 115 consecutive patients who received alemtuzumab therapy at 25 participating centers in Austria. Patients received a median of 3 prior lines of therapy (range, 1–11 prior lines of therapy), and 59% had fludarabine-refractory disease. Alemtuzumab was administered intravenously or subcutaneously with a planned schedule of 30 mg 3 times per week for up to 12 weeks. Patients received valacyclovir and trimethoprim/sulfamethoxazole for antiinfective prophylaxis.
The overall response rate was 23%, with complete responses achieved in 5% of patients. Stable disease (SD) was achieved in 36% of patients. After a median follow-up of 17.5 months, the median overall survival (OS) was 20.2 months for all patients. A multivariate Cox regression analysis that included pretreatment baseline characteristics, response to therapy, and cumulative dose of alemtuzumab indicated that bulky lymphadenopathy, the administration of ≥3 previous therapies, and lack of response to alemtuzumab remained significant independent risk factors for inferior OS. The median OS had not been reached for responding patients. The median OS was 29.5 months for patients with SD and 10.8 months for patients with progressive disease.
The broad use of alemtuzumab in the routine clinical practice setting is feasible and active in unselected patients with pretreated CLL, and the current results confirmed the activity and safety of this agent, as reported in previously published clinical studies. Cancer 2006. © 2006 American Cancer Society.
B-cell chronic lymphocytic leukemia (B-CLL) is a disorder characterized by the accumulation of abnormal mature B-lymphocytes and is the most common leukemia in Western countries. Although the introduction of purine analogs, such as fludarabine and chemotherapy combinations, have improved response rates in patients with CLL, the treatment of patients who have become refractory to fludarabine-based therapy remains an important clinical challenge. The survival outcome of patients with fludarabine-refractory CLL is poor, with a median overall survival (OS) of 10 to 12 months after the initiation of salvage chemotherapy after fludarabine failure.1, 2
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody that targets the cell surface glycoprotein CD52, which is expressed abundantly on normal and malignant B-lymphocytes and T-lymphocytes.3, 4 In a pivotal Phase II study that was conducted in heavily pretreated patients with fludarabine-refractory CLL (n = 93 patients), single-agent therapy with alemtuzumab resulted in an overall response rate (ORR) of 33% and a complete response (CR) rate of 2%.5 Alemtuzumab also has demonstrated considerable activity in the frontline treatment of CLL (n = 41 patients), with an ORR of 87% (CR, 19%).6 Although alemtuzumab monotherapy has been evaluated in a number of prospectively designed clinical trials, little is known about its therapeutic benefit in the routine clinical practice setting. Herein, we report the results of a retrospective study in 115 consecutive, unselected patients with advanced B-CLL who were treated with alemtuzumab in a routine clinical practice setting at 25 centers in Austria.
MATERIALS AND METHODS
Study Design and Patients
This retrospective study was conducted in consecutive, unselected patients with progressive B-CLL who required therapy and who had received at least 1 prior course of treatment. Patients received alemtuzumab between December 20, 2001, and January 12, 2006. Approval of data acquisition and analysis was obtained from the University of Innsbruck Ethics Committee (the local Institutional Review Board). Clinical data pertaining to treatment modalities, efficacy, and course of disease were collected from 25 clinical hematology-oncology centers in Austria.
During the first week of alemtuzumab therapy, the dose was escalated with usually intravenous (IV) administration of 3 mg on Day 1, 10 mg on Day 2, and 30 mg on Day 3. Subsequent doses of 30 mg were administered either by IV or subcutaneous (SC) delivery 3 times per week. For patients who received SC delivery (n = 58 patients), the majority (n = 41 patients) received IV administration during the dose-escalation phase. In accordance with the prescribing information, alemtuzumab usually was discontinued for 1 or more weeks if absolute neutrophil counts and platelet counts dropped below 250/μL and 25,000/μL, respectively.7 In several patients, however, therapy was continued in the presence of platelet counts <25,000/μL with platelet transfusion support. The intended duration of treatment was 12 weeks. Patients were retreated with alemtuzumab-based therapy or other therapies at the discretion of clinicians at participating centers. Because of the retrospective nature of the current study, no predetermined criteria were established for retreatment; the decision to retreat, the type of therapy, and the dosing schedule were individualized for each patient and largely were dependent on factors such as the quality of response or duration of response to initial alemtuzumab therapy.
