the Leeds General Infirmary, Leeds
    Birmingham Heartlands Hospitals, Birmingham
    Nottingham City Hospital, Nottingham
    Stobhill Hospital, Glasgow
    Manchester Royal Infirmary, Manchester
    Bournemouth Hosp, Bournemouth
    Queen Mary's Hospital, Sidcup
    Aberdeen Royal Infirmary, Aberdeen, United Kingdom
    Ilex Oncology, San Antonio, TX

    ABSTRACT

    PURPOSE: To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival.

    PATIENTS AND METHODS: Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 105 normal cells).

    RESULTS: Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months.

    CONCLUSION: MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.

    INTRODUCTION

    B-cell chronic lymphocytic leukemia (B-CLL) often has a prolonged and indolent course. Monotherapy with alkylating agents, such as chlorambucil, results in responses in most patients but less than 5% achieve a complete remission by National Cancer Institute-sponsored working group (NCI-WG) response criteria.1 Although randomized trials have demonstrated a higher response rate (and especially a higher complete remission [CR] rate) to fludarabine (up to 20% CR) compared with chlorambucil, these studies have failed to demonstrate a significant improvement in overall survival for fludarabine.2 One major reason the improved response rates are not translated into improved survival is that patients who experience treatment failure after receiving alkylating agents frequently respond to second-line fludarabine.2 Thus, the trials are in effect a randomization of first-line against second-line fludarabine. An additional reason for the failure to demonstrate a survival benefit is that the current NCI-WG definition of complete remission in CLL is permissive. The NCI-WG criteria have served an extremely valuable purpose in that they have facilitated the comparison of the results from various collaborative groups and CLL investigators.3 However they define CR as less than 30% lymphocytes in the bone marrow with a morphologically normal trephine biopsy, and by this definition there can be up to 5% CLL cells persisting in the marrow.4 Recent therapies for CLL, such as monoclonal antibodies and stem-cell transplantation, reduce CLL cells to a much lower level than previously possible. Modern techniques, such as four-color flow cytometry for the unique combination of B-CLL immunophenotypic antigens or allele-specific polymerase chain reaction for the immunoglobulin-gene rearrangement, can detect as few as a single CLL cell in 100,000 normal cells.5,6 The ability to detect extremely low levels of CLL and to eradicate CLL to below this level allows us to address whether the lack of improved survival for purine analogs compared with alkylating agents is primarily due to lack of efficacy. The most appropriate patients in whom to address the correlation of minimal residual disease (MRD) -negative remissions and survival are those with the worst prognosis. Although recent advances in our understanding of the biology of CLL, such as the adverse impact of p53 dysfunction (17p deletions or ataxia-teleangiectasia gene mutations),7 germ-line immunoglobulin genes, or ZAP-70 expression,8,9 allow the identification of patients at diagnosis with a poor prognosis, the worst prognostic group according to these variables has a median survival of approximately 3 years from diagnosis. Patients with CLL who have failed to respond to purine analogs have the poorest prognosis, with a median survival of approximately 10 months and 5-year survival of less than 10%.5,10

    The CD52 antigen is highly expressed on most normal and malignant lymphocytes.11 Alemtuzumab is a humanized monoclonal antibody specific to CD52 that results in lymphocyte clearance through antibody-dependent cell-mediated cellular toxicity, complement activation, and apoptosis.12 Alemtuzumab can induce responses in patients with CLL who have experienced disease relapse after fludarabine,13 and this results in MRD-negative remissions in a proportion of patients.4 Here we report the results of a strategy in which patients who have failed to respond adequately to purine analogs were treated to maximum response, including attempting to achieve an MRD-negative remission as defined by four-color MRD flow cytometry analysis of the bone marrow. Patients received alemtuzumab to maximum response followed by either combined alemtuzumab with fludarabine and/or stem-cell transplantation for patients not achieving MRD negativity. We report here the outcome of 91 patients treated with alemtuzumab in a series of clinical trials organized through our institution in accordance with this treatment strategy.

    PATIENTS AND METHODS

    Ninety-one patients with CLL at eight centers received alemtuzumab in clinical trials after local ethical approval. The patients all gave written informed consent. All patients with CLL treated with alemtuzumab from July 1996 to May 2003 are included. All had failed to respond to treatment or had experienced disease relapse after prior therapy; 88 had received a previous purine analog-containing therapy and 44 were refractory to or had experienced disease relapse within 6 months of the purine analog. The remaining three patients had failed to respond to combination chemotherapy but did not receive purine analogs because of active Coombs-positive hemolytic anemia.

