Monoclonal antibody therapy of chronic lymphocytic leukemia

Abstract

Cure of patients with chronic lymphocytic leukemia (CLL) has been an elusive goal. The recent availability of active monoclonal antibodies has rekindled enthusiasm for new and innovative therapeutic approaches. Alemtuzumab, induces responses in about a third of patients with relapsed or refractory CLL following therapy with fludarabine and an alkylating agent. Whereas, rituximab has limited activity in previously treated patients, response rates of 50–70% have been reported in those without prior therapy. Recent data on combinations with rituximab and chemotherapy have shown promise for improving patient outcome. Newer antibodies in development include the primatized monoclonal antibody lumiliximab (IDEC-152), directed against CD23. Other biological approaches include the use of antisense oligonucleotides, proapoptic small molecules, and vaccines directed against the malignant B cells. The rational development of combinations of these promising approaches may eliminate the need for chemotherapy, leading to safer and more effective approaches for patients with CLL.

Introduction

Despite decades of clinical trials, chronic lymphocytic leukemia (CLL) remains an incurable disorder. Fludarabine induces higher response rates than alkylating agents, which are also more durable; however, evidence for a prolongation of survival is lacking [1, 2]. Thus, more effective therapies are clearly needed. Moreover, chemotherapy is associated with a number of untoward effects including myelosuppression, immunosuppression resulting in opportunistic infections and secondary malignancies.

The concept of an immune approach to therapy of infectious diseases and, potentially malignancies, dates back more than a century ago to the work of Paul Ehrlich, the founder of modern immunology. He theorized a “magic bullet”, predicting the possibility of a monoclonal antibody that was capable of killing tumor cells with limited the damage to normal body tissues [3]. The first trials of monoclonal antibodies in B-cell malignancies dates back over 20 years following the identification of B-cell surface antigens. Early studies identified a signal of activity in non-Hodgkinȁ9s lymphomas (NHL) [4–6]. However, it took almost 2 decades until the availability of humanized or human antibody preparations were available, and for hybridoma technology to permit the generation of sufficient quantities of antibodies for large-scale clinical trials [7]. As a result, there is an ever increasing list of monoclonal antibodies being evaluated in CLL (Table 1).

Table 1.

Unconjugated monoclonal antibodies for CLL

Antibody	Target	Status in US
Alemtuzumab (campath)	CD52	Commercial
Rituximab (rituxan)	CD20	Commercial
Lumiliximab (IDEC-152)	CD23	Phase I
hA20s	CD20	Phase I
Bevacizumab (avastin)	VEG-F	Phase II

Anti-CD5 monoclonal antibodies

Chronic lymphocytic leukemia cells are characterized by the expression not only of the B-cell antigens CD19 and CD20, but also CD5, CD23, and CD52. This characteristic phenotype makes these cells excellent targets for monoclonal antibody therapy. One of the earliest antibodies in CLL clinical trials was T101, which was directed against the CD5 antigen. Unfortunately, this antibody, when used either unconjugated or conjugated to an immunotoxin or radioisotope, was abandoned for further clinical study because of its limited activity with excessive toxicity [8–11]. Early trials with antiidiotype antibodies were also disappointing [12, 13].

Alemtuzumab (CAMPATH-1H)

Alemtuzumab was the first monoclonal antibody approved by regulatory agencies for the treatment of CLL. Alemtuzumab is a humanized antibody that targets the CD52 antigen. CD52 is expressed on virtually all lymphocytes at various stages of differentiation, as well as monocytes, macrophages, and eosinophils [14]. The only other site of expression is the male reproductive tract. The highest levels of expression of CD52 appear to on T-prolymphocytic leukemia (PLL) cells, followed by B-CLL, with the lowest levels expressed on normal B cells [15]. Hematopoietic stem cells, erythrocytes, and platelets do not express this antigen and, therefore, they should be spared from direct antibody effects.

