Management Guidelines for the Use of Alemtuzumab in Chronic Lymphocytic Leukemia

Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia

AO¨ sterborg1,2,RFoa`3,RFBezares4, C Dearden5,MJSDyer6, C Geisler7,TSLin8, M Montillo9, MHJ van Oers10, C-M Wendtner11 and KR Rai12

1Department of Hematology, Karolinska University Hospital, Stockholm, Sweden; 2Department of Oncology, Karolinska Institute, Stockholm, Sweden; 3Division of Hematology, Department of Cellular Biotechnologies and Hematology, ‘Sapienza’ University, Rome, Italy; 4Department of Hematology, Hospital General de Agudos, Buenos Aires, Argentina; 5Department of Haemato-Oncology, The Royal Marsden Hospital and Institute of Cancer Research, London, UK; 6MRC Toxicology Unit, University of Leicester, Leicester, UK; 7Department of Hematology, Rigshospitalet, Copenhagen, Denmark; 8Division of Hematology and Oncology, The Ohio State University, Columbus, OH, USA; 9Department of Hematology, Niguarda Ca’ Granda Hospital, Milan, Italy; 10Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands; 11Clinic I of Internal Medicine, University of Cologne, Cologne, Germany and 12Division of Hematology-Oncology, Long Island Jewish Medical Center, New Hyde Park, NY, USA

