Alemtuzumab was initially approved for the treatment of patients with CLL who had failed both alkylating agents and fludarabine therapy. Monotherapy with intravenous (IV) alemtuzumab produced overall response rates (ORR) of 33–54% in patients with advanced stage, relapsed and/or refractory CLL (Table I) (Osterborg et al, 1997; Keating et al, 2002a; Rai et al, 2002; Ferrajoli et al, 2003; Lozanski et al, 2004; Moreton et al, 2005). In the pivotal phase 2 study, 93 patients with fludarabine-relapsed or refractory disease were treated with IV alemtuzumab 30 mg three times weekly for up to 12 weeks. The ORR was 33% [2% complete response (CR), 31% partial response (PR)] (Keating et al, 2002a). The median overall survival (OS) was 32 months among responding patients and 16 months for the entire cohort. These results were encouraging because the median survival among patients with fludarabine-refractory CLL who received alternative salvage therapy was <1 year (Keating et al, 2002c). Alemtuzumab is effective in clearing CLL from the peripheral blood and bone marrow compartments, but induces lower responses in patients with bulky lymphadenopathy (>5 cm lymph node diameter) (Osterborg et al, 1997; Keating et al, 2002a; Moreton et al, 2005). The reason for this is not clear but may be related to decreased penetration of the antibody in bulky lymph nodes, or mechanisms protecting against antibody-mediated killing at that site. Subcutaneous (SC) administration of alemtuzumab produces similar efficacy in patients with relapsed/refractory CLL, compared with IV alemtuzumab. In a phase 2 study by the German CLL Study Group (GCLLSG), 109 patients with fludarabine-refractory CLL were treated with SC alemtuzumab three times a week for up to 12 weeks. An ORR of 33% was achieved (CR 4%, PR 27%). The median progression-free survival (PFS) was 7·7 months and the median OS was 19·1 months (Stilgenbauer et al, 2007). Because of the similar efficacy regardless of administration route, a registration trial (CAM203) is ongoing to support the regulatory filing for SC usage of alemtuzumab.
Toxicities occurring with alemtuzumab monotherapy are categorized as infusion-related, haematological, and infectious events, and guidelines are available for their prevention and management (Keating et al, 2004). In studies involving patients with relapsed/refractory CLL, the most common adverse events were infusion-related toxicities (e.g. fever, rigors, nausea, dyspnoea, hypotension), which were primarily grade 1 or 2 and resolved with continued therapy (Osterborg et al, 1997; Keating et al, 2002a; Rai et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005). Infusion-related reactions associated with SC administration were reduced (except for local injection site reactions) and severe reactions were rare (Stilgenbauer et al, 2007). Haematological toxicities with either IV or SC administration are generally transient and included thrombocytopenia (grade 3 or 4 in 27–50% of patients) and neutropenia (grade 3 or 4 in 34–67%) (Osterborg et al, 1997; Keating et al, 2002a; Lundin et al, 2002; Rai et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005). Infectious events are common in patients with refractory CLL (Perkins et al, 2002) and occur as a result of decreased immune function associated with CLL itself as well as immunosuppression induced by prior therapeutic regimens. Grade 3 or 4 infections were reported in 24–35% of patients with relapsed and/or refractory CLL treated with alemtuzumab (Osterborg et al, 1997; Keating et al, 2002b; Rai et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005). Cytomegalovirus (CMV) reactivation occurs in 10–30% of patients with relapsed and/or refractory disease treated with alemtuzumab (Keating et al, 2002a; Nguyen et al, 2002; Ferrajoli et al, 2003; Moreton et al, 2005), but deaths related to CMV are rare. The consensus guidelines on the management of patients treated with alemtuzumab stress the importance of screening or monitoring for CMV reactivation and to initiate therapy promptly with ganciclovir or its equivalent upon confirmation of reactivation (Keating et al, 2004). In a randomized trial, patients receiving alemtuzumab received prophylaxis with either valaclovir 500 mg orally daily or valganciclovir 450 mg orally twice daily, the use of prophylactic valganciclovir was highly effective for prophylaxis of CMV reactivation in patients receiving alemtuzumab (O’Brien et al, 2008).