The first anti-CD52 antibodies were isolated in the 1980s in an attempt at identifying antibodies that could kill T cells by activating human complement. An IgM antibody was initially selected (CAMPATH-1M), followed by CAMPATH-1G, a murine derivative [16] demonstrated clinical activity in refractory CLL even in patients who had failed CAMPATH-1M. Alemtuzumab (CAMPATH-1H, the humanized antibody) was subsequently found to be effective and was brought to widespread clinical trials. The mechanisms of action of alemtuzumab include complement mediated cytotoxicity, antibody dependent cellular cytotoxicity, and induction of apoptosis [17].

Dose and schedule of administration

The optimal dose and schedule of alemtuzumab administration remains to be defined. The currently recommended dose and schedule was determined by several I/II studies in which alemtuzumab was administered from once to 10 days using doses that ranged from 0.5 mg to 80 mg [18]. Activity was observed in patients with rheumatoid arthritis; however, the associated lymphopenia was of concern to rheumatologists, limiting enthusiasm for further development. This same observation stimulated the interest of hematologists/oncologists in exploring this agent in lymphoid malignancies. In these initial studies, there were 175 NHL patients entered including 36 with CLL. While 25–80 mg could be safely delivered in the absence of premedication, subsequent clinical trials have included premedication with diphenhydramine, and acetaminophen, along with prophylaxis for pneumocystis carinii and herpes.

The currently approved schedule of alemtuzumab involves a dose of 3 mg delivered on day 1, escalating to 10 mg on day 2 and then to 30 mg three times weekly as soon as the infusion related reactions are tolerable. The duration of therapy generally lasts 12 weeks, although some studies suggested that additional benefit may be achieved with longer treatment duration [19].

Alemtuzumab is associated with important clinical activity in patients with CLL [19–27] (Table 2). In one of the initial studies, Ósterborg et’al. [19] reported a phase II study in previously treated patients with CLL only three of whom had received prior fludarabine. The response rate was 42%, with 4% complete remission (CR). The likelihood of disease eradication varied with the site of involvement; CLL cells were rapidly cleared from the blood of 97% of patients, while the bone marrow became normal in 36%, with a reduction in splenomegaly in 32%. The median duration of response was 12 months [6–25+].

Table 2.

Alemtuzumab in CLL

Investigator [ref.]	Pts	Prior theraphy	CR (%)	RR (%)
Österborg [19]	29	+	4	42
Bowen [20]	6	+	50	50
Rawstron [21]	17	+	50	70
McCune [24]	13	+	31	46
Stilgenbauer [27]	11	+	18	55
Rai [26]	136	+	2	33
Keating [22]	92	+	7.4	39.8
Österborg [23]	11	−	33	89
Lundin [25]	41	−	19	87

The data that led to the approval of alemtuzumab by regulatory agencies were primarily derived from a pivotal trial that included 93 patients, who had failed prior therapy with fludarabine and who had also received an alkylating agent [22]. Patient characteristics included a median age of 66 years, 76% with Rai stage II or IV disease, and a median of 4.1 months from the previous therapy. Almost half of the patients had never responded to nucleoside analog therapy. The response rate was 33%, including 2% CR. In addition, six patients had clearing of CLL from all sites, but with persistent anemia or thrombocytopenia that improved on long-term follow-up. The median time to response was 1.5 months. The likelihood of response was inversely related to lymph node size: while 74% of those with adenopathy responded including 27% complete responders, 64% of lymph nodes 0–<2 cm completely resolved, but only 15% of those 2–<5, and none >5 cm. The median duration of response was 8.7 months with a median survival of 16 months, 32 months in responders. Infections occurred in 55% of patients during the study, which were mild to moderate in 26, and severe or life-threatening in 25. Of concern was the reactivation of cytomegalovirus (CMV) in seven patients. Causes of death included progressive disease in 37 patients, two due to autoimmune hemolytic anemia or immune thrombocytopenia, and infection in 17 patients.