    The patient characteristics are summarized in Table 1. There were 74 men and 17 women, with a median age of 58 years (range, 32 to 75 years) and a median of three previous therapies (range, one to eight), excluding splenectomy or radiotherapy. Ninety patients had a WHO performance status of 0 to 2, and one patient had WHO grade 3 because of airway obstruction due to a hemorrhagic mass. No patient had received prior therapy with alemtuzumab. Treatment immediately before alemtuzumab was given at a median of 9 months (range, 2 to 41 months) and responses are summarized in Table 2. In total, 44 (50%) patients were refractory to purine analogs defined by failure to respond to purine analogs41 or relapse within 6 months of responding to a purine analog-containing regime.3

    Patients underwent physical examination before starting therapy, including spleen and lymph nodes measurement, and were staged according to the Rai and Binet classifications. All patients had whole-body computed tomography scans. Bone marrow aspirate (MRD flow cytometry) and trephine biopsies were performed before treatment and then once every 4 weeks during alemtuzumab therapy. Blood counts were performed every week during therapy.

    Patients received alemtuzumab 30 mg three times a week until maximum response; 84 patients received intravenous alemtuzumab and seven patients received subcutaneous alemtuzumab. All patients had blood and bone marrow analyzed for morphologic evidence of CLL and for MRD negativity using four-color flow cytometry before, during, and after therapy. The response rates of a small number of the patients have been reported previously, but with only limited survival data and shorter follow-up, and these reports included survival of patients not treated with alemtuzumab.4,14

    Aim of Therapy

    Patients were treated until they reached the best possible remission, including the eradication of MRD. Thus patients in CR by clinical examination and morphologic assessment of the blood and bone marrow but with detectable CLL by MRD flow cytometry continued alemtuzumab until maximum response.

    Definition of Response

    The primary objective was to assess the response by NCI-WG criteria. Patients who achieved the criteria for a CR but had disease present by four-color flow cytometry were labeled as having MRD-positive CR. Patients who had responded with resolution of all detectable disease below the limits of the assay sensitivity were labeled as having MRD-negative responses. Secondary objectives were to assess survival after therapy and the toxicity of alemtuzumab.

    Alemtuzumab Therapy

    Alemtuzumab was given intravenously over 2 hours. The dose was escalated starting at 3 mg daily, increasing daily as tolerated to 10 and 30 mg according to infusion-related side effects. All 12 patients who failed to escalate to a 30-mg dose by the end of week 1 successfully achieved the 30-mg dose by the end of the second week. Premedication with paracetamol (1 g orally) and chlorpheniramine (10 mg intravenously) was administered to all patients. Therapy was withheld if the neutrophils decreased below 0.25 x 109/L, if the platelets decreased below 25 x 109/L, or if there was a serious infection. Granulocyte colony-stimulating factor was recommended when the neutrophil count decreased below 1 x 109/L, was given three times a week, and resulted in the neutrophil count increasing to more than 1 x 109/L in the majority of patients. Therapy was stopped if there was no response (NR) or progressive disease while receiving therapy, if the treatment was not tolerated, or if an MRD-negative response was achieved. Patients received cotrimoxazole or an alternative as Pneumocystis carinii pneumonia prophylaxis, and acyclovir 200 mg twice daily as prophylaxis against herpes viruses. Patients were assessed with physical examination every 4 weeks during therapy and at the end of therapy. Toxicity was assessed using NCI criteria.

    Cytomegalovirus Reactivation

    Patients were monitored each week for the reactivation of cytomegalovirus (CMV) by polymerase chain reaction (PCR) after one patient died as a result of CMV pneumonitis. When the CMV PCR was positive, the test was repeated immediately; the test was also repeated if patients with a positive test result received intravenous ganciclovir even when asymptomatic. For most patients with CMV reactivation, alemtuzumab therapy was stopped during ganciclovir therapy, but in the most recent four asymptomatic patients, alemtuzumab therapy was continued.

    Statistical Analysis

    Overall survival and treatment-free duration were calculated from the date of the start of alemtuzumab to the date of death and the start of relapse therapy, respectively. Survival analysis was calculated according to Kaplan and Meier methodology.15

    RESULTS

    Patients received 1 to 16 weeks (median, 9 weeks) of alemtuzumab therapy. Ten patients (11%) received less than 4 weeks of therapy; in five patients this was due to early death from CMV pneumonitis, invasive aspergillosis, sepsis, progressive disease, and hemorrhage. One patient stopped therapy after 1 week because of a planned stem-cell collection but still achieved an MRD-positive CR, and went on to receive further alemtuzumab subsequent to relapse after stem-cell transplantation with NR to alemtuzumab. One patient stopped therapy because of cytopenias and herpes zoster infection, but received additional alemtuzumab 6 months later. Two patients refused additional therapy. One patient stopped therapy because of CMV reactivation at 3 weeks of therapy, but treatment was not restarted because an MRD-negative CR was attained.