The consensus views of an expert roundtable meeting are of which were deletions of 13q (55%), 11q (18%), and 17p (7%) presented as updated management guidelines for using and trisomy 12 (16%).3 Specific cytogenetic features were alemtuzumab in chronic lymphocytic leukemia. Since the strongly associated with disease course and survival; patients publication of previous management guidelines in 2004, clinical experience with alemtuzumab has grown significantly, espe- harboring 17p or 11q deletion had more rapidly progressing cially regarding its efficacy and safety, management of disease and shorter survival than patients with 13q deletion, 3,4 cytomegalovirus (CMV) reactivation, identification of patient trisomy 12 or normal cytogenetics. The poor prognosis of subgroups likely to benefit from alemtuzumab therapy and patients with 17p or 11q deletion is believed to be the result of subcutaneous administration of alemtuzumab. The updated abnormalities in the p53 pathway. The proportion of patients recommendations include (1) alemtuzumab monotherapy can with p53 abnormalities (17p deletion or p53 overexpression/ be safely used as first-line therapy; (2) suitable patient subgroups for alemtuzumab therapy include elderly patients, mutation) tends to be higher in the relapsed/refractory popula- patients with 17p deletion, patients with refractory autoimmune tion (50%, n ¼ 24) than in the previously untreated population 5 cytopenias and patients with profound pancytopenia at base- (7%, n ¼ 88). line due to heavily infiltrated bone marrow; (3) alemtuzumab For younger patients with symptomatic disease, combination treatment should be continued for 12 weeks (36 doses) chemotherapy with fludarabine and cyclophosphamide (FC) is whenever possible, and bone marrow examination may be highly effective and has become the standard first-line treat- considered at week 12 to evaluate response; (4) monitoring ment.4,6,7 Chemoimmunotherapy with fludarabine, cyclophos- CMV reactivation by weekly PCR is mandated during therapy; 8,9 when CMV reactivation becomes symptomatic or viremia phamide and rituximab (FCR) achieved high response rates, increases, alemtuzumab therapy should be interrupted and and was recently shown to improve response rates and anti-CMV therapy started; (5) subcutaneous administration is progression-free survival (PFS) significantly, compared with FC safe, easy to perform and appears equally effective compared alone, in both previously untreated and relapsed/refractory CLL with intravenous infusion and (6) our strong recommendation is in large randomized trials.10,11 The alkylating agent chlorambucil that alemtuzumab combination therapy and consolidation is still widely used, especially in elderly patients for whom the therapy shall not be used outside carefully controlled clinical 12 studies. goal of treatment is often cytoreduction and palliation. Leukemia (2009) 23, 1980–1988; doi:10.1038/leu.2009.146; Alemtuzumab (Campath and MabCampath; Bayer Health- published online 23 July 2009 Care Pharmaceuticals, Wayne, NJ, USA and MabCampath; Keywords: alemtuzumab; dosing schedule; elderly; infections; Bayer Schering Pharma, Berlin, Germany) is a recombinant safety humanized monoclonal antibody targeting the CD52 antigen. CD52 is a glycoprotein of unknown function that is highly expressed on cell surfaces of normal and malignant lymphocytes.13 Binding of alemtuzumab to CD52 on lymphocytes Introduction induces complement-dependent cytotoxicity,14,15 antibody-dependent cell-mediated cytotoxicity14 and direct cytotoxicity Chronic lymphocytic leukemia (CLL) is the most common (likely apoptotic cell death),16–18 although a direct cytotoxic leukemia in Western countries. In the United States, an effect of alemtuzumab was not observed in other studies and estimated 15 110 new cases of CLL and 4390 deaths due to therefore remains controversial.19,20 Alemtuzumab received this disease are expected in 2008.1 In Europe, more than accelerated approval in the United States and Europe in 2001 100 000 patients are believed to live with the disease.2 for patients who had been treated with alkylating agents and in Molecular heterogeneity is common in CLL. Cytogenetic whom fludarabine therapy had failed. A recent randomized analysis of 325 patients conducted at the time of CLL diagnosis phase III trial (CAM307) compared alemtuzumab with found that 82% had chromosomal aberrations, the most frequent chlorambucil as first-line treatment.21 Based on the positive results of this study, alemtuzumab received full approval and ¨ Correspondence: Professor A Osterborg, Department of Hematology, an expanded indication in September 2007 in the United States Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. 22 E-mail: [email protected] and in January 2008 in Europe. Received 8 April 2009; revised 25 May 2009; accepted 4 June 2009; A previous version of management guidelines, based mainly published online 23 July 2009 on clinical experiences with alemtuzumab in patients with Management guidelines for alemtuzumab in CLL AO¨sterborg et al 1981 fludarabine-refractory CLL, was published in 2004.23 Here, we with a maximum lymph node size Z 5 cm, an ORR of 76% and present updated guidelines that incorporate recent clinical data a median PFS of 11.1 months were achieved in the alemtuzu- and cumulative experience from more than 20 000 patients mab arm, compared with an ORR of 44% and a PFS of 8.8 treated with alemtuzumab since its approval in 2001. months in the chlorambucil arm. These findings were consistent with earlier results that showed an ORR of 86% in patients with lymph nodes 45 cm (compared with an ORR of 87% in patients Alemtuzumab monotherapy for CLL with lymph nodes p5 cm).24 It appears that patients with bulky lymphadenopathy (45 cm) may also benefit from first-line Alemtuzumab monotherapy in relapsed/refractory CLL has been alemtuzumab therapy. It should be noted, though, that most reviewed previously.23 We will focus on alemtuzumab mono- responses to alemtuzumab in patients with bulky lymphadeno- therapy as first-line treatment for CLL. The first such study was a pathy are PRs.24 Swedish phase II study. Patients with symptomatic CLL received First-line alemtuzumab therapy was generally well tolerated. first-line s.c. alemtuzumab 3 times weekly (t.i.w.) for up to 18 Incidences of grade 3 or 4 anemia and thrombocytopenia weeks with the target dose of 30 mg. An overall response rate were similar between the alemtuzumab and chlorambucil (ORR) of 87% (complete response (CR) 19%, partial response arms (Table 1).21 Although grade 3 or 4 neutropenia was (PR) 68%) was achieved in 38 evaluable patients.24 After a long- more common with alemtuzumab (41 vs 25%), febrile neutro- term follow-up, the median time to treatment failure (TTTF) was penia and sepsis were similarly rare in both arms. Cytomega- 28 months for all 38 evaluable patients, 32 months for the 33 lovirus (CMV) reactivation was the only drug-related serious responders and 77 months for the 7 patients who achieved CR. adverse event more common with alemtuzumab than with Compared with 75 carefully matched historical control patients chlorambucil.21 who received alternative first-line treatment, patients treated Although the CAM307 study demonstrated significantly with alemtuzumab achieved a higher ORR and CR rate, as well improved activity of alemtuzumab compared with chlorambu- as longer TTTF. The incidence of infection was similar in cil, these data should be considered in perspective, because patients receiving alemtuzumab and those receiving alternative chlorambucil is no longer considered the standard of care for treatment during both treatment and follow-up.25 most patients with CLL. Recent randomized studies have The efficacy and safety of first-line intravenous (i.v.) alemtuzu- established the role of FCR chemoimmunotherapy in both mab were investigated by Hillmen et al.21 in the randomized previously untreated and relapsed/refractory CLL, and it is likely phase III CAM307 study. Treatment-naive patients (N ¼ 297) were that FCR will be adopted as the new standard of care for the randomized to receive i.v. alemtuzumab 30 mg t.i.w. for up to 12 majority of patients. However, there may be subgroups of weeks or oral chlorambucil 40 mg/m2 every 28 days. Alemtuzu- patients who are unable to receive FCR or may not achieve good mab therapy achieved significantly higher ORR, CR rates and response to FCR and who therefore may benefit from longer PFS compared with chlorambucil (ORR 83 vs 55%, CR alemtuzumab therapy in the first-line setting. Such patient rate 24 vs 2%, PFS 14.6 vs 11.7 months), with a 42% reduction in subgroups are discussed further in the following section. the risk of disease progression or death (hazard ratio ¼ 0.58; As with most new cancer therapeutics, alemtuzumab is P ¼ 0.0001). Alemtuzumab was also superior to chlorambucil relatively expensive. Our recommendations are based solely on with respect to time to alternative treatment and minimal residual clinical data without considering pharmacoeconomics. disease (MRD) negativity.21 Response rates for alemtuzumab compared favorably with those of single-agent rituximab (CR 9%, PR 49%).26 Importantly, alemtuzumab was shown to be effective Recommendations in patients with poor-risk cytogenetics (ORR 64% in patients with 17p deletion and 87% in patients with 11q deletion).21 In this section, we provide our recommendations regarding the Patients in the CAM307 study were prospectively stratified by use of alemtuzumab and patient management. The recommen- factors such as age and size of lymph nodes. Among patients dations are also briefly summarized in Table 2.

