Fludarabine in Combination With Alemtuzumab Is Effective and Feasible in Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leu
http://www.100md.com
《临床肿瘤学》
the Department of Hematology and Oncology
Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne
Department of Hematology and Oncology, University of Erlangen, Erlangen
Department of Hematology and Oncology, University of Kiel, Kiel
Department of Hematology, Robert-Bosch-Hospital, Stuttgart
Outpatient Center for Hematology and Oncology, Siegburg, Germany
ABSTRACT
PURPOSE: To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL).
PATIENTS AND METHODS: A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment.
RESULTS: The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred.
CONCLUSION: The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.
INTRODUCTION
B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in North America and Europe, and its prevalence is increasing with the increasing average age of Western populations.1 Treatment decisions are hindered by the difficulty in distinguishing between patients who will not require treatment and for whom a watchful waiting strategy might be appropriate and patients in whom the disease will progress and who require a more aggressive treatment.2 Although B-CLL is currently incurable, recent developments are gradually making an impact on the natural history of the disease. These include promising new treatment options using highly active agents.
Fludarabine is one of the most effective agents for patients with B-CLL, with overall response (OR) rates of 50% to 60% in previously treated patients3,4 and 60% to 80% in previously untreated patients.4-6 When evaluated in prospectively randomized trials, fludarabine has achieved significantly higher rates of complete response (CR) and partial response (PR)4,6,7 compared with chlorambucil monotherapy and most alkylating agent–based regimens, which typically have OR rates of 63% to 71%. Duration of response and treatment-free intervals for patients treated with fludarabine are superior compared with alkylating agents.6 However, all patients ultimately relapse because of the clonal expansion of residual tumor cells.8
Another recent improvement is the ability to detect residual B-CLL cells in the peripheral blood or bone marrow at a threshold of one malignant cell per 104 to 105 normal leukocytes by flow cytometry. This technique allows one to easily monitor the clearance of CLL cells from the blood and bone marrow.
To possibly enhance the therapeutic efficacy and eradicate residual malignancy, novel, fludarabine-based combination therapies are emerging. Combinations of fludarabine with a variety of agents have shown better antitumor effects. This includes alkylating agents,9-13 anthracyclines,14,15 and monoclonal antibodies,16,17 both in clinical studies and in vitro.18-20 Of these combination options, the addition of fludarabine to monoclonal antibody therapy is highly promising because their modes of action are complementary, making synergistic effects plausible.
Alemtuzumab is currently approved for the treatment of refractory B-CLL. The standard dosing schedule of up to 12 weeks of treatment at 30 mg three times weekly has demonstrated an OR rate of 33% in fludarabine-refractory patients21,22 and 87% in previously untreated patients.23 As a single agent, alemtuzumab is highly active in both blood and bone marrow24 and is able to reduce disease burden at these sites to levels below those detectable by polymerase chain reaction25 or four-color flow cytometry.26 The eradication of minimal residual disease seems to be associated with prolonged survival.27-29 Impressive response rates (82%) have been observed in patients without significant lymphadenopathy, whereas a lower response rate (25%) was observed in patients with bulky lymph nodes.22,30
Recently, Kennedy et al17 reported on six CLL patients treated with a combination of fludarabine and alemtuzumab (FluCam) who were refractory to both drugs when administered as single agents. Five of six patients achieved a remission, including one patient with CR in whom disease was eradicated from previously inaccessible nodal sites. These findings emphasize the synergistic effects of FluCam and provide a strong rationale for further studies.
We investigated the use of FluCam for the treatment of patients with relapsed or refractory B-CLL. This new regimen was administered for 3 days every 4 weeks to explore the potential additive effects of these two drugs and increase the convenience for the patients treated.
PATIENTS AND METHODS
This phase II, open-label, single-center trial investigated the efficacy of FluCam in patients with relapsed or refractory B-CLL. Approval was obtained from the institutional review board for these studies and in accordance with an assurance filed with and approved by the Department of Health and Human Services; all patients gave written informed consent according to the Declaration of Helsinki. Adults ( 18 years of age) with relapsed or refractory B-CLL were eligible. Diagnosis was established using the 1996 National Cancer Institute (NCI) Working Group criteria.31 Patients must have received at least one prior therapy; any prior treatment with fludarabine, alemtuzumab, or rituximab must have been completed at least 6 months before study entry. Patients were required to have adequate bone marrow function (absolute neutrophil count 1,500/μL). Patients were excluded if they had a WHO/Eastern Cooperative Oncology Group performance status of more than 2, a history of severe infection (grade 4) within the 3 months before treatment, a history of anaphylactic reaction after exposure to humanized monoclonal antibodies, concurrent severe diseases, or an active secondary malignancy. Patients were also excluded if they had received any prior chemotherapy or radiotherapy for any neoplastic disease other than B-CLL.