Antiinfective prophylaxis with valacyclovir (500 mg 2 or 3 times daily) and trimethoprim-sulfamethoxazole (960 mg twice daily 2 or 3 days per week) were given according to accepted guidelines.5, 8 At most of the treatment centers, patients were monitored routinely for cytomegalovirus (CMV) reactivation using the phosphoprotein 65 antigenemia assay or polymerase chain reaction assays. CMV-specific antiviral prophylaxis was not administered routinely; however, patients with symptomatic CMV reactivation were treated promptly with IV ganciclovir, usually followed by oral ganciclovir.
The following variables were documented at baseline: disease stage according to the Rai classification; leukocyte count; the presence of hepatomegaly, splenomegaly, and/or bulky lymphadenopathy (>5 cm); and the presence of autoimmune phenomena, such as hemolytic anemia and thrombocytopenia. The interval from primary diagnosis until initiation of alemtuzumab, as well as the number of previous therapies and the status of refractoriness to fludarabine, also were documented. A previous therapy was counted as a separate series of treatments when it was initiated at disease progression, regardless of whether a new regimen was administered or the former regimen was reinitiated. Similar to a previous study,5 fludarabine failure was defined as failure to achieve a CR or partial response (PR) according to the National Cancer Institute Working Group (NCI-WG) criteria9 or disease recurrence within 6 months after the last dose of fludarabine administration.
Patients who had received at least 1 dose of alemtuzumab were evaluable for efficacy and safety. Efficacy was documented in all but 10 patients who could not be evaluated for response because they died prematurely (n = 9 patients) or were switched to other therapy (n = 1 patient). Duration of treatment was defined as the interval between the first dose and last dose of alemtuzumab. Response was evaluated according to NCI-WG criteria9 after the last administration of alemtuzumab, including patients who received prolonged therapy (n = 19 patients), 2 months after the last dose and thereafter if there was a delayed response (e.g. normalization of cytopenias). For documentation of CR, PR, or stable disease (SD), the response had to persist for at least 2 months. In patients with obvious delayed response (e.g. normalization of cytopenia), the final response was identified at the time of the best response. For documentation of a response, appropriate radiographic evaluations, including either computed tomography or sonography studies of the abdomen and chest radiographs, were mandatory. Bone marrow examination was required for documentation of CR. Other therapeutic endpoints that were assessed included OS, time to disease progression in responding patients, time to treatment failure, and time to retreatment after the last dose of alemtuzumab. Disease progression was documented according to NCI-WG criteria.9 OS was measured from the time therapy was initiated in each patient. The last follow-up data available for this analysis were from June 30, 2006.
Any toxicity observed from the first administration of alemtuzumab until 2 months after the last dose was considered treatment related. Significant infectious episodes (defined as Common Toxicity Criteria Grade ≥2) were documented in addition to CMV reactivation and CMV disease, death from any cause, Richter transformation, and hypersensitivity reactions Grade ≥2. Because patients in this study were not enrolled in a prospective clinical trial, data on Grade 1 and 2 toxicities were limited and, thus, were not analyzed.
Comparisons of response rates (ORR and CR) between patient subgroups (based on baseline categorical characteristics) were made by using chi-square analysis. Event-related data (OS; time to treatment failure; time to disease progression in patients who achieved a CR, PR, or SD; and time to retreatment) were estimated by using the Kaplan–Meier method, and comparisons of outcomes between categorical subgroups were made by using the log-rank test. For baseline characteristics and treatment-related parameters that were associated with OS, the hazard ratio was calculated by using multivariate Cox regression analysis.
Patient demographics and baseline characteristics are detailed in Table 1. The median age was 66 years (range, 46–88 years), and the majority of patients had Rai Stage III or IV disease (72%). At the initiation of alemtuzumab therapy, the median duration since diagnosis of CLL was 59 months. Previously in their disease course, 5 patients had manifestations of Richter transformation, and 2 patients had peripheral blood prolymphocyte increases >15%. However, such features were not present at the time alemtuzumab therapy was initiated in those 7 patients, probably because of eradication by previous treatment regimens. Approximately 33% of patients had bulky lymphadenopathy (defined as lymph nodes measuring ≥5 cm), and large proportions of patients had splenomegaly (65%) and hepatomegaly (26%). Patients had received a median of 3 prior lines of therapy (range, 1–11 prior lines of therapy). With respect to prior therapies, 104 patients (90%) had received fludarabine (alone or in combination), 103 patients (90%) had received alkylating agents, 48 patients (42%) had received anthracyclines, and 25 patients (22%) had received rituximab. The combination of fludarabine and cyclophosphamide was received by 22 patients (19%). Other treatments that were administered as prior therapies (mostly administered in combinations) included vincristine (n = 73 patients), vinorelbine (n = 6 patients), bendamustine (n = 3 patients), ifosfamide (n = 3 patients), cladribine (n = 4 patients), cisplatin (n = 2 patients), cytarabine (n = 2 patients), bleomycin (n = 1 patient), and procarbacine (n = 1 patient). Among the 104 patients who had received prior treatment with fludarabine-based therapies, 68 patients (59% overall) were considered refractory to fludarabine, as defined previously,5 and 27 patients (23% overall) were considered fludarabine-sensitive. Previous response to fludarabine was unknown in 8% of patients. The median duration of alemtuzumab therapy was 7.5 weeks (range, 1–29 weeks), and the median cumulative dose administered was 390 mg (range, 11–1333 mg). The median alemtuzumab dose administered per week was 50 mg (range, 13–93 mg per week), which was analyzed only for the proportion of patients who received at least 8 weeks of alemtuzumab therapy (n = 57 patients).
