Based on the activity in the refractory and relapsed settings, Hainsworth and colleagues administered rituximab to previously untreated CLL patients. A total of 70 patients (39 with SLL and 31 with CLL) were treated with rituximab (375 mg/m2 weekly for 4 weeks) and then reevaluated at 6 weeks. Those with stable disease or an objective response were treated with maintenance rituximab using a standard 4-week schedule, every 6 months, for a maximum of 4 courses. At the time of the report, 57 patients were evaluable, with 44% having an objective response at 6 weeks (9% complete response), and 44% having stable disease. The median progression- free survival in these patients was 35 months. Table 2 summarizes the data of selected clinical trials using rituximab in CLL.[18-22,64]
Despite the evidence of activity of rituximab in CLL patients, there is a clear discrepancy between the high rate of response in follicular lymphoma patients compared with CLL patients. Several factors might contribute to this difference. Expression of CD20 on CLL cells is dim-only 20% to 30% of the level found in patients with follicular lymphoma. In fact, in a study reported by Nguyen and colleagues, the only responding patient had a higher expression of CD20 compared with the nonresponders.[ 23] In addition, soluble CD20 has been demonstrated in the plasma of patients with CLL. It can act as a sink for the antibody (especially with a higher circulating B-cell count), causing rapid clearance of rituximab and resulting in unfavorable pharmacokinetics. The common finding of splenomegaly in patients with SLL or CLL might affect rituximab pharmacokinetics as well.
Others have attempted treating autoimmune hemolytic anemia in CLL patients with rituximab in combination with cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar), and dexamethasone(Drug information on dexamethasone). All patients but one achieved normal hemoglobin levels, with a median duration of response in excess of 12 months. However, in their recent update, the same investigators reported that five of the eight responding patients suffered a relapse at a median of 13 months. Those five patients were re-treated with rituximab (375 mg/m2 on day 1), cyclophosphamide (750 to 1,000 mg/m2 on day 2), and 12 mg of dexamethasone given intravenously on days 1 and 2, and orally on days 3 through 7. Cycles were repeated every 4 weeks until the best achievable response was obtained. All five patients achieved a second remission with a median duration of response of 7+ months at the time of the report.
In general, rituximab has been very well tolerated. Side effects are typically confined to the infusion period, and many investigators have described a "cytokine-release syndrome" characterized by fever, chills, nausea, vomiting, hypotension, and occasionally dyspnea.[15,28] Byrd and colleagues noted that these side effects were increased in older patients, and that these reactions were associated with elevated serum levels of inflammatory cytokines, including interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNFalpha), and interferon-gamma. Although it is controversial, some investigators have suggested that because this syndrome occurs more frequently during the initial infusion and the high circulating white cell count contributes significantly to the ele- vated cytokine levels,[18,20] this might explain why some patients have developed tumor lysis syndrome with rituximab.
However, tumor lysis syndrome is rarely seen with classic CLL, and most cases have been associated with the leukemic phase of mantle cell lymphoma or prolymphocytic leukemia. Premedicating with steroids during the first cycle or beginning with a 2-day infusion (100 mg of rituximab on day 1 and the remainder on the following day) may minimize this problem. After completion of therapy with rituximab, long-term complications are unusual, with the most common adverse effect being B-cell depletion, lasting 6 to 9 months.
From a practical point of view, the majority of patients receive rituximab at an infusion rate starting at 50 mg/h, and are premedicated with acetaminophen and diphenhydramine(Drug information on diphenhydramine). In the absence of symptoms, the infusion rate is increased gradually until completion of therapy. If symptoms are witnessed, the infusion should be stopped and the symptoms managed. Unless it is contraindicated, the antibody should then be given again at a slower rate.
Alemtuzumab in CLL
The original monoclonal antibody Campath-1M was a rat immunoglobulin (IgM), and although it demonstrated in vitro cytotoxicity, there was no evidence of clinical efficacy. Subsequently, a rat IgG2a anti-CD52 monoclonal antibody was produced, and from this a class-switch IgG2b variant was derived (these antibodies differed in their constant region genes). The IgG2b monoclonal antibody (Campath-1G) was capable of eliciting antibody-dependent cellular cytotoxicity by binding human Fc receptors or effector cells and by mediating complement lysis.[32,33] Campath-1G can deplete tumor cells from blood, marrow, spleen, and skin, although it was less effective against lymph nodes or extranodal masses.[ 34] The introduction of genetic manipulation of Ig genes allowed a series of human CD52 antibodies to be produced. The human IgG1 version (alemtuzumab) was chosen for initial trials because it showed optimal activation of cellular and complement-mediated effector mechanisms, making alemtuzumab(Drug information on alemtuzumab) the first completely humanized monoclonal antibody.