Treatment
Dose escalation of alemtuzumab was performed on consecutive days from 3 mg to 10 mg to 30 mg or with repeated administration at the previous dose if that dose had been accompanied by adverse events greater than grade 2 in severity. FluCam was then administered for a total of 3 consecutive days; this was repeated every 28 days for a total of four cycles in the first 14 patients (Fig 1). After the first interim analysis including 14 patients indicated that toxicity was tolerable, the total number of cycles was increased to six for the following 22 patients. The length of the first alemtuzumab infusion in cycles not preceded by dose escalation was prolonged from 2 to 4 hours. Premedication was administered before the first alemtuzumab infusion in each cycle and thereafter if clinically indicated, including clemastine (2 mg intravenously), acetaminophen (1 g orally), and prednisone (100 mg intravenously). In patients with a WBC count more than 50,000/μL, bulky disease, or a medical history of hyperuricemia, allopurinol (300 mg/d) was administered before the first infusion and thereafter if clinically indicated.
Antimicrobial prophylaxis comprised trimethoprim/sulfamethoxazole (960 mg/d) and valacyclovir (500 mg, twice daily). In the event of clinical or laboratory cytomegalovirus (CMV) reactivation, valacyclovir was replaced by oral or intravenous ganciclovir (500 mg, three times daily). Prophylaxis was administered from day 1 and continued for at least 2 months after the completion of therapy. Antifungal treatment (fluconazole 100 mg/d) was administered at the first sign of fungal infection until resolution.
The treatment was postponed in the event of an absolute neutrophil count of less than 500/μL and was discontinued if recovery did not occur within 14 days. Physical examination and full laboratory and diagnostic evaluations were performed at each cycle, including evaluation of lymph nodes, liver, and spleen.
Restaging (CR, PR, stable disease [SD], and progressive disease [PD]), according to NCI criteria,31 was carried out at day 0 of cycle 3 and 1 to 3 months after the last cycle. Bone marrow aspiration and biopsy was performed 2 months after clinical and laboratory results had demonstrated CR. To confirm CR, the marrow sample had to be at least normocellular for the patient’s age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent for a definition of CR. If the bone marrow was hypocellular, the analysis was repeated after 4 weeks. For patients who fulfilled all the criteria for CR, confirmation was obtained using an abdominal ultrasound.
Follow-Up
Follow-up examinations, carried out as described earlier, were performed 3 months after the end of treatment and every 12 weeks thereafter until progression of disease.
End Points
The primary end point was the OR rate. Secondary end points were the quality of response, the toxicity profile, time to progression (TTP), and overall survival (OS).
Statistical Considerations
To evaluate the efficacy, safety, and feasibility, at least 28 patients were statistically required in this phase II study. This would result in a 90% CI of ± 15% given an OR rate of 70% and allowing for three patients lacking assessability. An interim analysis was planned after 14 patients had received treatment to rule out complete inefficacy or unacceptable toxicity, with the requirement that at least four (28%) of 14 patients should demonstrate a response for the study to be continued. The study would also be closed if more than six of 14 patients dropped out because of severe toxicity. Estimates of TTP and OS were calculated using the Kaplan-Meier method. TTP was defined as the date from initial administration of FluCam to the first date of objective measurement of disease progression, death, or requirement of new treatment. Survival was measured from the day of the first dose of alemtuzumab to death; deaths from all causes were included.
RESULTS
Patient Demographics
Patient demographics are listed in Table 1. Of the 36 B-CLL patients recruited, 22 had previously been treated with fludarabine (including 10 who had received fludarabine in combination with rituximab), of whom nine patients (41%) were refractory to fludarabine treatment, as defined by failure to respond or relapse within 6 months after treatment.21 Fourteen patients were treated with rituximab/chemotherapy, 27 were treated with alkylating agents, and four were treated with alemtuzumab alone. Details of prior treatments and responses to study treatment are listed in Table 2. The median time from first diagnosis to study entry was 5 years (range, 1.08 to 8.08 years). Twelve patients were refractory to prior therapy. All patients had extensive bone marrow infiltration at baseline, and the majority had lymphadenopathy and/or splenomegaly. Twenty-nine patients (80%) were CMV immunoglobulin G–positive before study entry.
Treatment
All but one patient reached the target dose of alemtuzumab in 3 consecutive days. Because of initial safety concerns before the start of the study, the initial target number of cycles was set to four and was subsequently increased to six after the first interim analysis. Four of the first 14 patients did not receive the full four cycles of treatment; in two patients, FluCam was postponed after cycle 2 and discontinued because of prolonged aplasia (3 months in one patient and 6 weeks in the other patient). The first of these patients had entered the study with autoimmune hemolytic anemia (hemoglobin < 5 g/dL) and achieved CR without hemolytic activity after cycle 2 of FluCam. In two patients, therapy was stopped after cycle 3 because of unsatisfactory response (one PD and one SD). In the remaining 22 patients, 11 patients did not reach the target number of six cycles. In three patients, therapy was stopped by the physician because of lack of compliance; four patients had infections or PD, one of whom developed Richter’s transformation after cycle one. In this patient with 11q23 deletion, no association to Epstein-Barr virus could be detected. Another four patients showed delayed recovery of bone marrow after sufficient tumor response.