Table 1 Safety results from CAM307 study: adverse events in X10% of patients

Adverse event Alemtuzumab (n ¼ 147) Chlorambucil (n ¼ 147)

All grades, n (%) Grade 3 or 4, n (%) All grades, n (%) Grade 3 or 4, n (%)

Infusion related Pyrexia 94 (63.9) 12 (8.2) 5 (3.4) F Chills 73 (49.7) 5 (3.4) FF Urticaria 22 (15.0) 3 (2.0) 1 (0.7) F Hypotension 21 (14.3) 2 (1.4) FF Rash 18 (12.2) 1 (0.7) 1 (0.7) F

Hematologic Neutropenia NR 60 (41) NR 36 (25) Thrombocytopenia NR 18 (12) NR 17 (12) Anemia NR 16 (11) NR 26 (18)

CMV events Asymptomatic (with PCR positivity) 77 (52.4) 6 (4.1) 11 (7.5) F Symptomatic CMV 23 (15.6) 6 (4.1) FF Abbreviations: CMV, cytomegalovirus; NR, not reported; PCR, polymerase chain reaction. Modiﬁed from Hillmen et al.,21 with permission. 2007 American Society of Clinical Oncology. All rights reserved.

Leukemia Management guidelines for alemtuzumab in CLL AO¨sterborg et al 1982 Table 2 Summary of recommendations on alemtuzumab use

Recommendations

Treatment duration 12 weeks Route and dosage s.c. 30 mg t.i.w. after optional dose escalation Response assessment 1. Regular clinical examination (e.g., lymphocyte count, lymph node, organomegaly, B symptoms) 2. Bone marrow biopsy at week 12 Suitable patient population 1. Elderly patients (aged 465 years) 2. Patients with 17p deletion 3. Patients with pancytopenia due to heavily inﬁltrated bone marrow 4. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia

Patient management Hematologic events Refer to alemtuzumab prescribing information for treatment interruption and dose modiﬁcation.27 Use supportive therapy (G-CSF or irradiated blood product) when indicated Infections Cotrimoxazole prophylaxis for P. jirovecii pneumonia and aciclovir prophylaxis for herpes virus CMV reactivation Clinical watch and weekly CMV test Refer to O’Brien et al.28 for treatment of CMV reactivation Infusion-related events Antihistamine and acetaminophen premedication Corticosteroid prophylaxis is recommended, but at week 1 only Injection-site skin Antihistamine and acetaminophen premedication reactions Corticosteroid prophylaxis is recommended, but at week 1 only Abbreviations: CMV, cytomegalovirus; G-CSF, granulocyte colony-stimulating factor; s.c., subcutaneous; t.i.w., three times per week.