|Characteristic||No. of patients (%)|
|Median age (range), y||66 (46–88)|
|Median months from diagnosis to alemtuzumab (range)||59 (3–282)|
|Stage I||8 (7)|
|Stage II||24 (21)|
|Stage III||21 (18)|
|Stage IV||62 (54)|
|Response to prior fludarabine|
|No prior fludarabine||11 (10)|
|Median no. of prior lines of therapy (range)||3 (1–11)|
|Median levels of β2-microglobulin (range), mg/L||4.2 (1.3–13.6)|
|<13 cm||15 (13)|
|13–19 cm||50 (44)|
|≥20 cm||24 (21)|
|Prior splenectomy||5 (4)|
|<5 cm||68 (59)|
|≥5 cm||37 (32)|
Response to alemtuzumab therapy could be evaluated in 105 patients. For the remaining 10 patients, response was not evaluable because of death during therapy or within 2 months after therapy (n = 9 patients) or because of early termination of alemtuzumab therapy followed by a change in therapy as a result of intolerance to alemtuzumab (immediate thrombocytopenia with a platelet count of 2000/μL, probably because of idiopathic thrombocytopenic purpura; n = 1 patient). The ORR for all 115 patients was 23%, with CR and PR rates of 5% and 17%, respectively (Table 2). Stabilization of disease, which was associated with substantial clinical benefit (e.g. normalization of peripheral blood values, decrease in B symptoms), was achieved in 36% of patients. Moreover, among 11 patients who presented with autoimmune hemolytic anemia (including 3 patients who had concurrent immune thrombocytopenia; i.e., Evans syndrome) at baseline, 8 patients (73%) responded to alemtuzumab treatment with normalization or improvement in hemoglobin and platelet levels. In patients who achieved an objective therapeutic benefit (CR, PR, or SD), the response rates in different disease compartments are detailed in Table 3. In particular, treatment with alemtuzumab resulted in marked clearance of disease in the peripheral blood and bone marrow.
|Characteristic||No. of Patients||NCI-WG response: No. of patients (%)||P*|
|All patients†||115||6 (5)||20 (17)||41 (36)||38 (33)||10 (9)||26 (23)|
|Stage I-III||53||3 (6)||10 (19)||20 (38)||15 (28)||5 (10)||13 (25)||NS|
|Stage IV||62||3 (5)||10 (16)||21 (34)||23 (37)||5 (8)||13 (21)|
|<11 g/dL||64||1 (2)||8 (12)||21 (33)||25 (39)||9 (14)||9 (14)||.022|
|≥11 g/dL||50||5 (10)||11 (22)||20 (40)||13 (26)||1 (2)||16 (32)|
|<5 cm||68||5 (7)||14 (21)||25 (37)||20 (29)||4 (6)||19 (28)||.017|
|≥5 cm||37||1 (3)||2 (5)||13 (35)||17 (46)||4 (11)||3 (8)|
|Refractory||68||2 (3)||7 (10)||19 (28)||30 (44)||10 (15)||9 (13)||.06|
|Sensitive||27||2 (7)||6 (22)||14 (52)||5 (19)||0 (0)||8 (30)|
|Treated||104||5 (5)||15 (14)||38 (37)||36 (35)||10 (10)||20 (19)||.008‡|
|Naive||11||1 (9)||5 (46)||3 (27)||2 (18)||0 (0)||6 (55)|
|No. of prior lines of therapy|
|1–2||47||4 (9)||13 (28)||18 (38)||9 (19)||3 (6)||17 (36)||.004|
|≥3||68||2 (3)||7 (10)||23 (34)||29 (43)||7 (10)||9 (13)|
|≤4 mg/L||29||3 (10)||8 (28)||11 (38)||5 (17)||2 (7)||11 (38)||.01|
|>4 mg/L||31||0 (0)||3 (10)||11 (36)||16 (52)||1 (3)||3 (10)|
|Disease site||% CR||% PR||% SD|
|Peripheral blood (n = 67)||60||25||15|
|Lymph nodes (n = 61)||23||21||56|
|Bone marrow (n = 21)||52||29†||19|
|Spleen (n = 53)||11||34||55|
|Liver (n = 12)||33||0||67|