Safety and Toxicity
A total of 140 cycles were assessable for toxicity. Adverse effects are listed in Table 3. Toxicity was assessed according to the NCI-sponsored workshop guidelines.31 Acute first-dose events, such as fever and rigors, which are often observed with the administration of monoclonal antibodies,32,33 were minimized by concomitant use of corticosteroids and carefully adapting the infusion rate of alemtuzumab to clinical symptoms. Acute infusion-associated adverse effects (fever, chills, and skin reactions) were mild (grade 1 to 2) in the majority of patients and were observed predominantly in association with initial alemtuzumab doses. Subsequently, alemtuzumab was well tolerated, allowing patients to proceed smoothly through to combined chemoimmunotherapy. NCI Common Toxicity Criteria (CTC) grade 4 infectious complications were seen in three patients, of whom two were refractory to prior therapy and FluCam.
The major toxicity in 140 assessable cycles was myelotoxicity, with 44% grade 3 to 4 leukopenia, 26% grade 3 to 4 neutropenia, and 30% grade 3 to 4 thrombocytopenia. Patients with massive lymphadenopathy were more prone to signs of cytokine release syndrome, resulting in fever and exanthema in the first two cycles of treatment. Other side effects were less common (Table 3). Three patients suffered from CTC grade 1 to 2 supraventricular tachyarrhythmia while under treatment, but the relationship to therapy was unlikely. In two patients, CTC grade 2 transient cerebral or cerebellar ischemic attacks after the first course of FluCam were seen, but the patients recovered completely and completed the full number of cycles.
There were only two CTC grade 3 subclinical CMV reactivations (patients 15 and 23), despite 80% of patients being CMV immunoglobulin G–positive at baseline. Both patients were treated with intravenous ganciclovir until CMV polymerase chain reaction was repeatedly negative. In two patients (patients 8 and 31) with primary PD, therapy had to be stopped because of fungal pneumonias (Aspergillus fumigatus). One of the patients (patient 8) died 6 weeks later with PD. One patient (patient 15), who was also affected by CMV reactivation, died from an Escherichia coli sepsis after cycle 3. Another patient with fever in aplasia tested positive for Pseudomonas aeruginosa and was successfully treated with intravenous antibiotics.
Immunorecovery
CD4 T-cell counts decreased immediately on treatment and recovered slowly during follow-up (Fig 2). The median time to recover to CD4 counts greater than 200/μL was 8 months after the last cycle was administered. Despite the fact that T-cell recovery was slow and infectious prophylaxis was stopped in most patients 2 or 3 months after the end of study, infections were mainly seen during the first 3 months of therapy.
Response
The OR rate was 83% (95% CI, 67% to 93%) according to NCI criteria, with 11 patients (30%; 95% CI, 17% to 48%) achieving a CR and 19 patients (53%; 95% CI, 36% to 69%) achieving a PR (Table 4). One patient (3%; 95% CI, 0% to 16%) had SD, whereas five patients (11%; 95% CI, 5% to 30%) had PD. When analyzed by subgroups, the responses were as follows. Eight of the 12 patients who were refractory to prior therapy responded (four CRs and four PRs). In 24 patients who had disease relapse at study entry, seven CRs and 15 PRs were documented. Twenty-two patients pretreated with a fludarabine-containing regimen were included, and the majority showed good response to FluCam (six CRs, 12 PRs, three PDs, and one SD). Of the nine patients who had been refractory to fludarabine, six responded to FluCam. Three of four patients with alemtuzumab pretreatment showed PR. One patient achieved SD despite being refractory to fludarabine/rituximab and alemtuzumab monotherapy. The first 14 patients received a target number of four cycles of treatment, which was increased to six cycles after the first interim analysis. OR rates for these two groups were 86% and 82%, respectively. As described earlier, 15 patients did not receive the full target number of cycles for a variety of reasons. For these patients, an OR rate of 67% was documented.
The lymphocytosis present at baseline resolved rapidly in most patients during the first two cycles of treatment (Fig 3). The maximal cumulative response in the peripheral blood was achieved after cycle 2.
Response Duration and OS
The median OS for all patients was 35.6 months, with TTP of 12.97 months. For patients achieving a complete remission (n = 11), the median OS has not been reached, and the median TTP was calculated as 21.9 months. Figures 4 and 5 show the OS and TTP, respectively, with a median follow-up of 15 months.
Autoimmune Hemolysis
Seven patients had known active autoimmune hemolytic anemia and/or autoimmune thrombocytopenia when entering the trial. In all patients, clinical and laboratory activity of autoimmune phenomena were diminished or resolved, and there was no need for transfusions after therapy. Criteria for the control of autoimmune activity were the normalization of haptoglobin, bilirubin, lactate dehydrogenase, and hemoglobin. For both patients with autoimmune thrombocytopenia, a normalization of platelet count was documented. Another nine patients were included with transfusion-dependent thrombocytopenia and/or anemia caused by bone-marrow infiltration before therapy; all patients were successfully treated and had no need for transfusions after therapy.
DISCUSSION
Two major findings emerge from this phase II study. First, the combination of fludarabine and alemtuzumab in the new FluCam schedule is effective in this group of heavily pretreated/refractory B-CLL patients, with an OR rate of 83% (CR rate, 30%) and a median OS of 35.6 months for all patients. Second, this new regimen is well tolerated and feasible with only three of 36 patients developing CTC grade 4 infections.
