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Originally published as JCO Early Release 10.1200/JCO.2005.04.6037 on April 17 2006 © 2006 American Society of Clinical Oncology. Alemtuzumab As Consolidation After a Response to Fludarabine Is Effective in Purging Residual Disease in Patients With Chronic Lymphocytic Leukemia
From the Department of Hematology, Department of Pathology, Laboratory of Flow Cytometry, Transfusion Medicine Service, Niguarda Ca'Granda Hospital, Milano; and the Department of Pharmacology IRCCS, Istituto di Ricovero e Cura a Carattere Scientifico-Policlinico S. Matteo, Pavia, Italy Address reprint requests to Marco Montillo, MD, Dipartimento di On cologia Ematologia, Divisione di Ematologia, Ospedale Niguarda Ca'Granda, Piazza Ospedale Maggiore 3, 20162, Milan, Italy; e-mail: marco.montillo{at}ospedaleniguarda.it
Purpose Treatment with alemtuzumab has resulted in negative responses for minimal residual disease (MRD) in patients with chronic lymphocytic leukemia (CLL). In a prior analysis we demonstrated that it is possible to achieved MRD negativity, as assessed by polyclonality of immunoglobulin heavy chain after consolidation with alemtuzumab. This phase II study evaluated 34 patients with CLL who received alemtuzumab consolidation in an effort to improve the quality of their response to fludarabine-based induction. Subsequent peripheral blood stem-cell (PBSC) collection and transplantation, tolerability, and pharmacokinetics also were assessed. Patients and Methods Thirty-four patients younger than 65 years who had a clinical response to fludarabine-based induction therapy received alemtuzumab 10 mg subcutaneously three times per week for 6 weeks. PBSCs were collected after mobilization with cytarabine and granulocyte colony-stimulating factor. Blood samples for pharmacokinetics study were taken between days 1 and 31. Results The complete response rate improved from 35% after fludarabine induction to 79.4% after alemtuzumab consolidation, including 19 patients (56%) who achieved MRD negativity. The most common adverse events were injection-site reactions and fever. Cytomegalovirus reactivation occurred in 18 patients, all of whom were successfully treated with oral ganciclovir. PBSC collection was successful in 24 (92%) of 26 patients, and 18 patients underwent autologous PBSC transplantation. Alemtuzumab plasma concentrations increased gradually during the first 2 weeks and accumulated more rapidly thereafter. Conclusion Subcutaneously administered alemtuzumab was effective, safe, and well tolerated as consolidation therapy in patients with CLL who responded to fludarabine induction therapy. Subsequent PBSCT was feasible thereafter.
Chronic lymphocytic leukemia (CLL) is a B-cell hematologic malignancy that affects approximately 120,000 persons in the United States, Europe, and Australia each year.1 Although CLL traditionally has been perceived as a disease of the elderly, with fewer than 25% of cases occurring in individuals younger than age 65 years,2 the rate of diagnosis among younger patients is increasing as a result of more prevalent use of routine blood testing.3 Because early therapeutic interventions for asymptomatic CLL have not been shown to improve survival, therapy is generally reserved for patients with symptomatic disease.4 Fludarabine, the current standard first-line therapy for CLL, is associated with substantially better clinical response rates compared with previous alkylating agent–based therapies. Despite the improved response rate, the duration of overall survival or quality of life–adjusted survival has been only moderately prolonged at best.5 The existence and level of minimal residual disease (MRD) is a powerful prognostic factor for relapse, and elimination of MRD in the bone marrow correlates well with longer overall survival compared with patients who do not achieve MRD negativity.6 Consequently, new treatment approaches for patients with an initial response to first-line chemotherapy are geared toward eliminating MRD. Approaches include the use of potent chemoimmunotherapy combination regimens earlier in treatment, consolidation with lymphocyte-depleting monoclonal antibodies, and peripheral blood stem-cell (PBSC) transplantation.3 Although autologous stem-cell transplantation has prolonged the duration of clinical remissions in CLL, this approach has not been shown to be curative.7 The primary factor that may account for this finding involves the likely persistence of MRD within the blood and bone marrow that may result in the contamination of reinfused stem cells with malignant cells. One interesting approach to achieving MRD negativity involves the use of monoclonal antibodies as consolidation therapy after fludarabine-based induction