Alemtuzumab as first-line treatment for CLL
Alemtuzumab monotherapy is highly active in patients with previously untreated CLL (Table II) (Lundin et al, 2002; Karlsson et al, 2006; Hillmen et al, 2007). A phase 2 trial investigated the activity and toxicity of SC alemtuzumab 30 mg three times weekly (following SC dose escalation from 3 mg) as a first-line therapy in 41 patients with symptomatic CLL, with an extended treatment period of up to 18 weeks (Lundin et al, 2002). The ORR among 38 evaluable patients was 87% (19% CR, 68% PR), and no apparent difference in response rates was observed among patients with advanced stage disease (81% ORR, 22% CR). However, CR was observed only among patients with minimal (<2 cm nodes) or no lymphadenopathy (Lundin et al, 2002). Consistent with the pivotal trial among relapsed/refractory patients, response rates by disease site showed significant clearance of malignant cells in the peripheral blood (95% CR) and bone marrow (45% CR, 21% nodular PR) while response was reduced in the lymph nodes (29% CR). Among patients who responded to alemtuzumab therapy, cumulative ORR by treatment duration and disease site suggested that although 12 weeks of therapy with SC alemtuzumab clears disease in the peripheral blood and lymph nodes (100% and 69% respectively), up to 18 weeks of therapy may be required to maximize response in the bone marrow (45% ORR at 12 weeks vs. 100% at 18 weeks) (Lundin et al, 2002). In a long-term follow-up analysis of the patients who responded to alemtuzumab therapy in this trial, the median time to treatment failure was 28 months (range 4 to 102+ months) (Karlsson et al, 2006).
Table II. Activity of single-agent alemtuzumab in first-line treatment of CLL.
|No. of patients||Rai stage III or IV disease, %||Median age, years (range)||Treatment regimen||Response rate, %||Median response duration, months (range)||Median OS, months||Reference|
|149||34||60 (35–86)*||IV alemtuzumab 30 mg TIW (up to 12 weeks)||ORR, 83 CR, 24||NR (not yet available)||NR (not yet available)||Hillmen et al (2007)|
|41 (38 evaluable)||68||66 (44–75)||SC alemtuzumab 30 mg TIW (up to 18 weeks)||ORR, 87 CR, 19||TTF 28 for all (4–102+); 32 for responders (7–102+)||NR||Lundin et al (2002)Karlsson et al (2006)|
A recent phase 3 randomized study evaluated alemtuzumab versus chlorambucil in first-line treatment of 297 patients with progressive CLL. Patients in the alemtuzumab arm received IV alemtuzumab 30 mg three times weekly for up to 12 weeks (Hillmen et al, 2007). The results from this study showed significantly superior response rates for alemtuzumab compared with chlorambucil (ORR 83% vs. 56%; P < 0·0001 and CR rates 24% vs. 2%; P < 0·0001), and confirmed earlier efficacy results of first-line SC alemtuzumab therapy. On the basis of the phase 3 study results, the Federal Drug Administration (FDA) approved single agent alemtuzumab for first-line treatment of CLL.
