Rituximab in Combination Therapy in CLL
Although many chemotherapeutic agents have been used with success in CLL, none has been proven curative. Fludarabine has shown better activity than alkylating agents in chemotherapy- naive patients, although the overall survival in randomized trials was not statistically different.[ 3,49] Because rituximab(Drug information on rituximab) has shown activity without significant toxicity in CLL, as discussed above, investigators have attempted to combine conventional therapies with the antibody-based approach. Byrd and colleagues reported preliminary results of a Cancer and Leukemia Group B trial (CALGB-9712) conducted as a randomized phase II study comparing concurrent rituximab and fludarabine with the same agents given sequentially.[50]
Patients on the concurrent arm received fludarabine at 25 mg/m2/d (days 1-5, cycles 1-6), and rituximab at 375 mg/m2 (days 1 and 4 of cycle 1, and day 1 of cycles 2-6). Patients on the sequential arm received fludarabine as in the concurrent regimen followed by a 2-month therapy hiatus, then rituximab at 375 mg/m2/wk for 4 weeks. Both arms included previously untreated patients. Preliminary results suggest better response in the concurrent arm (90% vs 77% overall response), and a complete response rate that reached statistical significance (47% compared with 28%, P = .04).
Others have reported similar efficacy with this combination. Schulz and colleagues treated CLL patients who were anthracycline- and fludarabinenaive with overlapping cycles of fludarabine (25 mg/m2/d, days 1-5, cycles 1-4) and rituximab (375 mg/m2 on day 1 of cycles 3-6). The overall response rate in 29 evaluable patients was 90%, with 34% achieving a complete response.[51] Although this combination is showing promising results, its superiority to single-agent fludarabine or other traditional therapies requires confirmation in phase III randomized studies.
FCR Protocol
Since fludarabine has shown in vitro and in vivo synergy with alkylating agents,[52] specifically cyclophosphamide(Drug information on cyclophosphamide),[ 53] investigators have attempted a triple regimen combination with fludarabine, cyclophosphamide, and rituximab (FCR) in an effort to improve response rates in refractory patients and those who were previously untreated. Garcia- Manero and colleagues treated relapsed CLL patients with FCR (rituximab at 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2-6, fludarabine at 25 mg/m2 on days 2-4 of cycle 1 and days 1-3 of cycles 2-6, and cyclophosphamide at 250 mg/m2 on days 2-4 of cycle 1 and days 1-3 of cycles 2-6).[54] To date, 136 patients are evaluable for response, 28 (21%) of whom achieved a complete response, and 68 (50%) of whom obtained a partial response, for an overall response rate of 71%. Complete molecular remission was observed in 5 of the 14 complete response patients (36%) using polymerase chain reaction (PCR) technology on bone marrows from these patients. The same regimen was tested in previously untreated patients, yielding higher response rates.
Recent Updates on the Outcome of Chronic Lymphocytic Leukemia Patients Treated With the FCR Regimen at the M.D. Anderson Cancer CenterWierda and colleagues reported on 135 evaluable patients treated with the same FCR protocol mentioned above. Eighty-five patients (63%) had a complete response, with a molecular remission demonstrated in the bone marrow of 56% of complete response patients (as detected by PCR assay).[55] At a median follow-up of 12 months, median time to treatment failure has not been reached (Table 4). In both studies, the combination therapy was well tolerated without increased toxicity compared to historical controls. Nausea was observed in 20% of patients, while fatigue, vomiting, and diarrhea were noted in 11%, 6%, and 2%, respectively. Although the incidence of grade 4 neutropenia was observed with higher frequency than in patients treated with fludarabine and cyclophosphamide alone, there was no increase in the incidence of major infections (sepsis or pneumonia).
The current FCR regimen shows excellent activity and compares favorably with all prior regimens for CLL. The activity and superiority of this regimen, however, requires validation in a larger randomized multiinstitutional study before being advocated as a new standard of care.
Rituximab and Pentostatin
A phase II multicenter trial to evaluate the safety and efficacy of pentostatin (Nipent) in combination with rituximab in patients with low-grade NHL and CLL is under way.[56] Patients in this study receive rituximab on day 1 at 375 mg/m2 followed by both agents on days 8, 15, and 22. Pentostatin is given at a dose of 4 mg/m2. Cycles are repeated after 1 week of rest. The outcome of this ongoing trial is not yet available, but the interest in adding antibodies to conventional agents proves a shift toward a more targeted approach in CLL. As discussed previously, others have attempted treating autoimmune hemolytic anemia in CLL patients with rituximab, cyclophosphamide, and dexamethasone(Drug information on dexamethasone) with promising results.