therapy. Alemtuzumab is a humanized monoclonal antibody that binds CD52, an antigen expressed at high density (approximately 400,000 per cell) on most normal and malignant T- and B-cell lymphocytes. T-lymphocytes, natural-killer cells, monocytes, and macrophages also express the CD52 antigen,8-10 but it is not expressed on hematopoietic stem cells and is rarely expressed on granulocytes.11 Single-agent alemtuzumab has been shown to be effective when used as first-line therapy12 or in patients with relapsed or refractory disease.6,13 When used in combination with fludarabine, alemtuzumab was shown to induce MRD-negative responses in patients who did not respond to either agent alone.14 The effects of more aggressive chemotherapeutic regimens (ie, those capable of eradicating MRD), however, may jeopardize subsequent collection of hematopoietic stem cells, either through a poisoning effect of chemotherapy on the stem-cell compartment or because of the ineffective hematopoietic activity in the stem-cell compartment in patients with CLL.15 Notably, the administration of intermediate-dose cytarabine has been shown to overcome these effects and allow successful stem-cell collection in patients with CLL.16 Furthermore, a preliminary study from our group suggests that alemtuzumab does not interfere with subsequent PBSC mobilization and collection.15 At our institution, the standard approach to treating patients with CLL who are younger than 65 years with active disease includes an initial course of fludarabine-based induction chemotherapy. In patients who achieve a response, chemotherapy is followed by autologous CD34+ stem-cell collection and transplantation. Our institution conducted a pilot study with nine patients, which showed that alemtuzumab consolidation improves initial response when administered for in vivo purging of MRD after fludarabine-based chemotherapy.16 Moreover, data demonstrate that the elimination of MRD with alemtuzumab improves overall survival.6,17 In an effort to maximally eliminate disease before PBSC mobilization and collection, our treatment protocol was expanded to include the use of alemtuzumab in patients who responded to either fludarabine alone or a combination of fludarabine plus cyclophosphamide, but who still have detectable residual disease. This study examines the efficacy of alemtuzumab in purging residual disease in patients who have responded to fludarabine-based induction therapy. Because intravenous alemtuzumab administration is associated with infusion reactions,18 another goal of this study was to examine the safety and pharmacokinetics of subcutaneously administered alemtuzumab. Finally, we investigated the feasibility of collecting CD34+ cells after sequential treatment with fludarabine and alemtuzumab.
Patients Men and women younger than age 65 years who had B-cell CLL and had achieved nodular partial remission (PRn) or partial remission (PR) with fludarabine-based induction therapy according to National Cancer Institute–sponsored Working Group (NCI-WG) criteria were enrolled onto the study.19 Patients who reached complete remission (CR) were eligible only if at the end of induction therapy residual disease could be detected by consensus primer polymerase chain reaction (PCR). Before the initiation of fludarabine-based treatment, patients were required to meet the criteria for active CLL as defined by the NCI-WG guidelines.19 This protocol was reviewed and approved by the Institutional Ethics Committee of the Niguarda Ca’Granda Hospital (Milan, Italy). All patients signed an informed consent form before becoming eligible to participate in this trial.
Study Design and Treatment Alemtuzumab (Campath; supplied by Ilex Oncology, Guilford, United Kingdom, and Schering SpA, Segrate, Italy) treatment began not before 8 weeks after the discontinuation of chemotherapy. Alemtuzumab was administered subcutaneously three times per week for 6 weeks. The dose was escalated from 1 mg as an initial dose to 3 mg for the second dose and 10 mg thereafter. To avoid injection-site reactions, patients were premedicated with 1,000 mg acetaminophen and 10 mg chlorpheniramine. All patients received prophylactic anti-infective treatment with cotrimoxazole (one tablet administered orally three times per week) and acyclovir (400 mg orally every 12 hours) for the duration of treatment and for 6 months after the discontinuation of alemtuzumab. Patients were monitored weekly by early pp65 antigenemia test throughout the study for cytomegalovirus (CMV) reactivation. Patients showing more than 10 positive cells were treated promptly with ganciclovir, whereas patients with fewer than 10 positive cells received therapy only if a follow-up test showed an increase in the number of positive cells.