For patients in whom fludarabine treatment has failed, the prognosis is poor, with only approximately 40% of patients surviving beyond 12 months and a median survival of 10 months.21,34 Thus, the results presented here compare favorably with those reported by others. In our study, the median OS was 35.6 months for all patients, with TTP of 21.9 months for patients with CR and 12.9 months for patients with PR. Patients had received up to eight different prior treatments. Fludarabine was the preceding therapy in 22 patients (62%) either as a single agent or in combination with other cytotoxic agents or rituximab. Importantly, nine (41%) of 22 patients had experienced treatment failure with fludarabine, but six of these patients responded to FluCam. One third of the patients (12 of 36 patients) included were refractory to prior therapy.
In a similar group of fludarabine-refractory patients treated with alemtuzumab as salvage therapy, a median survival of 16 months for all patients and 32 months for responders had been reported.21 However, the treatment used in the present study was of shorter duration, and the total dose of cytotoxic agents was lower. Although the patient population had advanced disease and multiple pretreatments, the response rates seen in our study are usually only observed in untreated or fludarabine-naive patients when receiving a combined-modality regimen. Here, the CR rates ranged between 32% and 47%.16,35 The results observed with the FluCam combination also compare favorably with a sequential regimen in which fludarabine was followed by alemtuzumab (CR in one of six patients).17 The impression that concomitant immunochemotherapy using FluCam might be superior to sequential treatment is supported by preclinical data36 and the results from a randomized trial that demonstrated that fludarabine and monoclonal antibody treatment (rituximab) administered concurrently are superior to fludarabine and monoclonal antibody administered sequentially (OR rate, 90% v 77%; CR rate, 47% v 28%, respectively).35
Synergy of the two compounds in the FluCam regimen is also suggested by the achievement of SD in a patient who was clearly progressive and completely refractory to both single-agent alemtuzumab and a fludarabine/rituximab combination. In addition, the combination of FluCam was highly effective in eight of 10 patients (four CRs and four PRs) who had relapsed after prior response to fludarabine/rituximab chemoimmunotherapy.
When used together, FluCam can extend the benefits of monotherapy into additional disease sites; alemtuzumab monotherapy is notably efficient at clearing disease from the blood and bone marrow but less effective in reducing massive lymph nodes. Here, we obtained many responses at nodal disease sites, thus increasing the number of CRs according to NCI criteria.
The responses observed in this trial were achieved with a cumulative exposure to FluCam that was lower compared with their dose as single agents. The standard regimen of fludarabine is 5 days at 25 mg/m2/d for six cycles, resulting in a total dose of 750 mg/m2. The standard regimen of alemtuzumab is 12 weeks of treatment at the target dose of 30 mg, administered three times weekly, resulting in a total dose of 1,080 mg. With a median number of four cycles for all patients, the FluCam combination regimen delivers a total of 360 mg/m2 of fludarabine and 360 mg of alemtuzumab; this corresponds to doses of 50% and 33%, respectively, compared with the single-agent regimens. The 3-day regimen, which is administered on consecutive days and repeated on day 28, is more convenient compared with the standard 5-day fludarabine regimen and the thrice weekly administration of alemtuzumab over 12 or 16 weeks.
One of the main characteristics of the toxicity profile of both alemtuzumab and fludarabine is an increased vulnerability to infections because of profound lymphocytopenia, including a reduction of CD4+ T cells after treatment. Given the advanced and refractory status of many patients, FluCam was well tolerated. This might, in part, be a result of the rapid response to treatment and the fact that we used long-lasting and broad anti-infectious prophylaxis. Patients developing severe infections were those patients who had a rather poor performance status at study entry and patients with PD under treatment with FluCam.
Currently, more fludarabine-based combinations are emerging for patients with relapsed and refractory B-CLL. The most promising agents that are being combined with fludarabine seem to be cyclophosphamide9,10,12 and mitoxantrone.15,20,37,38 Combined chemoimmunotherapy with monoclonal antibodies might further enhance efficacy. Recently, Wierda et al39 reported on a combination of fludarabine, cyclophosphamide, and rituximab. This combination induced the highest CR rate ever reported in a clinical trial of previously treated patients with CLL. Therefore, randomized phase III trials are urgently needed to define the optimal combination, dose, and schedule of immunotherapy.
A major limitation of our study was that biologic risk factors, such as VH mutational status, interphase cytogenetics, ZAP70 expression, or p53 mutational status, were not determined. In follow-up protocols of regimens, such as fludarabine, cyclophosphamide, and alemtuzumab (CLL2L protocol of the German Chronic Lymphocytic Leukemia Study Group), the secondary end point is to assess the response in biologic-defined risk groups.
In conclusion, the new combination regimen of FluCam is effective, with an acceptable toxicity profile, in patients with relapsed or refractory B-CLL. On the basis of these promising results, a comparative multicenter phase III trial of FluCam with fludarabine alone in the second-line treatment of B-CLL has been initiated (CAM314).