As expected, infusion-related reactions were common with first-line IV alemtuzumab therapy, but most reactions were mild, with grade 3/4 reactions in only 14% of patients (Hillmen et al, 2007). Although the precise mechanism for infusion-related events is still unclear, it is believed that events such as fevers and rigors can be attributed to the intense cytokine release that occurs with IV administration of alemtuzumab. The most common grade 3 or 4 treatment-emergent adverse events were haematological toxicities, with grade 3 or 4 neutropenia and thrombocytopenia reported in 42% and 18% of patients respectively. The incidence of febrile neutropenia, however, was only 5% with IV alemtuzumab, which was comparable to the 3% incidence observed in the chlorambucil arm. Grade 3 or 4 infectious events occurred in 16% of patients (grade 3 in 15%) treated with alemtuzumab, with an additional 2% experiencing grade 3 or 4 CMV infection. The overall incidence of symptomatic CMV reactivation was 11%, which was similar to the 10% incidence reported with first-line SC alemtuzumab (Hillmen et al, 2007). In the phase 2 study of first-line therapy with SC alemtuzumab, infusion-related reactions (except for fever and local injection site reactions) were substantially reduced compared with IV delivery (Lundin et al, 2002). Reduced infusion reactions may be attributed to slower rate of absorption and accumulation in plasma. The incidence of severe haematological toxicities with SC alemtuzumab was similar to that seen with IV administration of alemtuzumab, and no patients developed febrile neutropenia. Interestingly, in the study with first-line SC alemtuzumab therapy, no bacterial infections grade >1 were noted, and only one case of severe fungal infection (Pneumocystis jiroveci pneumonia) was observed in a patient who could not tolerate anti-infective prophylaxis (Lundin et al, 2002). Although IV and SC delivery of alemtuzumab induce similar response rates, the toxicity profile is improved with the SC route because of the reduced incidence of common infusion-related reactions associated with IV administration.
The potential use of alemtuzumab in combination with chemotherapy in CLL was first indicated in a small study that treated patients who were refractory to single-agent therapy with both fludarabine and alemtuzumab (Kennedy et al, 2002). In this study, five of six patients treated with this combination achieved a response to therapy. These findings have been confirmed in larger studies treating patients with relapsed and/or refractory CLL (Table III) (Elter et al, 2005; Sayala et al, 2006). In a phase 2 trial of 36 patients, evaluating the activity of fludarabine and alemtuzumab administered concurrently on the first 3 d of a 4-week cycle, for up to six cycles (FluCam regimen), the ORR was 83% (30% CR, 53% PR), and six of the nine fludarabine-refractory patients and three of the four patients who had received prior alemtuzumab responded to combination therapy. The median OS for all patients was 35·6 months and has not yet been reached for patients achieving a response (Elter et al, 2005). Of note, among patients with autoimmune haemolysis (n = 7) or transfusion-dependent thrombocytopenia and/or anaemia (n = 9) prior to study initiation, all cases resulted in resolution of cytopoenia and independence from transfusions following therapy with alemtuzumab. Infusion-related reactions were the most common adverse events seen with FluCam treatment and were primarily grade 1 or 2 in severity and occurred during the initial infusions with alemtuzumab (Elter et al, 2005). Grade 3 or 4 haematological toxicities included leucopenia in 44% of 140 assessable treatment cycles, thrombocytopenia in 30% and neutropenia in 26%. Major infections (grade 3 or 4) were observed in 11% of patients, including two cases of grade 3 CMV reactivation. The incidence of symptomatic CMV reactivation (6%) was low, considering that 80% of patients were CMV-seropositive prior to treatment (Elter et al, 2005). Based on these promising results, a randomized, prospective, phase 3 study is currently under way comparing the efficacy and safety of FluCam with fludarabine. In another phase 2 study, in which single-agent SC alemtuzumab (30 mg three times weekly after dose escalation) was administered, patients with suboptimal responses (i.e., progressive disease at week 6 or stable disease at week 12) were eligible to receive alemtuzumab in combination with oral fludarabine (Cam Flud regimen) (Sayala et al, 2006). In the final analysis of 49 evaluable patients, alemtuzumab monotherapy (median duration, 18·8 weeks) produced an ORR of 45% (14% CR, 31% PR), which included five minimal residual disease (MRD)-negative CRs and one MRD-negative PR (in a patient who had persistent cytopenia). The combination regimen with CamFlud was administered to 17 patients, with a final ORR of 49% (16% CR) (Table III) (Sayala et al, 2006).