Response to alemtuzumab was assessed according to the criteria established by the NCI-WG19 (Table 1). CR was defined as disappearance of all palpable disease, accompanied by normalization of blood counts (polymorphonuclear leukocytes, platelets, and hemoglobin), and bone marrow biopsy results showing less than 30% lymphocytes with no evidence of disease. Patients with PRn met the same criteria, with the exception that lymphoid nodules were detectable on bone marrow biopsy. Patients with PR had a
Pharmacokinetics Plasma concentrations of alemtuzumab were determined with enzyme-linked immunosorbent assay developed and validated in the Laboratory of Pharmacokinetics in the Department of Pharmacology at Istituto di Ricovero e Cura a Carattere Scientifico-Policlinico S. Matteo. Unknown alemtuzumab plasma concentrations were interpolated from a standard curve plotted according to a four-parameter logistic curve-fitting program (Riasmart adapted; Packard Bioscience, Meriden, CT). Blood samples were collected on days 1, 3, 5, 15, 17, 22, and 31. On day 15, blood samples were taken at 1, 2, 3, 4, 6, 8, and 12 hours after subcutaneous administration of alemtuzumab. Alemtuzumab plasma concentrations were calculated before administration (Cpredose) on days 3, 15, 17, and 22; area under the curve from 0 to 12 hours (AUC0-12 hours) was calculated on day 15.
PBSC Collection
Statistical Analysis
Demographic and Baseline Clinical Characteristics A total of 34 patients, 23 male and 11 female, were enrolled onto the study and received alemtuzumab subcutaneously. The median patient age was 55.5 years (range, 40 to 63), and all completed the planned 6 weeks of alemtuzumab consolidation. Of the 17 patients who were evaluated for immunoglobulin heavy-chain variable region (IgVH) gene mutation status, five tested negative for mutations in this gene (Table 1). Before receiving consolidation treatment with alemtuzumab, 31 had received first-line intravenous fludarabine monotherapy 25 mg/m2 for 5 consecutive days, every 28 days. A median of six cycles was administered (range, four to six cycles). In addition, one patient received combination fludarabine 25 mg/m2 for 3 days plus cyclophosphamide 250 mg/m2 for 3 days as first-line therapy every 28 days for six cycles. The last two patients initially received three cycles of fludarabine monotherapy, but after showing a poor response in the lymph nodes, they were switched to treatment with fludarabine plus cyclophosphamide for three cycles. Patient characteristics and first-line treatments administered before alemtuzumab are listed in Table 1. Before receiving consolidation with alemtuzumab, 12 patients showed a CR, seven were in PRn, and 15 patients had PR (Table 2). All patients tested positive for MRD by consensus primer PCR. Alemtuzumab was administered after a median of 16 weeks (range, 12 to 76 weeks) of rest from the last dose of chemotherapy. Persistence of bone marrow hypoplasia required a prolonged 76-week interval between the last course of chemotherapy and consolidation with alemtuzumab in only one patient.
Response Consolidation with alemtuzumab improved the quality of responses achieved after fludarabine therapy in 18 patients, according to NCI-WG criteria. Of the 15 patients who had PR, nine patients improved to CR and three patients improved to PRn. Of the seven patients who achieved PRn with fludarabine-based treatment, six had PR after alemtuzumab. After alemtuzumab treatment, 27 patients (79.4%) achieved CR, and 19 of these patients (56%) achieved molecular undetectable disease as defined by PCR negativity. Among the five patients with unmutated IgVH status, two achieved CR, and one of these patients had MRD-negative status. Nine (75%) of the 12 patients who had a mutation in IgVH achieved CR, and seven of these patients (58%) had a molecular response.
Feasibility of PBSC and Survival After Alemtuzumab
All 34 patients have been observed for a median of 25.5 months (range, 4 to 45 months) since alemtuzumab administration. Eighteen patients have undergone PBSC transplantation after a median of 11 months from the end of immunotherapy, and 17 are in CR at a median follow-up of 28 months after alemtuzumab treatment (range, 11 to 42 months) and a median of 14.5 months after PBSC transplantation (range, 1 to 31 months). Of the 16 patients who did not undergo PBSC transplantation, seven experienced disease progression after a median of 7 months (range, 1 to 16 months); two of these patients experienced relapse after PBSC collection. The remaining nine patients, eight in CR and one in PR, are progression free after a follow-up of 17 months (range, 4 to 45 months). Among these nine patients, two are on the waiting list for PBSC collection and two are on the waiting list for transplantation. Of the remaining five patients, PBSC collection was not performed in two patients: severe immune thrombocytopenia required a splenectomy in one patient, and the other patient refused transplantation. Of the two patients with adequate collection, one did not receive high-dose therapy because of a brain ischemic event, and the other did not receive high-dose therapy because of personal reasons. The last patient had inadequate PBSC collection to undergo transplantation.