    Response

    Forty-nine patients (53%) treated with alemtuzumab responded according to NCI-WG response criteria (Table 1). The probability of a patient responding was associated with their degree of lymphadenopathy. The overall response rate (ORR), CR, and MRD-negative response rates were as follows: patients with no lymphadenopathy, 29 (87%) of 33 ORR; 24 (72%) of 33 CR, and 13 (39%) of 33 MRD-negative status; patients with lymphadenopathy with the largest single node of 5 cm or less, 19 (40%) of 47 ORR, eight (17%) of 47 CR, and five (11%) of 47 MRD-negative status; patients whose largest lymph node was larger than 5 cm in diameter, one (9%) of 11 ORR, zero (0%) of 11 CR, and zero (0%) of 11 MRD-negative status. This difference in response rates was reflected in an improved overall survival for patients with less nodal disease (Fig 1). Thus patients with lymph nodes  5 cm in diameter were significantly less likely to respond to alemtuzumab than those with largest nodes of less than 5 cm or those with no lymphadenopathy (P < .0001). An MRD-negative CR was also significantly more likely to occur in those with no lymphadenopathy compared with those with lymphadenopathy (P = .0004).

    Twenty-two (50%) of the 44 assessable purine analog-refractory patients responded to alemtuzumab compared with 25 (64%) of the 39 assessable purine analog-responsive patients. The response rate to alemtuzumab in purine analog-refractory and nonrefractory patients was not significantly different. The ORR was superior for patients with a lower number of prior therapies: 32 (71%) of 45 patients who had received one or two prior therapies compared with 17 (37%) of 46 patients who had previously received three or more different therapies (P = .0005). Patients with a WHO performance status of 0 or 1 had better ORRs than those with a performance status of 2 or 3 (45% and 4%, respectively; P = .005).

    MRD-Negative Patients

    Table 3 lists the clinical details of the 18 patients who attained an MRD-negative remission. No patient with bulky disease achieved an MRD-negative remission, whereas 13 (72%) of the 18 patients achieving an MRD-negative remission had no lymphadenopathy on clinical examination or computed tomography scanning before alemtuzumab therapy. Eight (44%) MRD-negative patients had not responded to previous purine analogs. Two patients died 5 and 32 months after commencing therapy, one from mycobacterium avium intracellulare infection with progressive pulmonary deterioration and the other from invasive aspergillosis. The remaining 16 (88%) MRD-negative patients are alive at a median duration of follow-up of 36 months (range, 3 to 65 months). Overall and treatment-free survival (TFS) was significantly higher in MRD-negative CR patients compared with the other patients (Figs 2 and 3). The 18 patients achieving an MRD-negative response were free of treatment for a median of 10 months (range, 4 to 43 months) before alemtuzumab treatment and 14 of these patients remain treatment free at a median of 36 months follow-up (range, 3 to 61 months).

    Four MRD-negative patients subsequently underwent stem-cell transplantation as part of a planned approach. Two had an HLA-matched sibling allogeneic nonmyeloablative transplant and two an autologous stem-cell transplant. Six (33%) of the 18 MRD-negative responders had therapy-induced cytopenias after alemtuzumab and were therefore classified as partial remissions (PRs) in NCI-WG terms despite having no evidence of residual disease either clinically or by MRD assessment.

    Overall Survival and TFS

    The Kaplan-Meier survival curves for overall survival and TFS are shown in Figures 2 and 3. Those patients who achieved an MRD-negative CR had a significantly longer TFS than patients with MRD-positive CR, PR, or NR (P < .0001). Median overall survival was significantly longer in MRD-negative patients than in those who had an MRD-positive CR, a PR, or NR (median not reached for MRD-negative CRs, 60 months for MRD positive CRs, 70 months for PRs, and 15 months for NR; P = .0007). Eight patients have converted to MRD positivity at a median time of 28 months from alemtuzumab therapy (Fig 4).