Rai et’al. [26] reviewed the data from a compassionate use protocol including 136 heavily pretreated, fludarabine refractory patients, which confirmed the safety and efficacy of this agent in a broad community setting. Overall 39.8% of patients responded, with 7.4% CR and a median time to progression of 7.3 months for the responders.

Toxicities of alemtuzumab

The major toxicities of alemtuzumab can be distinguished into those that are immediate and others that are more delayed. Despite premedication with acetominophen and diphenhydramine in the pivotal trial, infusion of this antibody was associated with rigors in 90% of patients, that were grade III in 14%; fever was noted in 85% (17% grade III, 3% grade IV), grade I or II nausea in 53%, vomiting in 38% (1% grade III), while a third of patients experience a mild to moderate rash [22]. These adverse events tend to decrease in frequency and severity over the subsequent weeks of treatment. Because of the risk of opportunistic infections, patients also received prophylactic antimicrobial therapy with trimethoprim sulfamethoxazole and acyclovir or famciclovir. Despite administration of these agents, at least one infection occurred in 55% of these patients, which were severe or life-threatening in 27% of patients. CMV reactivation was detected in seven patients and Herpes simplex in six. Opportunistic infections occurred in 11 patients during treatment and an additional seven events during follow-up. Nevertheless, patients who responded to therapy tended to experience fewer Infections. Results from the compassionate use experience were similar in that 32% of patients experienced at least one infection that were fatal in two of them [26]. The frequency of infections in relapsed and refractory patients appears to be lower than with fludarabine in a similar patient group [28].

In an attempt at reducing the acute adverse events, Lundin et’al. [25] administered the antibody by the subcutaneous route to 41 patients with previously untreated, advanced CLL requiring treatment. The response rate was 87% including 19% complete remissions; however, most responses occurred after 18 weeks of therapy as a result of the more delayed attainment of serum levels by this route [29]. Although 90% of patients experienced local injection site reactions, most were only grades I–II in severity, with a single grade III toxicity, and these reactions generally disappeared within 2 weeks despite continued therapy. Three patients withdrew from study within the first week because of the local reactions. Of note was that the infusional reactions were relatively mild, with only 17% of patients experiencing rigors. More serious reactions were not reported. Recently, the German CLL Study Group presented an interim analysis of their trial of subcutaneous alemtuzumab in previously treated patients [30]. The response rate of 36% with 2% complete remissions is comparable to the pivotal trial using the intravenous preparation [22]. The Cancer and Leukemia group B (CALGB) conducted a phase II study of fludarabine for 4 months followed by subcutaneous alemtuzumab for 6 weeks [31]. The investigators concluded that the activity of alemtuzumab by the subcutaneous route was lower than their previous experience with a similar study design in which the alemtuzumab was given intravenously [32]. The explanation for this observation is not clear, but may reflect an effect of the differences in pharmacokinetics of the two routes given the short course of antibody therapy [29].

Alemtuzumab combinations and sequences

Alemtuzumab has been combined with other active agents including fludarabine. Kennedy et’al. [33] combined alemtuzumab with fludarabine in six patients with refractory diseases, who had failed a median of eight courses and 12 weeks of either agent, respectively. Five patients responded to the combination, including one CR. Long-term follow-up of those cases is not available. More recently, Elter et’al. [34] reported a combination of these two drugs given on days 1–3 monthly for up to six cycles. The overall response rate in the first 34 patients was 85% with 29% complete remissions. Using four-color flow cytometry, the absence of minimal residual disease in the peripheral blood was noted in 44%. CMV reactivation was detected in two patients, one of whom died of bacterial sepsis; two other patients developed fungal pneumonia.