Treatment duration and response assessment (PCR)-based CMV monitoring becomes common practice, CMV We recommend that alemtuzumab therapy be given for at reactivation can be detected early and managed effectively. least 12 weeks (36 doses) whenever possible, unless there are Late-occurring infections are possible, particularly in relapse/ clear signs of progressive disease, and that bone marrow refractory patients. The management of CMV events and non- assessment be performed no earlier than week 12 (level of CMV infectious complications will be discussed below in further evidence: nonrandomized trials24,29,30). detail. Our recommendation is based on the rationale to maximize quality of response without causing undue toxicity. Our overall experience with alemtuzumab suggests that the length of Dose recommendations and administration routes therapy correlates with the quality of remission, which in turn The approved dosing schedule of alemtuzumab is 30 mg correlates with patient outcomes. In patients receiving alemtu- through i.v. infusion over 2 h (not i.v. push or bolus) t.i.w. for zumab therapy, although CR may be observed in the peripheral 12 weeks, after dose escalation from 3 to 10 to 30 mg daily or as blood of almost all patients by week 4 (regardless of eventual tolerated. This regimen has been used in the majority of clinical bone marrow response), significant depletion of CLL cells in trials. The alemtuzumab prescribing information cautions that the bone marrow may not begin until circulating CLL cells single doses higher than 30 mg and weekly cumulative doses have been completely eradicated from peripheral blood.24,30 higher than 90 mg may increase the incidence of pancytope- Thus, longer treatment duration (such as 12 weeks or more) nia.27 A small study indicated that a lower dose (10 mg) of seems to be required to achieve maximal response in the bone alemtuzumab may also be effective,33 but in the absence of marrow.24,29,30 Whether therapy should be extended beyond further studies, a lower dose is not recommended at present. We 12 weeks remains uncertain, although some trials indicate recommend that less-frequent dosing (once or twice per week) that prolonged therapy may be beneficial (particularly with s.c. be avoided, because unpublished observation from early trials administration, which has slower pharmacokinetics).24,31 We in the 1990 s indicated that t.i.w. dosing of single-agent recommend that such decisions should be made on an alemtuzumab may be superior to less-frequent dosing with individual basis at the discretion of the treating physician. respect to clinical effectiveness (level of evidence: empirical). A recent survey indicates that in clinical practice, however, The alemtuzumab prescribing information can be referred alemtuzumab therapy is often stopped at weeks 7–8, possibly to for recommended dose modifications for neutropenia based on ‘cosmetic’ response observed in the peripheral blood and thrombocytopenia; no modification is recommended for rather than in the bone marrow (personal communications with lymphopenia.27 Bayer Schering Pharma). We want to emphasize the importance Subcutaneous administration has emerged as a feasible and of maintaining a full course of 12-week therapy (unless there are effective delivery route for alemtuzumab. In the study by Lundin signs of disease progression) and assessing response in the bone et al.,24 41 previously untreated CLL patients received s.c. marrow. alemtuzumab at a dose of 30 mg t.i.w. for up to 18 weeks after Twelve-week alemtuzumab therapy generally has an accep- s.c. dose escalation. Transient first-dose skin reactions occurred table safety profile in first- or later-line treatment.21,32 As with s.c. administration, prolonging duration of the dose- discussed in previous guidelines, toxicity with single-agent escalation phase to 2 weeks in some cases; other first-dose alemtuzumab therapy typically occurs early and on a relatively reactions were rare or absent with the exception of low-degree predictable schedule, allowing for implementation of appro- fever. The response rates and duration of response were similar priate prophylaxis and management strategies. Moreover, the to those seen with first-line i.v. alemtuzumab.21,24 In a phase II incidence of adverse events decreases over time, and CMV trial in patients with fludarabine-refractory CLL (CLL2H trial of events are rare after week 8.23 As polymerase chain reaction the German CLL Study Group), s.c. alemtuzumab was given at