Table III. Activity of combination therapy with alemtuzumab combination therapy in relapsed/refractory CLL.
|No. of patients||Median no. of prior therapies (range)||Flu-refractory, %||Median age, years (range)||Treatment regimen||Response rate, %||Median time-to-progression, months||Median OS, months||Reference|
|36||2 (1–8)||25||61 (38–80)||Flu 30 mg/m2 IV, days 1–3 + alemtuzumab IV 30 mg days 1–3 of 4-week cycle, up to six cycles (FluCam)||ORR, 83 CR, 30||13 for all; 22 for patients with CR||36 for all; not reached for patients with CR||Elter et al (2005)|
|50 (49 evaluable)||NR||100||64 (41–79)||Alemtuzumab SC 30 mg TIW monotherapy; if PD at week 6 or SD at week 12, alemtuzumab SC 30 mg TIW + Flu oral 40 mg/m2 days 1–3 every 4 weeks (CamFlud)||Monotherapy: ORR, 45 CR, 14 MRD(−) CR, 10 CamFlud (addition of Flu in n = 17): ORR, 49 CR, 16||NR||21 for all; 25 for responders; 13 for no response||Sayala et al (2006)|
|39 (20 evaluable)||1||NR||64 (48–78)||Flu 25 mg/m2 IV, C 200 mg/m2 IV, alemtuzumab SC 30 mg on days 1–3 every 28 d for up to six cycles||ORR, 70 CR, 25||NR||NR||Elter et al (2008)|
|74||3 (1–6)||43||58 (39–79)||C 250 mg/m2 IV (days 3–5), Flu 25 mg/m2 IV (days 3–5) Alemtuzumab 30 mg IV (days 1, 3 and 5) Rituximab 375–500 mg/m2 (day 2), every 28 d for up to six cycles||ORR, 65 CR, 24||26||19||Wierda et al (2006)|
The combination of fludarabine (F), cyclophosphamide (C) and alemtuzumab (Cam), the FCCam regimen, was evaluated in a recent phase 2 study. Thirty-nine patients with relapsed/refractory CLL received the FCCam regimen (F 25 mg/m2 IV, C 200 mg/m2 IV, alemtuzumab 30 mg SC given on days 1–3 every 28 d for up to six cycles). Of the 20 evaluable patients, the ORR was 70% (CR 25%, PR 45%). All patients with CR became MRD-negative (Elter et al, 2008). The FCCam regimen appeared to be highly effective in reducing bulky lymph nodes (>5 cm) (T. Elter and M. Hallek, unpublished data). The most serious side effects were thrombocytopenia and neutropenia. Infectious events included two CMV reactivation, one Herpes zoster reactivation and 12 fever of unknown origin (Elter et al, 2008).
The combination of cyclophosphamide, fludarabine, alemtuzumab and rituximab (CFAR) has been evaluated in previously treated CLL patients (Wierda et al, 2006). The CFAR regimen consisted of C 250 mg/m2, days 3–5; F 25 mg/m2, days 3–5; alemtuzumab 30 mg IV days 1, 3 and 5, and rituximab 375–500 mg/m2 day 2, repeated every 28 d for up to six cycles. Of 74 patients who completed treatment, the ORR was 65% and CR was achieved in 24% of patients. CFAR was active in patients with 17p deletion (ORR 44%) and in patients who had prior chemoimmunotherapy [CR 19%, PR 37% in 43 patients previously treated with fludarabine, cyclophosphamide and rituximab (FCR)]. Median survival was 19 months for all patients, >35 months for patients with CR, 18 months for patients with PR, and 7 months for non-responders. Residual disease in bone marrow was assessed in all patients using two-colour flow cytometry. Of 18 patients with CR, all were free of residual disease (Wierda et al, 2006).