Several groups have delivered alemtuzumab after other chemotherapy to try to eradicate minimal residual disease (MRD). CALGB investigators treated patients with four cycles of fludarabine; alemtuzumab was delivered after a 2-month hiatus to patients with stable disease or better [32]. Disappointing response rates following fludarabine of 4% CR and 52% PR, were probably related to the reduced number of courses. However, following alemtuzumab, the response rate increased to 42% CR and 50% PR. Unfortunately, infections with CMV occurred in eight patients during or within 4 months of alemtuzumab, with one fatality. In their subsequent trial substituting subcutaneous alemtuzumab [31], three of 18 evaluable patients experienced reactivation of CMV, with no deaths from that infection. Four of eight partial responders after fludarabine became complete responders after alemtuzumab, while four of ten patients with stable disease improved to a partial response. The overall complete response rate was 18%, which was lower than the 42% noted above using intravenous alemtuzumab. Montillo et’al. [35] demonstrated that stem cell transplantation could successfully be performed in patients in whom alemtuzumab following chemotherapy had eradicated MRD (51%). They used an escalating schedule of alemtuzumab up to 10 mg three times a week, starting at least 8 weeks after fludarabine. This schedule was associated with CMV reactivation in 57%. Oȁ9Brien et’al. [36] demonstrated an improved response rate with fewer patients with MRD following the alemtuzumab consolidation; but, three patients developed a large cell NHL as a result of this therapy. In a randomized trial, patients treated with either fludarabine or fludarabine plus cyclophosphamide were randomized to alemtuzumab or observation. There were only 212 evaluable patients because the study was stopped early when 7/11 randomized to antibody experienced a severe infection [37].

Moreton et’al. [38] reported on 91 previously treated patients, 44 of whom were refractory to purine analogs. Following treatment with a median of 9 weeks of alemtuzumab, there were 36% complete responses and 19% partial responses. Treatment free survival was significantly prolonged in patients with a molecular CR than in those with a clinical and morphological CR, but with persistent MRD, whose survival was comparable to those with a partial response. Moreover, overall survival was not yet reached for the MRD− complete responders, but was 84% at 60 months compared with a median of 60 months for the MRD+ complete responders, 70 months for the partial responders and 15 months for the nonresponders.

A combination of cyclophosphamide, fludarabine, alemtuzumab and rituximab has been studied; however, the data on the 21 evaluable patients are preliminary [39]. However, five of these patients experienced reactivation of CMV.

Predicting response to alemtuzumab

In contrast to therapy with alkylating agents and nucleoside analogs, responses to alemtuzumab can be achieved in patients with p53 gene mutations [27, 40], which confers resistance to nucleoside analog therapy [41], as well as in those with unmutated immunoglobulin VH genes, 11q- or 17p-cytogenetic abnormalities [30]. FcgammaRIIIA and RIIA polymorphisms do not appear to predict response [42]. Early disappearance of CLL cells from the peripheral blood also predicts bone marrow clearance [43].

Rituximab

Rituximab has revolutionized the approach to patients with a wide variety of B-cell malignancies because of its activity, noncross resistance with chemotherapy, and favorable safety profile [44]. Following the demonstration of its activity in NHL, it soon entered clinical trials for patients with CLL/small lymphocytic lymphoma (SLL), two entities similar enough to be considered as one diagnosis in the World Health Organization (WHO) classification [45]. Nevertheless, response rates were lower in patients with CLL/SLL (10–15%) than in the those with relapsed or refractory follicular NHL (46–58%) [44, 46–55] (Table 3). There is no clear explanation for this observation; however, it has been attributed to the low density of expression of CD20 on these cells. However, this finding does not entirely explain the higher response rates in previously untreated patients and, therefore, may also relate to the reduction by prior treatment of the number of residual effector cells needed for antibody dependent cellular cytotoxicity (ADCC).

Table 3.