Leukemia Management guidelines for alemtuzumab in CLL AO¨sterborg et al 1983 30 mg t.i.w. for up to 12 weeks after i.v. or s.c. dose escalation. and/or targeted agents have not experienced similar safety The ORR was 32% (CR 4%, PR 28%), median PFS was 7.7 concerns.39,40,43,45 Our strong recommendation is that alemtu- months and median OS was 19.1 months.34 Again, in patients zumab-containing combination therapy shall not be used with refractory CLL, s.c. alemtuzumab showed similar efficacy, outside carefully controlled clinical studies (level of evidence: compared with i.v. alemtuzumab.32 First-dose skin reactions are unpublished randomized controlled trial). less prominent in previously treated patients than in those who Alemtuzumab has also been explored as consolidation received s.c. alemtuzumab as first-line treatment, and delay of therapy or as maintenance therapy. Encouraging activities of the second or third s.c. dose is not needed for previously treated alemtuzumab consolidation were observed, including improve- patients.24 It may also be possible to skip alemtuzumab dose ment in quality of response,47,48 MRD eradication49–51 and escalation; an up-front 30 mg dose resulted in acceptable side prolonged PFS.52 However, safety concerns (particularly in- effects without a delay in administration of the second dose.35,36 fectious toxicity) were raised in academic-center-based The s.c. route is also attractive because of the feasibility of trials51,53 and in a community-based trial.54 Other reported self-administration. In the study by Lundin et al., most patients studies of alemtuzumab consolidation therapy have not expe- were able to self-administer treatment after completion of the rienced similar safety problems.47–50 We strongly recommend dose-escalation phase and disappearance of skin reactions.24 that alemtuzumab should not be used outside carefully control- Subsequent studies also demonstrated the feasibility of self- led clinical trials as consolidation or maintenance therapy administration of s.c. alemtuzumab.37,38 The s.c. self-adminis- following any type of induction therapy (level of evidence: tration strategy has been successfully applied in routine practice randomized controlled and nonrandomized trials51,53,54). at many experienced centers, offering maximal convenience The causes for increased toxicity in some trials discussed and cost-saving, because a 36-visit schedule of 2 h infusions above are not clear and may be related to patient characteristics, required for i.v. alemtuzumab may be costly and difficult for dose/schedule of alemtuzumab and combination partners, many patients to accommodate. management strategies, ‘rest period’ between induction chemo- In light of these data on s.c. alemtuzumab, we recommend therapy and alemtuzumab consolidation, and/or other factors. It that s.c. administration may be used instead of i.v. administra- may be speculated that rapid elimination of CD52 þ leukemic tion. The recommended dosage of s.c. alemtuzumab is the same cells by combination therapy results in a low disease burden; as that of i.v. alemtuzumab (30 mg t.i.w. for 36 doses over 12 similarly, in the consolidation setting, patients have a low initial weeks). Regimens other than 30 mg t.i.w. are not recommended. disease burden because of prior induction therapy. As a Dose escalation may be prolonged to up to 2 weeks in the event consequence, the exposure of normal CD52 þ cells to alemtu- of symptomatic local skin reactions (level of evidence: zumab increases, leading to excessive depletion of immune nonrandomized trials24,34). cells and infectious toxicity. Further investigations are needed to better define the role of alemtuzumab combination therapy and consolidation therapy, which remain an active area of Combination therapy and maintenance therapy in CLL clinical investigation. Promising results have been reported for combination therapies of alemtuzumab with chemotherapy,39,40 chemoimmuno- 41,42 43–45 46 therapy, rituximab or high-dose methylprednisolone. Suitable patient populations for alemtuzumab Based on these results, two large phase III trials are ongoing to As discussed earlier, there are subgroups of patients who may evaluate the role of alemtuzumab combination therapies in CLL: 2 benefit from first-line alemtuzumab therapy. We will discuss (1) the CAM314 study (i.v. fludarabine 30 mg/m and i.v. alem- these patient subgroups in detail. tuzumab 30 mg for 3 days following dose escalation (FluCam) vs i.v. fludarabine 25 mg/m2 for 5 days, repeated every 28 days, as second-line treatment); this trial has now completed enrollment Elderly patients. First-line alemtuzumab therapy is effective (Genzyme, personal communication); (2) the HOVON 68 and safe in elderly patients.21,24 In CAM307 study, ORR among (Hemato-Oncologie voor Volwassenen Nederland) study (oral 53 patients X65 years of age who received alemtuzumab was fludarabine 40 mg/m2 and oral cyclophosphamide 250 mg/m2 76%, compared with 56% among 52 patients X65 years of age for 3 days and low-dose s.c. alemtuzumab (30 mg for 3 doses in who received chlorambucil (P ¼ 0.0409), whereas PFS was not cycle 1 and one dose in subsequent cycles) (FCCam) vs oral significantly different between the two groups.21 Similarly, high fludarabine 40 mg/m2 and cyclophosphamide 250 mg/m2 (FC), ORR was observed in elderly patients receiving first-line s.c. repeated every 4 weeks for 6 cycles, in first-line high-risk alemtuzumab,24 probably due to good tolerability and few early patients); this trial is continuing to accrue patients after several dropouts. Data and Safety Monitoring Board reviews. The GCF-LLC/MW Toxicity is an important factor to consider when formulating (Groupe Coope´rateur Français Leuce´mie Lymphoı¨de Chronique/ treatment plans for elderly patients. Although fludarabine Macroglobuline´mie de Waldenstro¨m) and GOELAMS (Groupe- induces high response rates, it is sometimes not well tolerated Oest-Est d’Etude des Leuce´mies et Autres Maladies du Sang) by elderly patients. Moreover, no survival benefits were have been conducting the CLL2007FMP trial, in which demonstrated for fludarabine over chlorambucil in first-line previously untreated patients with Binet stage B or C CLL have treatment of elderly patients in the German CLL5 study.55 On been randomized to receive FCR or FCCam (s.c. alemtuzumab the other hand, alemtuzumab induces a high response rate in 30 mg, oral fludarabine 40 mg/m2 and oral cyclophosphamide elderly patients without causing unacceptable toxicities. We 250 mg/m2 on days 1–3, repeated every 4 weeks for 6 cycles). conclude that alemtuzumab is a useful treatment option for This study was halted in January 2009 after the observation of an elderly patients if the goal of treatment is disease remission or if increased number of deaths in the FCCam arm, suggesting that the patient has aggressive disease (level of evidence: rando- the FCCam regimen was not tolerable in this trial (Dr Ste´phane mized controlled trial21). More generally, younger patients LePretre, personal communication, January 2009). Report of (o65 years) who have impaired renal function (and who are further information about this trial is pending. Other reported therefore less tolerant of fludarabine) may also be good trials of combinations of alemtuzumab with chemotherapy candidates to receive alemtuzumab therapy.