MRD eradication and consolidation therapy with alemtuzumab
A patient with morphological CR may still have considerable residual disease and the presence of residual malignant cell clones because of suboptimal therapy probably underlies eventual disease relapse. Moreover, clonal selection by suboptimal therapy may result in enrichment of clones with resistant genotype (such as 17p deletion), leading to eventual chemoresistance. For example, in patients relapsing after FCR therapy, the frequency of 17p deletion was 24%, much higher than that in the overall patient population (7%) (Tam et al, 2008). Therefore, there is considerable interest in using agents that could further decrease or eliminate residual disease. Recent developments of sensitive four-colour flow cytometry technology make it feasible to detect small numbers of residual CLL cells (detection limit: one in 104–105 leucocytes) in bone marrow specimens. The presence of residual CLL cells (MRD-positive) in bone marrow of patients achieving CR was associated with significantly decreased event-free survival and OS, compared with patients with CR who were MRD-negative (Rawstron et al, 2001). Therefore, in CLL as in other haematological malignancies, the goal of therapy should be to effectively eliminate MRD, which may be of particular relevance to certain patient subgroups, such as patients with high-risk cytogenetic profiles.
In a study of 91 heavily pretreated patients with relapsed and/or refractory CLL, alemtuzumab was administered until maximum response (including MRD negativity) (Moreton et al, 2005). Compared with previously published trials of alemtuzumab in patients with relapsed and/or refractory disease, this trial had a relatively low enrolment of patients (12%) with bulky lymphadenopathy (>5 cm lymph nodes). MRD was evaluated using sensitive four-colour flow cytometry of blood and bone marrow (Rawstron et al, 2001). After a median of 9 weeks of treatment, the ORR was 54% (35% CR), with MRD-negative remission achieved in 20% of patients (Table I) (Moreton et al, 2005). Importantly, 18% of the purine analogue-refractory patients achieved an MRD-negative remission, and the ORR in this traditionally difficult-to-treat subgroup was 50%. As expected, none of the patients with bulky lymphadenopathy achieved CR or MRD negativity. Patients with MRD-negative remission had significantly longer treatment-free survival (P < 0·0001) and OS (P = 0·0007) (Fig 1A and B) suggesting that achievement of MRD negativity may translate into prolonged remission duration and improved survival (Moreton et al, 2005). These findings suggest that MRD assessment may be more important than achievement of CR in evaluating response to therapy. Toxicities were similar to those reported in other trials of patients with relapsed and/or refractory CLL treated with alemtuzumab, including transient infusion-related reactions (fever or rigors in 76%; grade 3 or 4 in only 13%), common haematological toxicities (grade 3 or 4 neutropenia in 48%; thrombocytopenia in 46%), and major infections in 24% of patients. Of 149 patients treated upfront with alemtuzumab, 11 patients achieved a MRD-negative CR and 25 patients achieved a MRD-positive CR. PFS was longer in patients with a MRD-negative CR than in patients with a MRD-positive CR (Hillmen et al, 2007). The CFAR combination regimen was also evaluated for MRD response in previously untreated patients. Of 21 evaluable patients, 15 patients (71%) had a CR, one patient (5%) had nodular PR (nPR) and four patients (19%) had a PR. All patients with CR or nPR and three of four patients with PR achieved MRD-negative response (Wierda et al, 2007).
Figure 1. Kaplan–Meier analyses for (A) treatment-free survival (TFS) and (B) overall survival (OS) in patients with relapsed and/or refractory chronic lymphocytic leukaemia treated with single-agent alemtuzumab. (A) Median TFS was significantly increased in patients achieving minimal residual disease (MRD)-negative response (not reached) compared with patients with MRD-positive complete response (CR) (20 months), partial response (PR) (13 months), or no response (6 months) (P < 0·0001). (B) Median OS was significantly increased in patients with MRD-negative response (not reached) compared with patients with MRD-positive CR (60 months), PR (70 months), or no response (15 months) (P = 0·0007). (Reprinted from Moreton et al, 2005, with permission from the American Society of Clinical Oncology.)