Safety and Tolerability
Pharmacokinetic Results A pharmacokinetic study of alemtuzumab plasma concentration was conducted in 16 CLL patients with residual disease after chemotherapy. Alemtuzumab plasma concentrations increased gradually during the first 2 weeks of administration; however, alemtuzumab accumulated in the plasma during week 3 to a concentration 25.5-fold higher than that of the previous week and continued to increase during the administration period thereafter (Table 5). The median AUC0-12 hours was calculated to be 8.82 µg · h/mL (range, 0.044 to 14.27 µg · h/mL). An exploratory analysis evaluated the correlation between a quantitative response (polyclonal CR) and alemtuzumab AUC0-12 hours on day 15. On the basis of this analysis, one of four patients (25%) who had an AUC0-12 hours less than 5 µg · h/mL achieved CR, whereas all 12 patients (100%) who had an AUC0-12 hours more than 5 µg · h/mL achieved CR (Fig 1).
In this population of young patients (< 65 years old) with fludarabine-sensitive CLL, consolidation therapy with alemtuzumab was effective, safe, and well tolerated. CR was achieved by 79.4% of patients; moreover, 56% of the study population achieved MRD negativity, as assessed by consensus primer PCR. The Wilcoxon rank sum test for paired data demonstrates that the quality of response (CR, PR, or PRn) significantly improved after alemtuzumab consolidation (P < .0001); the same significant improvement (P < .0001) also was seen with the McNemar test for the dichotomous end point CR versus non-CR. Importantly, the subsequent mobilization of PBSC was not compromised, allowing for successful collection in 24 patients, of whom 18 went on to receive autologous PBSC transplantation. At the most recent follow-up, 14.5 months after PBSC transplantation, 17 patients remain in remission. Similarly, an additional nine patients who did not receive PBSC transplantation remain in remission after a median follow-up of 17 months. Results from this study compare favorably with those from an earlier investigation by O’Brien et al,21 in which alemtuzumab consolidation was administered for the treatment of residual disease in patients with CLL. The slightly lower response (overall response rate, 46%) and molecular remission rates (38%) may be attributed, at least in part, to differences in the patient populations and in the induction chemotherapy used in each study. Most notably, in the study by O’Brien et al,21 patients were more heavily pretreated; 66% of patients had received two or more prior therapies. Several recent studies have established the feasibility and efficacy of alemtuzumab administered as consolidation therapy to improve the quality of response to fludarabine-based induction regimens.17,21 Early experience suggests that improvement in the quality of response rates with alemtuzumab consolidation may translate into increases in progression-free and overall survival.21 Notably, the current study provides the first evidence demonstrating the feasibility of using alemtuzumab consolidation therapy in patients who subsequently will undergo PBSC. Among the six patients in whom PBSCs were adequately collected but who did not undergo transplantation, two are on a waiting list for transplantation, two had disease progression before transplantation, one refused transplantation, and one patient did not undergo transplantation for medical reasons. The safety profile of alemtuzumab has been well characterized. Intravenous administration of alemtuzumab frequently has been associated with infusion reactions (ie, rigor, fever, chills, nausea, and hypotension), whereas subcutaneous administration of alemtuzumab is a means to reduce or eliminate the occurrence of such reactions. To that end, subcutaneous administration reactions observed during the current study were mostly limited to the first week of therapy and were significantly milder than those observed in earlier studies of intravenous administration.18 Although CMV reactivation was evident in approximately half of the patients, progression to CMV infection was controlled successfully using oral ganciclovir, and active disease was prevented in all 18 patients who tested positive for CMV during the study. Notably, three of these patients did not require treatment because of the spontaneous resolution of pp65 positivity. Pharmacokinetic analyses during treatment of subcutaneous alemtuzumab 10 mg/d three times a week showed that the drug gradually increases during the first 2 weeks and accumulates rapidly in the blood thereafter. Notably, an exploratory analysis correlating molecular CR rate to the AUC0-12 hours on day 15 of alemtuzumab therapy suggests that patients who achieve a level more than 5 µg · h/mL have a greater chance at achieving CR compared with patients who achieve levels less than 5 µg · h/mL. Consolidation therapy with alemtuzumab seems to be a feasible and effective approach for younger, treatment-naïve patients with CLL who achieve either a PR or CR with fludarabine chemotherapy but remain MRD positive. Consolidation therapy with alemtuzumab not only resulted in improved CR rates but, in a majority of patients, also achieved complete purging of detectable residual disease. Subcutaneous alemtuzumab administration was safe and well tolerated and, in the majority of patients, resulted in stable, therapeutic plasma drug concentrations. A better understanding of alemtuzumab therapeutic concentration and pharmacokinetic profile may lead to a more rapid and effective treatment regimen. Importantly, alemtuzumab consolidation therapy did not interfere with the subsequent collection of CD34+ cells for PBSC transplantation after the appropriate mobilization regimens. PBSC transplantation was successful, with long-term molecular remission observed in a substantial number of patients.