Leukemia Management guidelines for alemtuzumab in CLL AO¨sterborg et al 1984 Patients with 17p deletion. The presence of 17p deletion disease.60 Case reports and small case series have described the and/or p53 mutations is predictive of the worst prognosis in CLL, efficacy of alemtuzumab in treating refractory, life-threatening characterized by rapid disease progression and shortest survi- AIHA and autoimmune thrombocytopenia in patients with CLL. val.3 These outcomes are thought to be related to the loss of In five patients with advanced CLL and severe, transfusion- functional tumor suppressor p53. Accumulating data have dependent, therapy-resistant AIHA, treatment with s.c. or i.v. demonstrated that response to alemtuzumab is independent of alemtuzumab 30 mg t.i.w. for up to 12 weeks produced an the status of 17p deletion or p53 mutations. The first evidence increase of at least 2 g per 100 ml in hemoglobin concentration came from a case report of a patient with fludarabine-refractory, and eliminated the requirement for transfusion in 4–7 weeks.61 17p-deleted CLL who achieved MRD-negative CR following A schedule of low-dose s.c. alemtuzumab (10 mg t.i.w. for 10 alemtuzumab therapy.56 In the CLL2H study of s.c. alemtuzu- weeks) in heavily pretreated patients with CLL and transfusion- mab in fludarabine-refractory patients, the ORR was 54% dependent AIHA achieved an increase of at least 2 g per 100 ml among 13 patients with 17p deletion.34 In another study of in hemoglobin concentration and independence from transfu- s.c. alemtuzumab in patients with fludarabine-refractory dis- sions in 5–8 weeks.62 ease, the ORR in 15 patients with p53 mutations or 17p deletion Although alemtuzumab itself may cause AIHA, according to was 40%.57 A database review of previously treated patients the product label, we maintain our recommendation that who received alemtuzumab i.v. or s.c. found that ORR did alemtuzumab may be given to patients with AIHA or not differ significantly between patients with p53 deletions autoimmune thrombocytopenia who do not respond to conven- (50%) and patients without p53 deletions (55%).58 In the tional therapy. Alemtuzumab may also be considered one of CAM307 study, 11 patients in the alemtuzumab group and 10 several options for patients who present up front with active patients in the chlorambucil group had 17p deletion. Among autoimmunity when anti-CLL therapy is also needed (level of those patients, ORR and median PFS appear superior in evidence: case reports and small case series61,62). the alemtuzumab arm (64% and 10.7 months, respectively) compared with the chlorambucil arm (20% and 2.2 months, respectively), although the differences did not reach a significant Patient management 21 The 2004 guidelines provided detailed recommendations level. Finally, a recent phase II trial investigated the efficacy of 23 first-line low-dose (10 mg t.i.w.) s.c. alemtuzumab therapy in for prophylaxis and patient management. Here, we provide patients with 17p deletion. Of 48 patients enrolled, CR was a brief review and update of this information. observed in 7% of patients and PR in 33% of patients. Two patients achieved MRD negativity as assessed by four-color flow Hematologic events. Transient and reversible cytopenias cytometry.59 It should be noted that although alemtuzumab is an are common with alemtuzumab treatment. Platelet nadirs effective therapy for patients with 17p deletion, these patients occur mostly during weeks 2– 4; neutrophil nadirs are typically still have a poor prognosis. Among the patients who received observed between weeks 4 and 6. Both neutropenia and alemtuzumab in the CAM307 study, those with 17p deletion thrombocytopenia events are manageable, and adequate had a median PFS of only 10.7 months, compared with those recovery can usually be achieved by weeks 6 – 8. The with normal cytogenetics (19.9 months), trisomy 12 (18.3 alemtuzumab prescribing information summarizes recommen- months) or sole 13q deletion (24.4 months).21 Nevertheless, dations for treatment interruption and dose modification in the because no other alternative therapy has proven equally effec- event of neutropenia and thrombocytopenia. We recommend tive or superior to alemtuzumab in the 17p deletion sub- that alemtuzumab therapy should be stopped temporarily in population, we believe that alemtuzumab remains a reasonable the case of hemorrhage or febrile neutropenia (level of evidence: first- and later-line treatment option for these patients. We empirical). Past guidelines state that clinical judgment should be conclude that alemtuzumab is an effective treatment for patients exercised when incorporating granulocyte colony-stimulating with 17p deletion and that following alemtuzumab therapy, the factor (G-CSF) as supportive therapy in the event of absolute 23,63 option of allogeneic stem cell transplantation may be explored neutrophil count o500 per ml. We maintain the recom- without delay, especially for younger patients (aged o65 years) mendations of the 2004 guidelines on the use of G-CSF to avoid (level of evidence: randomized controlled and nonrandomized unnecessary delay and temporary stop of alemtuzumab therapy. trials21,34,56–58). We also recommend the use of irradiated blood product when supportive transfusion therapy is required (level of evidence: empirical). Because of the potential for transfusion-associated Patients with pancytopenia. Neutropenia, thrombocytope- graft-vs-host disease in severely lymphopenic patients, blood nia and transfusion dependence resulting from heavily infiltrated products should be irradiated before use. bone marrow and/or previous therapy make it problematic for patients with pancytopenia to receive stem-cell-toxic che- Infections. Compromised immune function combined with motherapy regimens, whereas alemtuzumab may clear the bone the immunosuppressive nature of alemtuzumab makes patients marrow with no major hematologic toxicity. Alemtuzumab with CLL susceptible to a variety of infections during and for therapy in this setting may even allow subsequent myelo- some period after treatment. One recent study revealed the suppressive therapy when blood counts have increased. For temporal alignment of T-cell and neutrophil nadirs with the the small subset of patients who present with pancytopenia at timing of appearance of CMV reactivation, pulmonary infection baseline due to heavily infiltrated bone marrow, alemtuzumab and all other infections (Figure 1), demonstrating that the may be considered an option for first-line therapy (level of median time of infection onset occurred after the median time of evidence: empirical). immune cell nadir.64 The incidence of infection appears to be lower in first-line alemtuzumab therapy than in second-line or Patients with autoimmune hemolytic anemia and auto- later therapy.21,32 Recommendations for management of non- immune thrombocytopenia. Autoimmune disorders are CMV infections remain unchanged from the 2004 guidelines.23 frequent in CLL, and autoimmune hemolytic anemia (AIHA), We maintain the recommendation that cotrimoxazole (or the most common one, is associated with more advanced pentamidine inhalation, for cotrimoxazole-allergic patients)