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Alemtuzumab has also been evaluated as consolidation therapy to eliminate MRD in patients responding to induction chemotherapy. As single-agent alemtuzumab has reduced activity in the lymph node compartment, initially debulking the tumour load with chemotherapy agents may optimize the activity of alemtuzumab and improve the initial response to chemotherapy while eliminating MRD. As summarized in Table IV, consolidation therapy with alemtuzumab improves the quality of remission and allows a substantial proportion of patients to achieve MRD negativity (O’Brien et al, 2003a,b; Wendtner et al, 2004; Montillo et al, 2006).
Table IV. Activity of alemtuzumab as consolidation therapy in CLL.
|No. of patients||Prior therapy||Induction chemotherapy||Response to induction chemotherapy||Alemtuzumab consolidation regimen||Response to alemtuzumab consolidation therapy||Reference|
|58 (49 evaluable)||Median 2 prior lines of therapy (range 1–7) ||Not specified||7 CR 19 nPR 32 PR||10 or 30 mg IV three times weekly for 4 weeks; if persistent MRD, four additional weeks of 30 mg||9 nPR improved to CR; 12 PR improved to nPR or CR; 11 MRD-negative responses among 29 patients assessed||O’Brien et al (2003a,b)|
|21||No prior therapy||Flu 25 mg/m2 IV, days 1–5 of 4-week cycle; or Flu 30 mg/m2 IV + C 250 mg/m2 IV days 1–3 of 4-week cycle (up to six cycles)||Alemtuzumab: 1 CR 10 PR Observation: 2 CR 2 nPR 3 PR 3 PD||30 mg IV three times weekly (up to 12 weeks)||3 CR 8 PR* 5 MRD-negative responses among six patients assessed||Wendtner et al (2004)|
|34||No prior therapy||Flu 25 mg/m2 IV, days 1–5 of 4-week cycle; or Flu 25 mg/m2 IV + C 250 mg/m2 IV days 1–3 of 4-week cycle|| 12 CR 7 nPR 15 PR||10 mg SC 3 times weekly for 6 weeks||27 CR (19 MRD-negative) 4 nPR 3 PR||Montillo et al (2006)|
Consolidation therapy with alemtuzumab improved responses in 53% of patients (among 49 evaluable), including MRD-negative responses in 11 of 29 evaluable patients (38%) as assessed by patient-specific polymerase chain reaction (PCR) assay (O’Brien et al, 2003a,b). The most common adverse events were infusion-related toxicities that were all grade 1 or 2 in severity. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 30% and 14% of patients respectively. Infections occurred in 37% of patients, including CMV reactivation in 22% (O’Brien et al, 2003b) and three patients developed Epstein–Barr virus-positive large cell lymphoma, which resolved without chemotherapy in all three cases.
In a comparative phase 3 trial conducted by the GCLLSG, 21 patients were randomized to receive observation or alemtuzumab consolidation therapy following first-line fludarabine-based induction therapy. The 11 alemtuzumab-treated patients were more likely to achieve MRD-negative remissions (five of six patients assessed) compared with observation-only patients (0 of three patients assessed) (Wendtner et al, 2004). After a median follow-up of 31·3 months from start of first-line treatment, only one relapse had occurred in the alemtuzumab arm compared with seven in the observation-only arm (Fig 2). Infusion-related toxicities were common among the patients receiving alemtuzumab but were grade 1 or 2 in severity in all cases. This GCLLSG trial was halted early because of a high incidence of severe infectious events in the consolidation arm, which included seven grade 3 infections and one case of grade 4 pulmonary aspergillosis. The GCLLSG study was reopened as a dose-finding phase 1 and 2 trial to evaluate the optimal dosing regimen with consolidation therapy.
Figure 2. Progression-free survival (PFS) in the randomized phase 3 study of the German CLL Study Group. Median PFS was significantly prolonged among patients randomized to receive alemtuzumab consolidation therapy (n = 11) compared with patients who were under observation only (n = 10) (not reached versus 27·7 months; P = 0·033).