Response to alemtuzumab therapy was not associated significantly with the following baseline characteristics: gender, age, presence of splenomegaly, degree of leukocytosis or thrombocytopenia, or disease stage (Table 2). Moreover, response was not associated with therapy-related parameters, such as duration of alemtuzumab therapy (<8 weeks vs. ≥8 weeks), weekly dose levels (<50 mg vs. ≥50 mg), cumulative alemtuzumab dose administered (<600 mg vs. ≥600 mg), or mode of administration (IV vs. SC data not shown). In contrast, response was significantly superior in patients who received fewer prior lines of therapy, patients who had lower levels of β2-microglobulin, patients with an absence of anemia (hemoglobin≥11 g/dL), and patients with an absence of bulky lymphadenopathy (Table 2). A trend toward superior response was observed in patients who had fludarabine-sensitive disease and in patients who were without hepatomegaly. Patients who had not received prior fludarabine therapy had a significantly superior response compared with patients who had received prior fludarabine.
The median OS after the initiation of alemtuzumab therapy was 20.2 months (Fig. 1A). In univariate analysis, OS was significantly dependent on the following baseline characteristics (Table 4): age, presence of anemia, β2-microglobulin, bulky lymphadenopathy (Fig. 1B), refractoriness to fludarabine, and the number of previous lines of therapy (Fig. 1C). In addition, in univariate analysis, OS also was dependent on NCI-WG response (Fig. 1D) and on the cumulative dose of alemtuzumab administered (≤600 mg vs. >600 mg) (Table 4). The median OS for patients who achieved a response (PR or CR) had not yet been reached, and the median OS was approximately 29.5 months for patients with SD; the median OS for patients who progressed during alemtuzumab therapy or within 2 months after the last dose of alemtuzumab was only 10.8 months (Fig. 1D). The median OS did not differ significantly between patients with SD and patients who achieved a PR (29.5 months vs. not reached; P = .16). Rai stage, thrombocytopenia, gender, method of alemtuzumab administration, and treatment institution did not influence OS in the current study. Among the patients who had fludarabine-refractory disease (n = 68 patients), those who achieved a CR, PR, or SD had a median OS of 42.5 months (n = 28 patients) (Fig. 2).
|Characteristic||No. of patients*||Median OS, m||P†|
|No. of prior lines of therapy|
|CR or PR||26||Not reached||<.001|
|CR or PR||26||Not reached||<.001|
|Overall cumulative alemtuzumab dose§|
Multivariate Cox regression analysis was performed by using 2 models. In the first model, pretreatment baseline characteristics that showed significance for OS in the univariate analysis were included (n = 105 patients); however, β2-microglobulin was not included in this model, because data were available for only 60 patients. Results from the multivariate regression analysis showed that the independent risk factors for shorter OS were greater number (≥3) of prior lines of therapy (hazard ratio, 2.89; 95% confidence interval [95%CI], 1.49–5.61; P = .002), bulky lymphadenopathy (hazard ratio, 2.08; 95%CI, 1.23–3.51; P = .006), refractoriness to prior fludarabine (hazard ratio, 2.00; 95%CI, 1.13–3.55; P = .018), and anemia (hazard ratio, 1.92; 95%CI, 1.10–3.35; P = .022). In the second Cox regression model, both pretreatment baseline characteristics and treatment-related parameters (i.e., response to therapy and cumulative dose of alemtuzumab) were included (n = 104 patients). According to the multivariate analysis for OS in this model, the independent risk factors for shorter OS were lack of response to treatment (hazard ratio, 4.49; 95%CI, 1.53–13.16; P = .006), ≥3 prior lines of therapy (hazard ratio, 2.51; 95%CI, 1.27– 4.93; P = .008), and bulky lymphadenopathy (hazard ratio, 1.92; 95%CI, 1.14–3.25; P = .015).