Leukemia Management guidelines for alemtuzumab in CLL AO¨sterborg et al 1985 CMV reactivation is to use up-front oral valganciclovir prophylaxis, which has been shown to be effective in preventing CMV events in patients receiving alemtuzumab-based therapy.65 In this study, however, 27% of patients had disease other than CLL, and only 12.5% of patients received alemtuzumab monotherapy (majority of patients received alemtuzumab combination therapy). Therefore, it remains uncertain whether such prophylactic strategy should be adopted in routine clinical practice. We think that valganciclovir prophylaxis may be used at the discretion of the treating physician in patients at elevated risk for CMV reactivation and that if it is used, patients should be monitored carefully because of the risks of myelosuppression.

Infusion-related events. Infusion-related adverse events are generally grade 1 or 2 and occur most commonly during the ﬁrst week of therapy. Recommendations for the management of infusion-related events remain unchanged from the 2004 23 Figure 1 Timing of immune cell nadirs and infectious events (From guidelines. Brieﬂy, oral premedication with antihistamine Moreton et al.,64 with permission. 2005 American Society of Clinical and acetaminophen are given before infusion. Corticosteroids Oncology. All rights reserved). (oral or i.v.) may also be used (at weeks 1–2). To manage rigors, infusion should be halted and i.v. pethidine be administered. Antiemetic agents are recommended for pethidine-associated prophylaxis be continued for at least 6 months following nausea. In the event of skin rash, additional oral antihistamine cessation of alemtuzumab therapy to minimize the risk of every 4 h is indicated, and oral hydrocortisone may be given in late-occurring Pneumocystis jirovecii pneumonia. We also keep severe cases. For patients who have experienced severe the recommendation that all patients must receive acyclovir infusion-related events, i.v. hydrocortisone premedication prophylaxis for 6 months after cessation of alemtuzumab should be added to subsequent infusions. If corticosteroids are therapy to minimize the risk of severe herpes virus reactivation used, they should be tapered off as soon as possible (within 1–2 (level of evidence: empirical). weeks).