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Patients up to 65 years of age with MRD following initial response to first-line fludarabine-based therapies were treated with alemtuzumab 10 mg SC three times weekly for 6 weeks (Montillo et al, 2006). Following alemtuzumab consolidation, the quality of remission was improved in (53%) and the CR rate improved from 35% to 79% after induction therapy) and an MRD-negative CR was achieved in 56% of patients. Peripheral blood stem cells (PBSC) were successfully harvested in 92% of the 26 patients undergoing stem cell collection. Among 18 patients who underwent SCT, 17 remained in CR at 14·5 months after transplantation. In addition, nine patients (eight CR, one PR) who did not undergo SCT remained progression-free at a median follow-up of 17 months (Montillo et al, 2006). The use of alemtuzumab as consolidation therapy after fludarabine-based induction did not compromise PBSC collection and engraftment and is therefore feasible for patients undergoing autologous SCT. First-dose reactions were primarily grade 1 or 2 in severity, and only one grade 3 rash and one grade 3 fever were reported. Notably, no bacterial or fungal infections occurred in this study; although there were 18 cases of CMV reactivation, active infections were prevented in all cases by prompt ganciclovir treatment (n = 15) or by spontaneous resolution (n = 3). One patient with an MRD-negative CR died because of Richter’s transformation.
Alemtuzumab in CLL patients with high-risk cytogenetics
Cytogenetic studies using fluorescence in situ hybridization (FISH) analysis with chromosome-specific DNA probes have demonstrated that genetic abnormalities are present in approximately 80% of patients with active CLL, even among those with previously untreated disease (Dohner et al, 2000; Dewald et al, 2003). The most common chromosomal abnormality in CLL is monoallelic 13q deletion; followed by 11q deletion, 12q trisomy, and 17p deletion, with many patients having more multiple chromosomal abnormalities. Patients with deletions to chromosome 17p, including the tumour suppressor gene TP53, have the worst prognosis, with rapid disease progression (median 9 months from diagnosis) and significantly decreased OS (median 32 months from diagnosis) compared to patients with other genetic abnormalities or normal cytogenetics (Dohner et al, 2000). In studies evaluating various prognostic factors in a multivariate regression model, the presence of 17p deletion emerged as a strong predictor of decreased OS, independent of the immunoglobulin heavy chain variable region (IGHV) mutational status (Krober et al, 2002, 2006; Oscier et al, 2002). The outcomes were very similar among patients with Binet stage A disease, providing evidence of the significant negative impact of high-risk genetic abnormalities on survival outcomes even in patients with early stage CLL.
Several large, independent clinical studies have demonstrated that 17p deletion predicts for significantly decreased response rates, PFS and/or OS in patients with CLL receiving first-line fludarabine-based regimens (Byrd et al, 2006; Catovsky et al, 2007; Grever et al, 2007). Gene expression profiling suggests that fludarabine induces a p53-dependent response in CLL cells (Rosenwald et al, 2004), and resistance to fludarabine therapy is associated with dysfunctional p53. In contrast, alemtuzumab has considerable efficacy in patients with high-risk cytogenetic profiles and is capable of inducing responses in patients with relapsed and/or refractory CLL regardless of 17p deletion or TP53 mutation status (Stilgenbauer & Dohner, 2002; Lozanski et al, 2004; Osuji et al, 2005). Further, preliminary data from the CamFlud trial suggested that alemtuzumab-based therapy can induce MRD-negative CRs even among fludarabine-refractory CLL patients with 17p deletions (Sayala et al, 2006). Collectively, these studies point to the potential benefit of a risk-stratified treatment approach in CLL. Pending results of larger, prospective trials, alemtuzumab-based therapy represents a rational choice for the first-line treatment of CLL patients with 17p deletion and may be useful in other high-risk cytogenetic abnormalities.