The CD52 protein (21-28 Kd glycosylated glycoprotein)-the function of which is still undefined-is composed of only 12 amino acids attached indirectly to the cell membrane through a glycosylphosphatidylinositol anchor. It is expressed at high density at approximately 5 * 105 molecules/ cell. It is usually present on most normal and malignant mature lymphocytes of T-and B-cell lineages as well as monocytes, is not expressed on hematopoeitic stem cells, and does not modulate in vitro or in vivo.[32,36]
Initial studies with alemtuzumab were performed in patients with NHL, with modest response rates (15% to 20%).[37,38] However, it was hypothesized that CLL could potentially be a better target for this antibody, as alemtuzumab demonstrated tumor regression in the bone marrow and peripheral blood, but not in bulky adenopathy. Based on the preliminary phase I dose-escalation studies, it was recommended that alemtuzumab should be administered at 30 mg three times a week for 4 to 12 weeks. Subsequently, phase II studies were conducted in patients with refractory and relapsed CLL as well as in patients with T-cell prolymphocytic leukemia (PLL).
Osterborg and colleagues investigated alemtuzumab in 29 refractory CLL patients showing a 38% partial response and 4% complete response, for an overall response rate of 42%, and a median duration of response of 12 months. Two recently reported abstracts have confirmed significant activity for alemtuzumab in CLL patients. The first was reported by Keating and colleagues, involving 93 CLL patients who failed fludarabine.[ 42] In this pivotal study, the overall intent-to-treat response rate was 33%, with 2% complete response, 31% partial response, and 59% stable disease. The projected median time to progression is about 9 months.
Kennedy and colleagues reported on 29 patients with refractory CLL who were treated with alemtuzumab, with 59% responding (34% complete response). Peripheral stem cell mobilization and collection did not appear to be affected by alemtuzumab. Nine responding patients pro- ceeded to peripheral blood stem-cell transplantation, with eight of those still alive at a median of 14 months. At the 2001 American Society of Hematology meeting, Rai et al reported on the largest number of patients who received alemtuzumab on a compassionate basis showing 7% complete response in 136 treated patients who had failed prior therapies. The progression-free survival was 7.3 months in responding patients, with an overall response of 40%.
Alemtuzumab has also been studied in previously untreated patients with impressive results. Osterborg and colleagues showed an overall response of 89% in a small group of patients, with response duration ranging from 8 to 24 months. Followup bone marrow examination is critical in patients receiving alemtuzumab, as peripheral blood remissions will often precede marrow clearing by several weeks. Table 3 summarizes pivotal studies with alemtuzumab in CLL.[40-44,46]
Studies in PLL
Pawson and colleagues studied the efficacy of alemtuzumab in 15 patients with T-cell PLL. Eleven patients (73%) had a major response, with nine (60%) achieving complete response. Re-treatment was feasible in three relapsed patients who achieved a complete response again, and two of those patients underwent autologous peripheral stem cell transplant. Dearden and colleagues recently showed that patients with refractory PLL have an excellent response to alemtuzumab. Although this response is usually not sustained, patients who undergo consolidative high-dose chemotherapy with autologous or allogeneic bone marrow transplantation appear to have longer disease-free intervals.
Intravenous administration of alemtuzumab is almost always associated with "first dose" reactions characterized by fever, rigors, and nausea due to cytokine release (TNF and IL-6).[41,45] Such reactions are not seen with subcutaneous administration, although local injection site reactions may occur.[ 41,46] Antiglobulin responses have not been observed with alemtuzumab. The major side effect is prolonged lymphopenia (both T and B cells) and profound immunosuppression, resulting in an increased risk of opportunistic infections, especially in heavily pretreated patients.[37,41,47] Lymphopenia mandates instituting prophylactic antibiotics once alemtuzumab therapy is initiated.
Antimicrobial prophylaxis is recommended for a minimum of 2 months following the last dose of alemtuzumab or until CD4+ counts are above 200 cells/mL. The median time to recovery of CD4+ counts to that level was 2 months; however, full recovery (to baseline) of CD4+ and CD8+ counts may take more than 12 months. Hematologic toxicity (neutropenia and thrombocytopenia) has been witnessed in all alemtuzumab phase II studies, and rare cases of severe fatal marrow aplasia have also been reported.[39,41,37]
Recently, several reports of cytomegalovirus (CMV) reactivation have been documented in patients treated with alemtuzumab. Thai and colleagues studied the incidence of such an infection in 34 patients with PLL or CLL who were treated with alemtuzumab between 1998 and 2001 at Stanford University. Although all patients received prophylactic antibiotics and antivirals, five patients (15%) developed CMV viremia at a median of 28 days after the first alemtuzumab infusion. All affected patients had a fever above 38.5°C, but otherwise normal chest radiographs and normal chemistries with nega- tive bacterial blood cultures. All patients responded to ganciclovir(Drug information on ganciclovir) (Cytovene) with resolution of their fever and viremia. The authors were not able to identify specific risk factors for developing CMV viremia, although a trend toward statistical significance was almost reached in patients with prior rituximab exposure (P = .07). Although the incidence of CMV viremia is not high, it is important to consider the diagnosis in any febrile patient who is undergoing alemtuzumab therapy.