CMV reactivation. Cytomegalovirus reactivation is a well- Injection-site skin reactions. Subcutaneous administration known complication of alemtuzumab treatment. O’Brien et al.28 of alemtuzumab is associated with injection-site skin reactions, estimated the incidence of CMV reactivation to be 4–29%, using including skin erythema and edema. Prophylaxis against first- data from seven clinical trials of single-agent alemtuzumab. In dose skin reactions following s.c. administration is identical to the first-line CAM307 study, 16% of alemtuzumab-treated that recommended for i.v. use. patients had PCR-positive, symptomatic CMV reactivation, and 52% had PCR-positive, asymptomatic CMV reactivation. All symptomatic patients successfully recovered following Repeat treatment and follow-up treatment interruption and anti-CMV therapy.21 Retreatment with alemtuzumab in responders has been assessed We recommend mandatory weekly monitoring for CMV in a small number of patients and has demonstrated promising reactivation by quantitative PCR during alemtuzumab therapy. results. A recent analysis of 17 patients demonstrates that Nevertheless, laboratory monitoring should never replace care- alemtuzumab retreatment in former responders can achieve PR ful clinical watch for early signs of CMV reactivation, such as and stable disease in 53 and 18% of patients, respectively. low-degree fever, fatigue and rising C-reactive protein. In such Overall survival was positively associated with the length of the cases, CMV PCR analysis must be conducted without delay. interval between the last dose of the initial course of A single positive CMV test in an otherwise asymptomatic alemtuzumab and start of retreatment. Median overall survival patient does not necessarily mandate treatment interruption. was 8.4 months among patients who required retreatment However, alemtuzumab therapy should be held in the event of within 10.3 months of the last dose of the initial course, whereas an increasing copy number of CMV in blood or symptomatic median overall survival was not yet reached among patients CMV reactivation. Alemtuzumab may be restarted in most cases who were retreated after a longer interval.66 following successful anti-CMV therapy, cessation of any Guidelines for retreatment are not well developed at present. symptoms and sustained negative CMV PCR (level of evidence: Our 2004 recommendations were based largely on case reports empirical). and personal communications, with dosing schedules indivi- We also emphasize that patients with fever and a negative dualized to the patient.23 The National Comprehensive Cancer CMV PCR analysis must be checked for other pathogens; the Network’s Clinical Practice Guidelines in Oncology for Non- most important actions include computed tomography scan of Hodgkin’s Lymphoma, v.2.2009, state that treatment options for the lungs (if needed, bronchoscopy þ bronchoalveolar lavage) patients with relapsed CLL are similar to those for patients for Pneumocystis diagnosis and blood cultures and PCR for receiving initial therapy and that considerations in the choice of diagnosis of adenovirus, Epstein–Barr virus and other potential treatment are the duration of remission and the agent(s) used for viral pathogens (level of evidence: empirical). initial therapy.67 Specific information regarding retreatment of The recently published CMV management guidelines can be relapsed patients with the same agent used for initial therapy is referred to for details of CMV management in patients receiving not included. More data are needed before specific guidelines alemtuzumab therapy.28 One suggested strategy to manage regarding alemtuzumab retreatment can be formulated.

Leukemia Management guidelines for alemtuzumab in CLL AO¨sterborg et al 1986 Conclusions and overall recommendations for chronic lymphocytic leukemia. J Clin Oncol 2005; 23: 4079–4088. After extensive discussion, we have agreed on the following 9 Wierda W, O’Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, recommendations: (1) alemtuzumab monotherapy can be safely and rituximab for relapsed and refractory chronic lymphocytic used as first-line therapy; (2) suitable patient subgroups for first- leukemia. JClinOncol2005; 23: 4070–4078. and later-line alemtuzumab therapy include elderly patients, 10 Hallek M, Fingerle-Rowson G, Fink A, Busch R, Mayer J, Hensel M patients with 17p deletion, patients with pancytopenia due to et al. Immunochemotherapy with fludarabine (F), cyclophos- heavily infiltrated bone marrow and patients with refractory phamide (C), and rituximab (R) (FCR) versus fludarabine and autoimmune cytopenia; (3) alemtuzumab treatment should be cyclophosphamide (FC) improves response rates and progression- continued for at least 12 weeks, whenever possible, and bone free survival (PFS) of previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL) (Abstract 325). marrow assessment should be considered at week 12 to Blood 2008; 112: 125. determine treatment response; (4) patients should be monitored 11 Robak T, Moiseev SI, Dmoszynska A, Solal-Ce´ligny P, Warzocha weekly for CMV reactivation during therapy, and therapy should K, Loscertales J et al. Rituximab, fludarabine, and cyclophos- be held in the event of symptomatic CMV reactivation; (5) s.c. phamide (R-FC) prolongs progression free survival in relapsed or administration is safe, simplifies treatment for patients and refractory chronic lymphocytic leukemia (CLL) compared with FC health care providers, and appears equally efficacious compared alone: final results from the International Randomized Phase III REACH Trial (abstract). Blood 2008; 112: lba–lb1. with i.v. administration and (6) our strong recommendation is 12 Byrd JC, Stilgenbauer S, Flinn IW. Chronic lymphocytic leukemia. that alemtuzumab-containing combination therapy and alemtu- Hematology (Am Soc Hematol Educ Program) 2004, 163–183. zumab maintenance therapy shall not be used outside carefully 13 Rossmann ED, Lundin J, Lenkei R, Mellstedt H, Osterborg A. controlled clinical studies. Variability in B-cell antigen expression: implications for the treatment of B-cell lymphomas and leukemias with monoclonal antibodies. Hematol J 2001; 2: 300–306. Conflict of interest 14 Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature 1988; 332: 323–327. All authors received an honorarium from Bayer Schering 15 Xia MQ, Hale G, Waldmann H. Efficient complement-mediated lysis of cells containing the CAMPATH-1 (CDw52) antigen. Pharma for participating in an advisory board meeting in Mol Immunol 1993; 30: 1089–1096. Madrid, Spain on 3 November 2007 that served as a starting 16 Mone AP, Cheney C, Banks AL, Tridandapani S, Mehter N, point for the guidelines discussion. The authors did not receive Guster S et al. Alemtuzumab induces caspase-independent cell an honorarium for preparing the guidelines nor for writing the death in human chronic lymphocytic leukemia cells through a paper. 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