    MRD-Negative Remissions After an Inadequate Response to Alemtuzumab

    Nineteen patients underwent stem-cell transplantation, of which 15 were autologous, three were sibling allogeneic transplantations, and one was a volunteer unrelated donor transplantation. Four patients who were MRD positive after alemtuzumab converted to MRD-negative status after autologous transplantation.

    Eight patients received alemtuzumab and fludarabine in combination because of a lack of response to their first treatment with alemtuzumab monotherapy. Two of these patients achieved an MRD-negative CR.

    Therefore, six patients who did not respond optimally to initial alemtuzumab went on to achieve an MRD-negative CR after therapy with autologous stem-cell transplantation (four patients) or alemtuzumab plus fludarabine in combination (two patients). There was a significantly longer survival for patients who achieved an MRD-negative CR compared with those who did not (P = .0002; Fig 5).

    Infusion-Related Toxicity

    Rigors and fever were the most common infusion-related toxicity, occurring in 68 patients (76%), and were more frequently grade 1 or 2 in severity (Table 4). Less frequent adverse events included fatigue (11%), dyspnea (4%), headache (4%), dizziness (3%), bronchospasm (2%), and diarrhea (2%). Adverse reactions declined in frequency by the end of week 3 of therapy. One patient developed anaphylaxis after the first dose and required adrenaline, but subsequently went on to escalate to therapeutic dose. Severe reactions were treated with intravenous hydrocortisone or intravenous pethidine. Nine patients (10%) were taking oral corticosteroids concomitantly for CLL or conditions related to it. An additional 22 patients (24%) received premedication with intravenous hydrocortisone as treatment for infusion-related adverse effects. Pethidine was given to 23 patients. Of 31 patients who received corticosteroids, 23 responded, and of 60 patients who did not receive corticosteroids, 26 responded. An overall response was more likely to occur in the group who received steroids in any form (P = .02). However, of the 31 patients who received corticosteroids, 18 developed an infection, compared with 21 of 60 who did not receive corticosteroids; thus, patients who received steroids were more likely to have an infection (P = .03).

    Cytopenias

    Neutropenia below 1.0 x 109/L occurred in 43 patients (48%) and neutropenia below 0.5 x 109/L occurred in 27 patients (30%). The nadir occurred at a median of 17 days (range, 0 to 87 days). Granulocyte colony-stimulating factor was administered to 18 patients (20%) with a median neutrophil count of 0.35 x 109/L (range, 0.02 to 0.6 x 109/L) and the neutrophil count increased to a median of 1.15 x 109/L (range, 0.5 to 9.2 x 109/L). Thrombocytopenia occurred in 65 patients (73%) and was less than 50 x 109/L in 41 patients (46%). Figure 6 illustrates the relationship between T-cell and neutrophil nadirs and infection.

    Infections

    Thirty-nine patients (43%) experienced one or more infections during or within 1 month of completing alemtuzumab therapy (Table 5). There were 19 mild (grade 1 or 2) infectious episodes and 33 severe (grade 3 or 4) episodes. There were 11 episodes of septicemia. Organisms cultured included alpha-hemolytic Streptococcus in two patients, Staphylococcus aureus in one patient, and Aeromonas maltophilia in one patient. A total of eight (8%) patients developed CMV reactivation at a median of 34 days after the start of therapy (range, 14 to 58 days). This led to death in one patient; all other occurrences resolved after appropriate antiviral therapy.

    There were three proven occurrences of fungal infection. This was invasive pulmonary aspergillosis in two patients (one fatal) and disseminated Pseudoallescheria boydii in one patient, which was fatal. There were two reports of probable invasive pulmonary fungal infection, one of which was fatal, and no occurrences of Pneumocystis carinii pneumonia.

    Infections After Alemtuzumab

    There were 31 documented infections in the period after alemtuzumab among 21 (23%) patients (excluding infections occurring during neutropenia after subsequent stem cell transplantation). Of these, nine were occurrences of pulmonary infection: two were herpes zoster reactivations, two were proven invasive aspergillosis, and one was a herpes simplex reactivation. CMV reactivation did not occur during the period after alemtuzumab therapy. The risk of infection after completing alemtuzumab therapy was not significantly different for responders or nonresponders. There were four infectious episodes in the 18 MRD-negative patients and 27-infectious episodes among the 73 patients who did not achieve MRD negativity. There was no significant difference in the rates of infection after therapy (P = .23). Infections after the cessation of alemtuzumab in non-MRD-negative CR patients occurred after a median of 9 months (range, 1 to 41 months) and in the MRD-negative patients after a median of 3 months (range, 1 to 12 months).