Rituximab in CLL/SLL

Investigator [ref.]	Patients	Prior Tx	CR (%)	RR (%)
McLaughlin [45]	33	+	0	13
Maloney [48]	3	+	0	0
Nguyen [47]	15	+	0	7
Piro [49]a	7	+	0	14
Winkler [50]	9	+	0	11
Foran [51]	29	+	0	14
Huhn [54]	28	+	0	25
Byrd [53]b	33	±	3	45
Oȁ9Brien [52]c	40	+	0	36
Hainsworth [55]d	15	−	NA	57
Hainsworth [56]	21	−	90	19

^aEight infusions; ^bthree times weekly; ^cphase I dose escalation; ^dincludes SLL patients; NA not available

Response rates are significantly higher when rituximab is used in patients with CLL/SLL who have not been previously treated (Table 3). Hainsworth et’al. [54, 55] noted that the response rate of 70% in 24 patients with SLL was comparable to that in 38 patients with a follicular histology (76%); however, the time to disease progression following maintenance rituximab was longer in the NHL patients. In a subsequent study by the same investigators, 44 previously untreated patients with stage III or IV CLL were treated with single agent rituximab, and those achieving a response by the sixth week received an additional 4 weeks of the antibody every 6 months. The response rate was 58% including 9% CR. Thus, it appears that single agent rituximab is less effective in inducing complete and overall response rates, with less durable remissions than standard fludarabine in previously untreated CLL [2].

Neither increasing the dose or dose density of administration of rituximab has improved the benefit of rituximab in CLL. Byrd et’al. [52] treated 33 previously treated or untreated patients with a schedule of thrice weekly rituximab. Thirteen patients experienced transient hypoxemia, hypotension or dyspnea, and one patient discontinued therapy because of infusion related toxicity, despite a schedule of stepped-up dosing. The overall response rate was 45% including 42% partial responses. Four patients were considered inevaluable for response; one died on day 3 of a pulmonary hemorrhage, one of a septic arthritis during week 2, and another a month later from sepsis and a gastrointestinal bleed, the last developed immune thrombocytopenia and required alternative therapy. The overall median duration of response was 10 months, but it was only 6 months patients who had failed prior fludarabine. Moreover, the median time to progression was only 6 months. Higher response rates were obtained in previously untreated patients and in disease that was relapsed after fludarabine compared with patients whose CLL was refractory to that therapy.

In a phase I trial, Oȁ9Brien et’al. [51] escalated the dose of rituximab dose from 375 mg/m² to 2,250 mg/m² . The dose limiting toxicity had not been reached. There was no clear correlation between dose and response rate in patients with CLL. Thus, this expensive regimen is not sufficiently promising or cost-effective to warrant further study.

More encouraging results have been produced with the combination of rituximab and chemotherapy. Investigators from the CALGB [56] conducted a randomized phase II trial of concurrent and sequential fludarabine and rituximab with 51 and 53 patients per arm, respectively. The overall response rate in the concurrent arm was 90% including 47% CR, and, in the sequential arm, 77% with 28% CR. However, if anything, the disease-free and overall survival suggest a trend in favor of the sequential approach. Myelosuppression was greater in the concurrent than the sequential arm with grade III and IV neutropenia of 37% versus 18%, respectively. However, this observation did not translate into a clinically meaningful difference as there were opportunistic infections in eight patients in the concurrent arm and 14 on the sequential arm. This combination appeared to prolong survival compared with historical controls treated with fludarabine alone [57]. The CALGB investigators completed a subsequent trial of fludarabine and rituximab followed by alemtuzumab that is undergoing analysis.

Building on their experience with the combination of fludarabine and cyclophosphamide, Keating et’al. [58] used the combination of fludarabine, rituximab, and cyclophosphamide in 224 previously untreated patients. The regimen included six cycles of fludarabine at 25 mg/m², cyclophosphamide 250 mg/m², days 2–4 of cycle 1 and days 1–3 of cycles 2–6, with rituximab at 375 mg/m² on day 1 of cycle 1 and 500 mg/m², day 1 of cycles 2–6. The median age of the patients was 58 years, and only a third hade Rai stage III–IV disease. The complete remission rate was 70%, with 10% nodular PR, and 15% PR. At the time of the report, there were nine relapses, all of whom were alive. Grade 3 neutropenia occurred in 24% and grade 4 in 28% of patients, although only 2.6% of courses were associated with major infections. This regimen has also been reported in 127 previously treated patients, who had received a median of two prior therapies; only 21% were refractory to prior fludarabine [59]. The CR rate was 25% with 16% nodular PR and 32% PR. The CR rate was 33% in fludarabine-sensitive compared with 6% in fludarabine-refractory patients, with 19% and 9% nodular PRs, respectively. Whether FCR is superior to FR is a subject of considerable controversy. The patients in the CALGB study [56] were older and had more advanced disease than in the experience of Keating et’al. [58] (Table 4). Remaining questions that require prospective comparative trials include whether rituximab clearly adds to either F or FC alone, and, if so, how FR and FCR compare with one another. However, the former would be difficult to conduct in the US because of the increasing bias toward using rituximab as part of the initial therapy of CLL.