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne
Department of Hematology and Oncology, University of Erlangen, Erlangen
Department of Hematology and Oncology, University of Kiel, Kiel
Department of Hematology, Robert-Bosch-Hospital, Stuttgart
Outpatient Center for Hematology and Oncology, Siegburg, Germany
ABSTRACT
PURPOSE: To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL).
PATIENTS AND METHODS: A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment.
RESULTS: The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred.
CONCLUSION: The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.
INTRODUCTION
B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in North America and Europe, and its prevalence is increasing with the increasing average age of Western populations.1 Treatment decisions are hindered by the difficulty in distinguishing between patients who will not require treatment and for whom a watchful waiting strategy might be appropriate and patients in whom the disease will progress and who require a more aggressive treatment.2 Although B-CLL is currently incurable, recent developments are gradually making an impact on the natural history of the disease. These include promising new treatment options using highly active agents.
Fludarabine is one of the most effective agents for patients with B-CLL, with overall response (OR) rates of 50% to 60% in previously treated patients3,4 and 60% to 80% in previously untreated patients.4-6 When evaluated in prospectively randomized trials, fludarabine has achieved significantly higher rates of complete response (CR) and partial response (PR)4,6,7 compared with chlorambucil monotherapy and most alkylating agent–based regimens, which typically have OR rates of 63% to 71%. Duration of response and treatment-free intervals for patients treated with fludarabine are superior compared with alkylating agents.6 However, all patients ultimately relapse because of the clonal expansion of residual tumor cells.8
Another recent improvement is the ability to detect residual B-CLL cells in the peripheral blood or bone marrow at a threshold of one malignant cell per 104 to 105 normal leukocytes by flow cytometry. This technique allows one to easily monitor the clearance of CLL cells from the blood and bone marrow.
To possibly enhance the therapeutic efficacy and eradicate residual malignancy, novel, fludarabine-based combination therapies are emerging. Combinations of fludarabine with a variety of agents have shown better antitumor effects. This includes alkylating agents,9-13 anthracyclines,14,15 and monoclonal antibodies,16,17 both in clinical studies and in vitro.18-20 Of these combination options, the addition of fludarabine to monoclonal antibody therapy is highly promising because their modes of action are complementary, making synergistic effects plausible.
Alemtuzumab is currently approved for the treatment of refractory B-CLL. The standard dosing schedule of up to 12 weeks of treatment at 30 mg three times weekly has demonstrated an OR rate of 33% in fludarabine-refractory patients21,22 and 87% in previously untreated patients.23 As a single agent, alemtuzumab is highly active in both blood and bone marrow24 and is able to reduce disease burden at these sites to levels below those detectable by polymerase chain reaction25 or four-color flow cytometry.26 The eradication of minimal residual disease seems to be associated with prolonged survival.27-29 Impressive response rates (82%) have been observed in patients without significant lymphadenopathy, whereas a lower response rate (25%) was observed in patients with bulky lymph nodes.22,30
Recently, Kennedy et al17 reported on six CLL patients treated with a combination of fludarabine and alemtuzumab (FluCam) who were refractory to both drugs when administered as single agents. Five of six patients achieved a remission, including one patient with CR in whom disease was eradicated from previously inaccessible nodal sites. These findings emphasize the synergistic effects of FluCam and provide a strong rationale for further studies.
We investigated the use of FluCam for the treatment of patients with relapsed or refractory B-CLL. This new regimen was administered for 3 days every 4 weeks to explore the potential additive effects of these two drugs and increase the convenience for the patients treated.
PATIENTS AND METHODS
This phase II, open-label, single-center trial investigated the efficacy of FluCam in patients with relapsed or refractory B-CLL. Approval was obtained from the institutional review board for these studies and in accordance with an assurance filed with and approved by the Department of Health and Human Services; all patients gave written informed consent according to the Declaration of Helsinki. Adults ( 18 years of age) with relapsed or refractory B-CLL were eligible. Diagnosis was established using the 1996 National Cancer Institute (NCI) Working Group criteria.31 Patients must have received at least one prior therapy; any prior treatment with fludarabine, alemtuzumab, or rituximab must have been completed at least 6 months before study entry. Patients were required to have adequate bone marrow function (absolute neutrophil count 1,500/μL). Patients were excluded if they had a WHO/Eastern Cooperative Oncology Group performance status of more than 2, a history of severe infection (grade 4) within the 3 months before treatment, a history of anaphylactic reaction after exposure to humanized monoclonal antibodies, concurrent severe diseases, or an active secondary malignancy. Patients were also excluded if they had received any prior chemotherapy or radiotherapy for any neoplastic disease other than B-CLL.
