Dr. Nabhan and his coauthors have written a comprehensive review of the use of monoclonal antibodies in the treatment of chronic lymphocytic leukemia (CLL). They have highlighted important clinical trials with newer antibodies, including apolizumab (Hu1D10, Remitogen) and IDEC-152 (anti- CD23). The authors concisely describe the use of rituximab (Rituxan) and alemtuzumab (Campath) as single agents and in combination therapy. Both antibodies have efficacy in the treatment of CLL, but both have limitations when used as single agents.
Common to both agents are the infusion-related reactions that can occur with the initial doses. These are generally mild to moderate, but can be severe in a minority of patients. Initial publications suggested that the more severe side effects seen with rituximab might be associated with high circulating lymphocyte counts; this has not subsequently been established as a risk factor. Some data suggest that the intensity of CD20 expression on circulating cells might correlate with infusion-related side effects, but this has not been proven.
Even when side effects are not severe, they are certainly bothersome and result in prolonged infusion/nursing time and patient inconvenience. Premedicating with corticosteroids may abrogate the side effects. In clinical trials, corticosteroids have not been used for several reasons. Corticosteroids have antitumor activity in lymphoid malignancies and their use in a trial assessing the efficacy of a new agent would cloud the data. Steroids may impede the immune system, the functioning of which might be important for the activity of these antibodies. At this point, both clinical and laboratory data suggest no contraindication to using steroids.
When CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) was given with or without rituximab in a randomized trial in patients with lymphoma, rituximab increased the efficacy of this regimen even though it contained a significant dose of prednisone.[ 1] In addition, data from Rose et al have shown in vitro that steroids may actually synergize with rituximab.[ 2] Currently, the CLL Consortium is conducting a trial using a combination of rituximab and highdose steroids.
A concern with the use of steroids, particularly in conjunction with alemtuzumab, is increased immunosuppression leading to infections. Since alemtuzumab binds to CD52, a pan-lymphocyte antigen, patients with CLL undergoing treatment with this antibody experience significant T-cell depletion; this has mandated the use of herpes and Pneumocystis carinii prophylaxis for all patients during therapy and for at least 2 months afterwards. Given the significant T-cell suppression associated with alemtuzumab, it is unlikely that a small dose of steroids added to the initial infusions would significantly impact the immunosuppression already occurring. The fact that all patients are already receiving prophylactic antibiotics makes that concern limited. Ideally, this should be investigated prospectively, but using steroids with initial doses of antibodies to prevent infusion- related side effects is a reasonable strategy.
Rituximab and Alemtuzumab: Efficacy
Rituximab and alemtuzumab have complementary areas of efficacy in the treatment of CLL. Rituximab lowers the white blood cell count and may reduce adenopathy, but has little effect on the bone marrow in patients with CLL, even when given at higher doses or with increased frequency. In contrast, alemtuzumab reduces white blood cells in almost all patients with CLL and effects significant clearing of bone marrow disease; efficacy is reduced in bulky lymph node sites.
In a pivotal trial of alemtuzumab administered to patients refractory to fludarabine (Fludara), the overall response rate was 33% with most remissions being partial. Nevertheless, within the group of responders, approximately 50% had completely normal bone marrow. This provides a rationale for combining these two agents, as has been done in trials conducted at Northwestern University and M. D. Anderson Cancer Center, clearly described in the article by Dr. Nabhan and colleagues.
The single-agent efficacy of these antibodies is important. Given that the vast majority of remissions are only partial, and that complete responses are rarely obtained, it is likely that more efficacious use of these antibodies will either be in less advanced disease or in combinations. Hainsworth et al and Thomas et al showed significantly higher response rates when rituximab was given to patients with previously untreated CLL; however, these were mostly partial remissions. Lundin et al demonstrated a very high response rate when alemtuzumab was administered to patients with previously untreated CLL, but a low com- plete response rate of 19%; all complete responses were seen in patients with lymph nodes smaller than 2 cm at the start of therapy. Thus, combination therapy is likely to be a better use of antibodies in the treatment of CLL.
Adding to Fludarabine-Based Therapy
Two recent trials described in this review suggest a benefit, particularly in terms of increasing the complete response rate, when rituximab was added to fludarabine-based chemotherapy. In the Cancer and Leukemia Group B randomized trial, fludarabine plus rituximab produced a statistically significant higher complete response rate than fludarabine alone. In the single-arm trial conducted at M. D. Anderson with a three-drug regimen of fludarabine, cyclophosphamide, and rituximab, complete responses were seen in two-thirds of patients and, importantly, molecular remissions were achieved. Both trials have shown that the addition of rituximab to fludarabine-based chemotherapy resulted in a higher rate of neutropenia. This was unexpected given that rituximab targets B cells; it is unclear why the addition of rituximab to chemotherapy would result in selective neutropenia. Nevertheless, as these regimens produce no mucosal damage, and as patients can tolerate a period of neutropenia in that setting, infections were not significantly more frequent in either trial with the antibody and chemotherapy combination.
In a small trial from England in patients with CLL refractory to fludarabine and alemtuzumab, the combination of both agents was extraordinarily effective and even produced molecular remissions. The M. D. Anderson group is currently conducting a trial in previously treated patients with CLL, adding alemtuzumab to the three-drug regimen of fludarabine, cyclophosphamide, and rituximab.
As response rates (particularly complete responses) are increasing and molecular remissions are seen, an important question is whether molecular remissions should be the goal of therapy and whether they impact time to progression. Data from trials in patients with lymphoma suggest that molecular remissions are an important end point in improving prognosis. It is often stated that even with newer agents such as fludarabine, survival has not been impacted in CLL. The study most often cited to suggest this lack of survival benefit is the Intergroup trial in which patients were randomized to receive chlorambucil (Leukeran) or fludarabine. Fludarabine produced higher complete response rates, higher overall response rates, and longer disease- free survival, but not overall survival. A common explanation for this was the crossover design in which patients failing chlorambucil would benefit from fludarabine.
However, the lack of survival improvement may be due to the low complete rate of 20% with fludarabine. These were morphologic complete responses, and did not include flow cytometry evaluation or the more sensitive polymerase chain reaction (PCR) assessment. Such low complete response rates may not translate into a survival benefit in the total study group; this may be noted once high-quality complete response rates (PCR) are achievable in over half of the patients, which would be possible with combination of monoclonal antibodies and chemotherapy.
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Coiffier B, Lepage E, Briere J, et al: CHOPchemotherapy plus rituximab compares withCHOP alone in elderly patients with diffuselarge-B-cell lymphoma. N Engl J Med346(4):235-242, 2002.
Rose AL, Smith BE, Maloney DG: Glucocorticoidsand Rituximab in vitro: Synergisticdirect antiproliferative and apoptotic effects.Blood 100(5):1765-1773, 2002.
Keatin MJ, Flinn I, Jain V, et al: Blood99(10):3554-3561, 2002.
Hainsworth J, Litchy S, Burris H, et al:Rituximab as first-line and maintenance therapyfor patients with small lymphocytic lymphoma(SLL) and chronic lymphocyticleukemia (CLL) (abstract 1530). Blood 98:363a,2001.
Thomas D, O’Brien S, Giles F: Singleagent rituxan in early stage chronic lymphocyticleukemia (CLL) (abstract 1533). Blood98:364a, 2001.
Lundin J, Kimby E, Bjorkholm M, et al:Blood 100(3):768-773, 2002.
Kennedy B, Rawstron A, Carter C, et al:Campath-1H and fludarabine in combinationare highly active in refractory chronic lymphocyticleukemia. Blood 99:2245-2247,2002.