Table 4.

Fludarabine–rituximab (FR) versus fludarabine–cyclophosphamide–rituximab (FCR) in previously untreated CLL

Regimen	CR/ORRa (%)	Setting	Median (age)	Stage 0–II (%)
FR (57;58)	47/90	Coop group	63	61
FCR (59)	69/95	Single center	58	67

^aComplete remission/overall response rate

Rituximab has also been used successfully to treat the complications of CLL or its therapy, including pure red cell aplasia [60], and fludarabine induced immune thrombocytopenia [61].

The combination of the two antibodies Rituximab + alemtuzumab has been studied by several groups [62, 63]. Faderl et’al. [63] treated 48 patients; 32 with CLL, 9 with CLL/PLL, 1 with PLL, 4 with mantle cell lymphoma, and 2 with Richterȁ9s transformation. The overall response rate was 52%, with only 8% CR. The median time to progression was 6 months. More than half the patients experienced an infection, with reactivation of CMV in 27%. Nabhan et’al. [62] treated 12 patients with a single PR. Clearly, this regimen is not ready for general clinical use.

Rituximab toxicities

Although rituximab is considered to be relatively well tolerate, more than 90% of patients with NHL experience some infusion related reaction, that is generally mild to moderate in severity [44, 64]. However, patients with CLL and others with a markedly increased number of circulating malignant lymphocytes may be at an increased risk of more serious complications including respiratory insufficiency and a rapid tumor clearance syndrome [49, 65]. The latter differs from typical “Tumor Lysis Syndrome” in that, in the former, the abnormalities of potassium, calcium, and phosphorus tend to be milder, and renal insufficiency is generally not as severe [49, 65, 66]. This syndrome generally begins within 30–60 min of the initial infusion, and is characterized by a rapid disappearance of lymphocytes from the peripheral blood with marked increases in uric acid and LDH, along with fevers, rigors, dyspnea, hypoxia, and hypotension, and may progress despite interruption of the infusion. Thrombocytopenia has been common, with abnormal coagulation studies in several cases. In the event that such complications occur, infusion of the antibody should be immediately interrupted and the patient managed with hydration, allopurinol, oxygen, and bronchodilators. None of the patients who have received subsequent infusions of the antibody experienced a recurrence of this adverse event. Patients with high white blood cell counts should be considered for prophylactic hydration, allopurinol and, in some cases, alkalinization of the urine.

G3139 plus rituximab

G3139 (oblimersen sodium; Genta Incorporated, Berkeley Heights, NJ, USA) is the first antisense molecule to be widely tested in the clinic for the treatment of human tumors. Bcl-2 is overexpressed in cells from most patients with CLL, which may contribute to chemotherapy resistance. The phase I/II experience with oblimerson as a single agent demonstrated that this agent was well tolerated, although at doses lower than those used to treat patients with solid tumors, and showed evidence of activity [67]. In a recently reported phase III trial, the addition of oblimerson to fludarabine and cyclophosphamide in relapsed patients resulted in a significant improvement in complete remission/nodular PR rate [68]. In vitro data suggest a positive interaction with rituximab, and clinical trials of the combination are being conducted. A multicenter study conducted at the Lombardi Comprehensive Cancer Center, Roswell Park Cancer Institute and Long Island Jewish Hospital is currently testing the feasibility and activity of the combination of fludarabine, rituximab, and oblimerson in both previously untreated and previously treated patients with CLL [69].