Treatment
Dose escalation of alemtuzumab was performed on consecutive days from 3 mg to 10 mg to 30 mg or with repeated administration at the previous dose if that dose had been accompanied by adverse events greater than grade 2 in severity. FluCam was then administered for a total of 3 consecutive days; this was repeated every 28 days for a total of four cycles in the first 14 patients (Fig 1). After the first interim analysis including 14 patients indicated that toxicity was tolerable, the total number of cycles was increased to six for the following 22 patients. The length of the first alemtuzumab infusion in cycles not preceded by dose escalation was prolonged from 2 to 4 hours. Premedication was administered before the first alemtuzumab infusion in each cycle and thereafter if clinically indicated, including clemastine (2 mg intravenously), acetaminophen (1 g orally), and prednisone (100 mg intravenously). In patients with a WBC count more than 50,000/μL, bulky disease, or a medical history of hyperuricemia, allopurinol (300 mg/d) was administered before the first infusion and thereafter if clinically indicated.
Antimicrobial prophylaxis comprised trimethoprim/sulfamethoxazole (960 mg/d) and valacyclovir (500 mg, twice daily). In the event of clinical or laboratory cytomegalovirus (CMV) reactivation, valacyclovir was replaced by oral or intravenous ganciclovir (500 mg, three times daily). Prophylaxis was administered from day 1 and continued for at least 2 months after the completion of therapy. Antifungal treatment (fluconazole 100 mg/d) was administered at the first sign of fungal infection until resolution.
The treatment was postponed in the event of an absolute neutrophil count of less than 500/μL and was discontinued if recovery did not occur within 14 days. Physical examination and full laboratory and diagnostic evaluations were performed at each cycle, including evaluation of lymph nodes, liver, and spleen.
Restaging (CR, PR, stable disease [SD], and progressive disease [PD]), according to NCI criteria,31 was carried out at day 0 of cycle 3 and 1 to 3 months after the last cycle. Bone marrow aspiration and biopsy was performed 2 months after clinical and laboratory results had demonstrated CR. To confirm CR, the marrow sample had to be at least normocellular for the patient’s age, with less than 30% of nucleated cells being lymphocytes. Lymphoid nodules should be absent for a definition of CR. If the bone marrow was hypocellular, the analysis was repeated after 4 weeks. For patients who fulfilled all the criteria for CR, confirmation was obtained using an abdominal ultrasound.
Follow-Up
Follow-up examinations, carried out as described earlier, were performed 3 months after the end of treatment and every 12 weeks thereafter until progression of disease.
End Points
The primary end point was the OR rate. Secondary end points were the quality of response, the toxicity profile, time to progression (TTP), and overall survival (OS).
Statistical Considerations
To evaluate the efficacy, safety, and feasibility, at least 28 patients were statistically required in this phase II study. This would result in a 90% CI of ± 15% given an OR rate of 70% and allowing for three patients lacking assessability. An interim analysis was planned after 14 patients had received treatment to rule out complete inefficacy or unacceptable toxicity, with the requirement that at least four (28%) of 14 patients should demonstrate a response for the study to be continued. The study would also be closed if more than six of 14 patients dropped out because of severe toxicity. Estimates of TTP and OS were calculated using the Kaplan-Meier method. TTP was defined as the date from initial administration of FluCam to the first date of objective measurement of disease progression, death, or requirement of new treatment. Survival was measured from the day of the first dose of alemtuzumab to death; deaths from all causes were included.
RESULTS
Patient Demographics
Patient demographics are listed in Table 1. Of the 36 B-CLL patients recruited, 22 had previously been treated with fludarabine (including 10 who had received fludarabine in combination with rituximab), of whom nine patients (41%) were refractory to fludarabine treatment, as defined by failure to respond or relapse within 6 months after treatment.21 Fourteen patients were treated with rituximab/chemotherapy, 27 were treated with alkylating agents, and four were treated with alemtuzumab alone. Details of prior treatments and responses to study treatment are listed in Table 2. The median time from first diagnosis to study entry was 5 years (range, 1.08 to 8.08 years). Twelve patients were refractory to prior therapy. All patients had extensive bone marrow infiltration at baseline, and the majority had lymphadenopathy and/or splenomegaly. Twenty-nine patients (80%) were CMV immunoglobulin G–positive before study entry.
Treatment
All but one patient reached the target dose of alemtuzumab in 3 consecutive days. Because of initial safety concerns before the start of the study, the initial target number of cycles was set to four and was subsequently increased to six after the first interim analysis. Four of the first 14 patients did not receive the full four cycles of treatment; in two patients, FluCam was postponed after cycle 2 and discontinued because of prolonged aplasia (3 months in one patient and 6 weeks in the other patient). The first of these patients had entered the study with autoimmune hemolytic anemia (hemoglobin < 5 g/dL) and achieved CR without hemolytic activity after cycle 2 of FluCam. In two patients, therapy was stopped after cycle 3 because of unsatisfactory response (one PD and one SD). In the remaining 22 patients, 11 patients did not reach the target number of six cycles. In three patients, therapy was stopped by the physician because of lack of compliance; four patients had infections or PD, one of whom developed Richter’s transformation after cycle one. In this patient with 11q23 deletion, no association to Epstein-Barr virus could be detected. Another four patients showed delayed recovery of bone marrow after sufficient tumor response.