Disease Recurrence and Progression
In the 82 patients who had disease progression during or after alemtuzumab therapy, progressive disease presented predominantly as a increasing peripheral lymphocyte count in 39 patients (48%), progressive lymphadenopathy in 33 patients (40%), Richter transformation in 2 patients (2%), and other (increasing lactate dehydrogenase, cachexia, unspecified) in 8 patients (10%). The median time to treatment failure (defined as the time to disease progression or death from the first dose of alemtuzumab, whichever occurred first) was 6.2 months. Among the 67 patients who achieved a therapeutic benefit (CR, PR, or SD), median time to disease progression from the last dose of alemtuzumab was 9.9 months.
After alemtuzumab therapy, 63 patients received 1 or more courses of treatment with different therapies, and the type of treatment administered was determined by the clinician at each treatment center according to the specific patient. Retreatment with alemtuzumab as monotherapy or in combination with chemotherapy was received by 33% and 6% of retreated patients, respectively. Other retreatment regimens included combination chemotherapy (17%), rituximab plus chemotherapy (14%), single-agent chemotherapy (11%), radiotherapy (8%), alemtuzumab maintenance (5%), and single-agent rituximab (5%). The median time to retreatment from the last dose of alemtuzumab was 8.0 months.
The most commonly observed complications were infectious events (Grade 2–4; 48%) and hypersensitivities (any grade; 46%). Severe toxicities included infection (Grade 3 and 4; 37%), neutropenia (Grade 4; 26%), thrombocytopenia (Grade 4, 21%), and hypersensitivity reactions (Grade 3 and 4; 8%). CMV reactivation, including 2 episodes of CMV pneumonia (2%), occurred in 13% of patients and was treated successfully with antiviral therapy in all patients. Death during therapy (or within 2 months after the last dose of alemtuzumab) occurred in 14 patients (12%), namely caused by sepsis (n = 7 patients), rapid disease progression (n = 2 patients), thrombocytopenic hemorrhage (n = 1 patient), pulmonary embolism (n = 1 patient), cardiac decompensation (n = 1 patient), and unknown causes (n = 2 patients). With regard to late complications, 1 episode each of reactivated pulmonary tuberculosis and gastroenteritis from Mycobacterium avium intracellulare was observed. One patient had a decrease in platelet level to 2000/μL after 1 week on alemtuzumab (cumulative dose, 73 mg), most likely attributable to newly acquired immune thrombocytopenia (corresponding to a previous observation by Haider and Cahill10). One patient experienced massive exacerbation of preexisting, Coombs-positive autoimmune hemolysis after 12 weeks on alemtuzumab (a decrease in hemoglobin levels to 6 g/dL at a cumulative dose of 856 mg), which was treated successfully with erythrocyte transfusion, IV immunoglobulin, steroids, and rituximab. Four patients (4%) developed skin malignancies during follow-up after alemtuzumab therapy (2 patients each developed melanoma and basal cell carcinoma), and 1 patient developed fatal lung cancer.
In the current study, we demonstrated that broad use of alemtuzumab monotherapy in heavily pretreated patients with CLL was beneficial in terms of response, symptom control, and survival for a substantial proportion of patients, even in the routine clinical environment. In our series of unselected CLL patients, therapy with alemtuzumab resulted in effective clearance of disease from the peripheral blood and bone marrow. Thus, the main therapeutic benefit was achieved in the peripheral blood and bone marrow compartments (Table 3), consistent with findings from previous reports of alemtuzumab therapy in patients with recurrent and/or refractory CLL.5, 11–13 The 23% ORR rate (CR rate, 5%) in the current study was somewhat lower than the response rates reported in a pivotal, multicenter, Phase II study with IV alemtuzumab (ORR, 33%; CR, 2%5) and in other previous studies.12–15 This finding may be explained in part by the potential differences across studies in baseline disease characteristics with prognostic relevance and variability in the level of adherence to the NCI-WG criteria for response.