Other antibodies under investigation

Anti-CD23

Since expression of CD23 is a characteristic feature of CLL cells, an antibody directed at this antigen is of interest. An anti-CD23 (IDEC-152; Lumiliximab) is a primatized monoclonal antibody, with strong similarity to the human antibody and no mouse component. The antibody inhibits IgE secretion in vitro and induces apoptosis of lymphoma cell lines. It binds complement and mediates ADCC by binding FcgammaRI and RII. In vitro data suggest a favorable interaction with rituximab [70]. The initial phase I trial with this agent included patients with progressive CLL, who had received a median of three prior regimens [71]. Toxicities included fatigue, nausea, and cough, with the dose limiting toxicities being neutropenia and headache. A reduction in the number of circulating lymphocytes occurred in 24 of 25 patients, while other experienced a reduction in lymph node size. A combination trial with rituximab, fludarabine and cyclophosphamide has been conducted and is being analyzed.

Bevacizumab

Data suggest a potential role for angiogenesis in CLL. Angiogenesis factors such as basic fibroblast growth factor (bFGF) upregulate bcl-2, delaying programmed cell death [72]. Bevacizumab is an anti-VEGF monoclonal antibody currently being evaluated in solid tumors and lymphomas [73–75]. This agent may also be of interest in CLL.

Radioimmunotherapy

The use of radiolabeled antibodies has expanded the therapeutic options for patients with NHL [76, 77]. However, radioimmunotherapy for the treatment of CLL has been limited by the frequent extensive bone marrow involvement. Lym-1 is a radioimmunoconjugate consisting of an I¹³¹ labeled mouse IgG kappa. The antibody recognizes a 31–35 kDa antigen presumed to be a polymorphic variant of the HLA-DR antigen, and thought to be specific for B cells, with a particular avidity for malignant B-cells [78–82]. Although responses were reported in patients with NHL and CLL, the failure to use standardized criteria for response made the data difficult to interpret. The future if this antibody is unclear. In a phase Ia, trial including ten patients, the naked antibody was well tolerated, but not active [83].

Y-90 ibritumomab tiuxetan and I-131 tositumomab are currently restricted to patients with less than 25% bone marrow involvement because of safety concerns. Nevertheless, Kaminski et’al. [84] reported their experience in 14 patients with SLL and a median of four prior regimens. Responses occurred in 64% of patients including 21% complete remissions. The median duration of response was 24.7+ months. Strategies are under development to reduce bone marrow involvement prior to RIT therapy.

The use of radioimmunotherapy in CLL is limited by the extent of bone marrow involvement. Thus, reducing the number of CLL cells in the bone marrow prior to radiotherapy by the administration of an agent that is effective in clearing the bone marrow, such as alemtuzumab, is a potentially interesting strategy.

Future directions

The increasing number of monoclonal antibodies active in the treatment of CLL provides promise that treatment for this disease may be moving from nonspecific cytotoxic agents to more specific biological therapies.

Recent advances in molecular technology may permit a more meaningful treatment selection based on specific targets. Other approaches being studied for the immunologic management of CLL include new, active proapoptotic small molecules [85], and vaccine therapy. Under experimental conditions, T cells isolated from patients with CLL can recognize and lyse allogeneic CLL cells demonstrating that these cells are functionally intact [86–89].

The availability of an expanding menu of monoclonal antibodies provides great promise for therapeutic advances in patients with CLL. Individually, these agents are unlikely to lead to significant outcome benefit. However, their ability to eliminate minimal residual disease may prolong survival of treated patients, thus providing an important goal for treatment strategies. The rational development of combinations of multiple antibodies directed at different targets, along with antisense oligonucleotides, proapoptotic small molecules, or other cytokines may provide a strategy that minimizes the dependency on chemotherapy while extending the lifespan of patients with CLL.