Although all authors completed the disclosure declaration, the following authors or their 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 description 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Jemal A, Tiwari RC, Murray T, et al: Cancer statistics, 2004. CA Cancer J Clin 54:8-29, 2004 2. Ries L, Eisner M, Kosary C: SEER Cancer Statistics Review, 1975-2001. Bethesda, MD, National Cancer Institute, 2004 3. Montserrat E: Role of auto- and allotransplantation in B-cell chronic lymphocytic leukemia. Hematol Oncol Clin North Am 18:915-926, 2004[CrossRef][Medline] 4. Ferrajoli A, O'Brien SM: Treatment of chronic lymphocytic leukemia. Semin Oncol 31:60-65, 2004[Medline] 5. Levy V, Porcher R, Delabarre F, et al: Evaluating treatment strategies in chronic lymphocytic leukemia: Use of quality-adjusted survival analysis. J Clin Epidemiol 54:747-754, 2001[CrossRef][Medline] 6. Moreton P, Kennedy B, Lucas G, et al: Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23:2971-2979, 2005 7. Montserrat E, Esteve J, Schmitz N, et al: Autologous stem-cell transplantation (ASCT) for chronic lymphocytic leukemia (CLL): Results in 107 patients. Blood 94:397a, 1999 (abstr 1758) 8. Fabian I, Flidel O, Gadish M, et al: Effects of CAMPATH-1 antibodies on the functional activity of monocytes and polymorphonuclear neutrophils. Exp Hematol 21:1522-1527, 1993[Medline] 9. Treumann A, Lifely MR, Schneider P, et al: Primary structure of CD52. J Biol Chem 270:6088-6099, 1995 10. Hale G, Xia MQ, Tighe HP, et al: The CAMPATH-1 antigen (CDw52). Tissue Antigens 35:118-127, 1990[Medline] 11. Gilleece MH, Dexter TM: Effect of Campath-1H antibody on human hematopoietic progenitors in vitro. Blood 82:807-812, 1993 12. Lundin J, Kimby E, Bjorkholm M, et al: Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 100:768-773, 2002 13. Keating MJ, Flinn I, Jain V, et al: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 99:3554-3561, 2002 14. Kennedy B, Rawstron A, Carter C, et al: Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia. Blood 99:2245-2247, 2002 15. Montillo M, Tedeschi A, Rossi V, et al: Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H. Leukemia 18:57-62, 2004[Medline] 16. Montillo M, Cafro AM, Tedeschi A, et al: Safety and efficacy of subcutaneous Campath-1H for treating residual disease in patients with chronic lymphocytic leukemia responding to fludarabine. Haematologica 87:695-700, 2002 17. Wendtner CM, Ritgen M, Schweighofer CD, et al: Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission: Experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia 18:1093-1101, 2004[CrossRef][Medline] 18. Bowen AL, Zomas A, Emmett E, et al: Subcutaneous CAMPATH-1H in fludarabine-resistant/relapsed chronic lymphocytic and B-prolymphocytic leukaemia. Br J Haematol 96:617-619, 1997[CrossRef][Medline] 19. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 87:4990-4997, 1996 20. Diss TC, Peng H, Wotherspoon AC, et al: Detection of monoclonality in low-grade B-cell lymphomas using the polymerase chain reaction is dependent on primer selection and lymphoma type. J Pathol 169:291-295, 1993[CrossRef][Medline] 21. O'Brien SM, Kantarjian HM, Thomas DA, et al: Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer 98:2657-2663, 2003[CrossRef][Medline] Submitted October 13, 2005; accepted March 3, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% reduction in palpable disease, as well as one of the following features: polymorphonuclear cells more than 1.5 x 109/L or improvement from baseline polymorphonuclear leukocyte levels, or platelets more than 100 x 109/L or 50% improvement from baseline levels without the need for transfusion. Bone marrow was examined every 6 months after completion of immunotherapy until evidence of relapse. 
= .05 and a power 1 – β = .99, a total of 30 patients (15 in the first and 15 in the second stage) would have been enough to detect a difference between an expected efficacy of 50% in achieving additional improvement using alemtuzumab. Enrollment of 15 patients in the second stage was planned only if improved response was documented in more than eight patients during the first stage of the trial. The forecast percentage difference in responders between chemotherapy and immunotherapy treatments was set at 40% (95% CI, 31.19% to 53.33%). 