    DISCUSSION

    We report that MRD-negative remissions after alemtuzumab therapy are a realistic goal for patients with CLL. Eradication of detectable MRD with alemtuzumab is most likely in patients with minimal or absent lymphadenopathy (12 of 33 achieving an MRD-negative CR). The impact of lymphadenopathy on response rate has been reported by other investigators.16,17 Negative remissions have also been reported in a high proportion of patients receiving alemtuzumab as a consolidation after a response to purine analogs when the overall bulk of disease is minimal.18 MRD-negative remissions translate into an improved overall and event-free survival.

    Six patients achieving MRD-negative status were classified as NCI-WG PRs because of therapy-related cytopenias.19 No significant difference in the TFS of patients who were MRD-positive CRs was observed compared with patients achieving a PR (60 v 70 months). These observations suggest that achieving MRD negativity is more important than achieving complete remission by NCI criteria.

    The observation that patients achieving MRD-negative remissions have a longer overall survival than those who do not achieve eradication of MRD could be due to several factors. The aim of therapy for the whole group was to achieve MRD negativity and it is possible that the patients in whom MRD can be eradicated might be biologically distinct from the remainder, and therefore might be a better prognostic group. However only approximately 10% of fludarabine-refractory patients treated with conventional salvage therapy would be expected to survive 5 years, and thus MRD-negative patients are surviving longer than would be predicted. In addition, MRD-negative remissions have previously been observed after autologous stem-cell transplantation5,20–22 and after treatment with combined fludarabine, cyclophosphamide, and mitoxantrone23; in all of these series, MRD-negative patients survive significantly longer than the MRD-positive patients. Thus, evidence from various studies indicates that MRD negativity is an end point of therapy that, if achieved, translates into an improved survival.

    Infections are the most common cause of morbidity and mortality in patients with CLL,24 particularly in patients who have been treated previously.25 The infections observed in this relapsed and refractory group of patients treated with alemtuzumab are similar to those observed in other series of previously treated patients with CLL who were treated on other salvage regimens. Depletion of T cells for several months after alemtuzumab therapy26 has been reported previously. However, infections after therapy in the MRD-negative patients all occurred within 1 year after therapy, with no reported late infections. Patients not in an MRD-negative CR developed infections after therapy for up to 41 months. Thus, infections arising in the longer term in the period after alemtuzumab therapy probably result from persistent disease rather than the long-term immunosuppressive effects of alemtuzumab.

    Patients receiving concomitant corticosteroids had significantly higher response rates than those who did not; however, they were also more likely to develop an infection. Overall, there was no significant effect on survival conferred by corticosteroids.

    MRD-negative remissions in CLL can be attained with autologous and allogeneic stem-cell transplantation, and the combination of alemtuzumab and fludarabine. In total, six patients who did not achieve an MRD-negative CR after alemtuzumab monotherapy achieved MRD negativity after additional therapy with one of these schedules. In total, 24 patients of the 91 eventually attained an MRD-negative CR.

    Peripheral-blood stem-cell collection in this series of patients was equally successful before and after therapy. This is supported by the finding that CD52 is not predominantly expressed on hematopoietic stem cells.27 It also supports the rationale for in vivo purging with alemtuzumab before stem-cell collection.28

    In conclusion, alemtuzumab can be administered to patients with relapsed and refractory CLL with an acceptable safety profile. Attaining an MRD-negative remission using alemtuzumab is a realistic goal in patients of all ages, leading to an improved overall survival and TFS.

    Authors' Disclosures of Potential Conflicts of Interest

    The following authors or their immediate family members have 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. Research Funding: Peter Hillmen, Genzyme, Schering Healthcare. For a detailed description of these 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 of Information for Contributors found in the front of every issue.

    Acknowledgment

    We thank the nursing and research staff, Leeds General Infirmary, Leeds, UK. We would also like to thank Dr Geoff Hale, Schering AG and Genzyme Corporation (formerly Ilex Oncology) for supporting these alemtuzumab trials.

    NOTES

    Supported by Ilex Oncology, the Leukaemia Research Fund, and Yorkshire Cancer Research.

    Patients have previously been included in the following publications in a minority and with very limited, if any, survival data: Rawstron AC et al4 (18 patients); Kennedy et al14 (six patients); Keating et al13 (three patients); and Rawstron AC, Kennedy B, Moreton P, et al: Early prediction of outcome and response to alemtuzumab therapy in chronic lymphocytic leukaemia. Blood 103:2027-2031, 2004 (43 patients but no follow-up or survival data).

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

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