Safety and Toxicity
A total of 140 cycles were assessable for toxicity. Adverse effects are listed in Table 3. Toxicity was assessed according to the NCI-sponsored workshop guidelines.31 Acute first-dose events, such as fever and rigors, which are often observed with the administration of monoclonal antibodies,32,33 were minimized by concomitant use of corticosteroids and carefully adapting the infusion rate of alemtuzumab to clinical symptoms. Acute infusion-associated adverse effects (fever, chills, and skin reactions) were mild (grade 1 to 2) in the majority of patients and were observed predominantly in association with initial alemtuzumab doses. Subsequently, alemtuzumab was well tolerated, allowing patients to proceed smoothly through to combined chemoimmunotherapy. NCI Common Toxicity Criteria (CTC) grade 4 infectious complications were seen in three patients, of whom two were refractory to prior therapy and FluCam.
The major toxicity in 140 assessable cycles was myelotoxicity, with 44% grade 3 to 4 leukopenia, 26% grade 3 to 4 neutropenia, and 30% grade 3 to 4 thrombocytopenia. Patients with massive lymphadenopathy were more prone to signs of cytokine release syndrome, resulting in fever and exanthema in the first two cycles of treatment. Other side effects were less common (Table 3). Three patients suffered from CTC grade 1 to 2 supraventricular tachyarrhythmia while under treatment, but the relationship to therapy was unlikely. In two patients, CTC grade 2 transient cerebral or cerebellar ischemic attacks after the first course of FluCam were seen, but the patients recovered completely and completed the full number of cycles.
There were only two CTC grade 3 subclinical CMV reactivations (patients 15 and 23), despite 80% of patients being CMV immunoglobulin G–positive at baseline. Both patients were treated with intravenous ganciclovir until CMV polymerase chain reaction was repeatedly negative. In two patients (patients 8 and 31) with primary PD, therapy had to be stopped because of fungal pneumonias (Aspergillus fumigatus). One of the patients (patient 8) died 6 weeks later with PD. One patient (patient 15), who was also affected by CMV reactivation, died from an Escherichia coli sepsis after cycle 3. Another patient with fever in aplasia tested positive for Pseudomonas aeruginosa and was successfully treated with intravenous antibiotics.
Immunorecovery
CD4 T-cell counts decreased immediately on treatment and recovered slowly during follow-up (Fig 2). The median time to recover to CD4 counts greater than 200/μL was 8 months after the last cycle was administered. Despite the fact that T-cell recovery was slow and infectious prophylaxis was stopped in most patients 2 or 3 months after the end of study, infections were mainly seen during the first 3 months of therapy.
Response
The OR rate was 83% (95% CI, 67% to 93%) according to NCI criteria, with 11 patients (30%; 95% CI, 17% to 48%) achieving a CR and 19 patients (53%; 95% CI, 36% to 69%) achieving a PR (Table 4). One patient (3%; 95% CI, 0% to 16%) had SD, whereas five patients (11%; 95% CI, 5% to 30%) had PD. When analyzed by subgroups, the responses were as follows. Eight of the 12 patients who were refractory to prior therapy responded (four CRs and four PRs). In 24 patients who had disease relapse at study entry, seven CRs and 15 PRs were documented. Twenty-two patients pretreated with a fludarabine-containing regimen were included, and the majority showed good response to FluCam (six CRs, 12 PRs, three PDs, and one SD). Of the nine patients who had been refractory to fludarabine, six responded to FluCam. Three of four patients with alemtuzumab pretreatment showed PR. One patient achieved SD despite being refractory to fludarabine/rituximab and alemtuzumab monotherapy. The first 14 patients received a target number of four cycles of treatment, which was increased to six cycles after the first interim analysis. OR rates for these two groups were 86% and 82%, respectively. As described earlier, 15 patients did not receive the full target number of cycles for a variety of reasons. For these patients, an OR rate of 67% was documented.
The lymphocytosis present at baseline resolved rapidly in most patients during the first two cycles of treatment (Fig 3). The maximal cumulative response in the peripheral blood was achieved after cycle 2.
Response Duration and OS
The median OS for all patients was 35.6 months, with TTP of 12.97 months. For patients achieving a complete remission (n = 11), the median OS has not been reached, and the median TTP was calculated as 21.9 months. Figures 4 and 5 show the OS and TTP, respectively, with a median follow-up of 15 months.
Autoimmune Hemolysis
Seven patients had known active autoimmune hemolytic anemia and/or autoimmune thrombocytopenia when entering the trial. In all patients, clinical and laboratory activity of autoimmune phenomena were diminished or resolved, and there was no need for transfusions after therapy. Criteria for the control of autoimmune activity were the normalization of haptoglobin, bilirubin, lactate dehydrogenase, and hemoglobin. For both patients with autoimmune thrombocytopenia, a normalization of platelet count was documented. Another nine patients were included with transfusion-dependent thrombocytopenia and/or anemia caused by bone-marrow infiltration before therapy; all patients were successfully treated and had no need for transfusions after therapy.
DISCUSSION
Two major findings emerge from this phase II study. First, the combination of fludarabine and alemtuzumab in the new FluCam schedule is effective in this group of heavily pretreated/refractory B-CLL patients, with an OR rate of 83% (CR rate, 30%) and a median OS of 35.6 months for all patients. Second, this new regimen is well tolerated and feasible with only three of 36 patients developing CTC grade 4 infections.