Response rates to alemtuzumab, as expected, were poorer in patients who had unfavorable baseline characteristics like bulky lymphadenopathy, ≥3 prior therapies, refractoriness to fludarabine, and elevated β2-microglobulin levels (Table 2). It is noteworthy on a practical basis that response rates with IV administration and SC administration were similar, suggesting that the mode of delivery of alemtuzumab does not affect its activity in patients with CLL.5, 15
In contrast to the comparably lower ORR, the median OS for the overall population in our study was 20.2 months, which compared favorably with the median OS reported in previous studies of patients with advanced-stage, recurrent, and/or refractory disease.5, 11, 13, 15 Among patients who responded to therapy, the median OS had not been reached at the time that this report was in preparation. Remarkably, the median OS was prolonged by approximately 30 months in patients with SD, which was not significantly inferior to the OS among patients who achieved a PR. This finding was not observed in the German CLL2H study16 and was not reported or analyzed in other previous prospective studies.5, 13, 14 Our results suggest that alemtuzumab may provide a meaningful therapeutic benefit, even in the absence of an objective clinical response. Various clinical and biologic factors reportedly have prognostic significance in patients with CLL. In the multivariate analysis that included only pretreatment baseline characteristics, the presence of anemia, bulky lymphadenopathy (>5 cm lymph nodes), refractoriness to fludarabine, and the administration of ≥3 previous therapies were significantly predictive of shorter OS. In a second multivariate analysis that included baseline characteristics, the variables treatment response, and cumulative alemtuzumab dose, lack of response to therapy (i.e., no CR or PR), bulky lymphadenopathy, and ≥3 previous therapies were significantly predictive of shorter OS. A similar observation was made in patients with recurrent and refractory CLL in a recently published study: Those authors reported that nonresponse to combination therapy with fludarabine, cyclophosphamide, and rituximab was a significant, independent factor for inferior OS in multivariate analysis.17 To the best of our knowledge, a multivariate analysis like that presented in this report has not been performed to date in studies that evaluated the therapeutic efficacy of alemtuzumab in patients with CLL.
In patients with CLL, refractoriness to fludarabine is a hallmark of adverse prognosis, with a median OS of 10 to 12 months calculated from start of treatment with conventional salvage therapy.1, 2 The median OS of approximately 15 months observed in our fludarabine-refractory patients who received alemtuzumab monotherapy was comparable to results reported in recent prospective studies.5, 15 It is noteworthy that a dramatic benefit in terms of increased survival was achieved among those patients who had fludarabine-refractory disease and achieved a CR, a PR, or SD. Thus, our data support the previous observations that response to alemtuzumab, either alone5, 15 or in combination with chemotherapy,18, 19 is capable of overcoming fludarabine resistance, which potentially translates into improved survival in patients who otherwise have dismal outcomes.
The incidence of severe toxicities observed in our study was comparable to the incidence reported in published clinical studies of single-agent alemtuzumab in patients with previously treated CLL.5, 11, 12, 14, 15, 20, 21 Toxicities were managed well in the vast majority of patients, demonstrating that alemtuzumab is safe for routine use at clinical centers when standard prophylaxis and diligent monitoring are employed. Given the previous observation that SC delivery of alemtuzumab markedly reduced the incidence of infusion-related toxicities with efficacy similar to that of IV administration, the SC mode of delivery may be preferable. Our current results support the feasibility of SC administration of alemtuzumab with efficacy comparable to that of IV delivery.
In this study, we demonstrated that the broad use of alemtuzumab in the routine clinical setting is active in patients with pretreated CLL and that it is manageable even in treatment centers with a relatively small volume of patients. Our findings largely confirm the activity and safety of alemtuzumab in patients with advanced, pretreated CLL reported previously in published clinical trials. Based on the current experience, we recommend the establishment of collaborative, multicenter studies within the community setting as part of an ongoing effort to provide valuable “real life” clinical experience with novel agents.
We authors thank Maoko Naganuma, MSc, for editorial support.
- 7Berlex Laboratories.Campath (alemtuzumab) [prescribing information]. Montville: Berlex Laboratories, 2005. Available at: http://www.berlex.com/html/products/pi/Campath_PI.pdf [accessed July 2005].
- 15Efficacy of subcutaneous alemtuzumab (Campath-1H) in genetic high-risk, fludarabine-refractory CLL: CLL2H study of the German CLL Study Group (GCLLSG) [abstract 041]. Ann Oncol. 2005; 2005: v43., , , et al.
- 16Subcutaneous Campath-1H (alemtuzumab) in fludarabine-refractory CLL: interim analysis of the CLL2H study of the German CLL Study Group (GCLLSG) [abstract 478]. Blood. 2004; 104: 140a., , , et al.
- 21Patients with refractory B-CLL and T-PLL treated with alemtuzumab (Campath) on a compassionate basis. A report on efficacy and safety of CAM511 trial [abstract 3165]. Blood. 2002; 100: 802a., , , .