For patients in whom fludarabine treatment has failed, the prognosis is poor, with only approximately 40% of patients surviving beyond 12 months and a median survival of 10 months.21,34 Thus, the results presented here compare favorably with those reported by others. In our study, the median OS was 35.6 months for all patients, with TTP of 21.9 months for patients with CR and 12.9 months for patients with PR. Patients had received up to eight different prior treatments. Fludarabine was the preceding therapy in 22 patients (62%) either as a single agent or in combination with other cytotoxic agents or rituximab. Importantly, nine (41%) of 22 patients had experienced treatment failure with fludarabine, but six of these patients responded to FluCam. One third of the patients (12 of 36 patients) included were refractory to prior therapy.
In a similar group of fludarabine-refractory patients treated with alemtuzumab as salvage therapy, a median survival of 16 months for all patients and 32 months for responders had been reported.21 However, the treatment used in the present study was of shorter duration, and the total dose of cytotoxic agents was lower. Although the patient population had advanced disease and multiple pretreatments, the response rates seen in our study are usually only observed in untreated or fludarabine-naive patients when receiving a combined-modality regimen. Here, the CR rates ranged between 32% and 47%.16,35 The results observed with the FluCam combination also compare favorably with a sequential regimen in which fludarabine was followed by alemtuzumab (CR in one of six patients).17 The impression that concomitant immunochemotherapy using FluCam might be superior to sequential treatment is supported by preclinical data36 and the results from a randomized trial that demonstrated that fludarabine and monoclonal antibody treatment (rituximab) administered concurrently are superior to fludarabine and monoclonal antibody administered sequentially (OR rate, 90% v 77%; CR rate, 47% v 28%, respectively).35
Synergy of the two compounds in the FluCam regimen is also suggested by the achievement of SD in a patient who was clearly progressive and completely refractory to both single-agent alemtuzumab and a fludarabine/rituximab combination. In addition, the combination of FluCam was highly effective in eight of 10 patients (four CRs and four PRs) who had relapsed after prior response to fludarabine/rituximab chemoimmunotherapy.
When used together, FluCam can extend the benefits of monotherapy into additional disease sites; alemtuzumab monotherapy is notably efficient at clearing disease from the blood and bone marrow but less effective in reducing massive lymph nodes. Here, we obtained many responses at nodal disease sites, thus increasing the number of CRs according to NCI criteria.
The responses observed in this trial were achieved with a cumulative exposure to FluCam that was lower compared with their dose as single agents. The standard regimen of fludarabine is 5 days at 25 mg/m2/d for six cycles, resulting in a total dose of 750 mg/m2. The standard regimen of alemtuzumab is 12 weeks of treatment at the target dose of 30 mg, administered three times weekly, resulting in a total dose of 1,080 mg. With a median number of four cycles for all patients, the FluCam combination regimen delivers a total of 360 mg/m2 of fludarabine and 360 mg of alemtuzumab; this corresponds to doses of 50% and 33%, respectively, compared with the single-agent regimens. The 3-day regimen, which is administered on consecutive days and repeated on day 28, is more convenient compared with the standard 5-day fludarabine regimen and the thrice weekly administration of alemtuzumab over 12 or 16 weeks.
One of the main characteristics of the toxicity profile of both alemtuzumab and fludarabine is an increased vulnerability to infections because of profound lymphocytopenia, including a reduction of CD4+ T cells after treatment. Given the advanced and refractory status of many patients, FluCam was well tolerated. This might, in part, be a result of the rapid response to treatment and the fact that we used long-lasting and broad anti-infectious prophylaxis. Patients developing severe infections were those patients who had a rather poor performance status at study entry and patients with PD under treatment with FluCam.
Currently, more fludarabine-based combinations are emerging for patients with relapsed and refractory B-CLL. The most promising agents that are being combined with fludarabine seem to be cyclophosphamide9,10,12 and mitoxantrone.15,20,37,38 Combined chemoimmunotherapy with monoclonal antibodies might further enhance efficacy. Recently, Wierda et al39 reported on a combination of fludarabine, cyclophosphamide, and rituximab. This combination induced the highest CR rate ever reported in a clinical trial of previously treated patients with CLL. Therefore, randomized phase III trials are urgently needed to define the optimal combination, dose, and schedule of immunotherapy.
A major limitation of our study was that biologic risk factors, such as VH mutational status, interphase cytogenetics, ZAP70 expression, or p53 mutational status, were not determined. In follow-up protocols of regimens, such as fludarabine, cyclophosphamide, and alemtuzumab (CLL2L protocol of the German Chronic Lymphocytic Leukemia Study Group), the secondary end point is to assess the response in biologic-defined risk groups.
In conclusion, the new combination regimen of FluCam is effective, with an acceptable toxicity profile, in patients with relapsed or refractory B-CLL. On the basis of these promising results, a comparative multicenter phase III trial of FluCam with fludarabine alone in the second-line treatment of B-CLL has been initiated (CAM314).
Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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