Alemtuzumab in Combination Therapy in CLL
Few reports have been published on alemtuzumab(Drug information on alemtuzumab) in combination with conventional therapies. The immunosuppression observed with alemtuzumab mandates exercising caution when adding this antibody to other agents; administering prophylactic antibiotics is warranted until patients are no longer at increased risk for opportunistic infections. Kennedy and colleagues treated five patients who were extremely refractory to traditional therapies with a combination of alemtuzumab and fludarabine.[57] In this study, all patients were refractory to fludarabine alone and to alemtuzumab alone. Patients received alemtuzumab for 8 to 16 weeks at a dose of 30 mg three times per week intravenously, with fludarabine at 25 mg/m2 for 3 to 5 days every 4 weeks during alemtuzumab therapy. Four of the five patients responded, with two achieving a complete response and two obtaining a partial response.
In all four responding patients, bone marrow examination showed no evidence of CLL, and molecular studies failed to demonstrate evidence of minimal residual disease. Despite the theoretical concern that patients receiving such a combination are at increased risk of opportunistic infections, none of these five patients had serious infections. Patients on this study, however, received prophylactic antifungals, and were monitored frequently for possible CMV reactivation. In a recently published update, these investigators confirmed their results and reported on a total of six patients. Of the five patients that responded, three had no morphologic evidence of CLL in their bone marrow.[58]
Currently, large randomized studies are being conducted in untreated CLL patients using either the combination of fludarabine and alemtuzumab or a sequential regimen of both agents. Theoretically, the combined arm would have more toxicity than the sequential arm. Results of these ongoing trials are not yet published, but it is anticipated that the standard approach to CLL will change in the near future, and that monoclonal antibodies will make their way into frontline therapy and into combination regimens.
Antibody Combinations
Phase I Study of Alemtuzumab/Rituximab in Relapsed or Refractory CLL: Study SchemaIn light of the fact that monoclonal antibody-based therapy is well tolerated and produces minimal side effects, we have initiated at Northwestern University a phase I study combining alemtuzumab with rituximab in patients with refractory and/or relapsed CLL.[59] Eligible patients must have a confirmed diagnosis of CLL or small lymphocytic lymphoma (SLL) in the leukemic phase. Patients must have expressed both CD20 and CD52, and have had adequate bone marrow reserve unless cytopenia is related to extensive bone marrow involvement. Patients must have failed traditional therapies. Prior exposure to alemtuzumab is not allowed, but prior exposure to rituximab is permitted if the last infusion was administered more than 6 months prior to initiating the current regimen. Patients have received therapy as outlined in the study schema in Table 5.
All patients receive premedication with diphenhydramine(Drug information on diphenhydramine) and acetaminophen. Fever and rigors are treated with hydrocortisone(Drug information on hydrocortisone) at 100 mg and/or meperidine at 25 mg, both given intravenously. Blood cultures are obtained where clinically indicated. Other infusion-related side effects (dyspnea, hypoxemia, and hypotension) are managed by temporary cessation of the infusion, hydration, and the appropriate medical intervention. Once these side effects are resolved, the infusion can be restarted at half the previous infusion rate. Because alemtuzumab produces major infectious complications, all patients are placed on trimethoprim(Drug information on trimethoprim) and sulfamethoxazole(Drug information on sulfamethoxazole) DS three times weekly, fluconazole(Drug information on fluconazole) (Diflucan) daily, and acyclovir twice daily. These prophylactic antibiotics are continued until 2 months after completion of therapy or until recovery of CD4+ counts. Neutropenic patients are started on ciprofloxacin(Drug information on ciprofloxacin) (Cipro), and the use of growth factor is allowed but not required.
At the time of our report, nine patients had already been enrolled, one of whom obtained a partial response by National Cancer Institute criteria, and a decline in absolute lymphocyte count had been noted in eight patients.[ 60] It should be noted that in this study, the combination has been well tolerated, without opportunistic infections, and that the infusionrelated toxicity is similar to what is usually reported with each antibody as monotherapy. We are currently expanding this study to administer alemtuzumab for a total of 8 to 12 weeks. Once the feasibility of this combination is achieved, a phase II study of the same regimen will be initiated. It is foreseeable that incorporating highdose rituximab in this regimen might produce a better response, but confirmatory trials are required.
In a similar study, Faderl and colleagues treated patients who expressed CD20 and CD52 with alemtuzumab and rituximab. Patients received rituximab at the standard dose for 4 weeks, and alemtuzumab at 3, 10, and 30 mg on days 3, 4, and 5 of week 1, and at 30 mg intravenously on days 3 and 5 weekly during weeks 2 through 4.[61] One patient obtained a complete response; the overall response rate was 43%. The combination was well tolerated without significant toxicity. Having established the feasibility of combining alemtuzumab and rituximab in this patient population will allow the addition of conven- tional chemotherapeutic agents to such a combination. Others have combined rituximab with epratuzumab (anti- CD22, LymphoCide) in relapsed or refractory NHL, and have concluded that this combination is safe and well tolerated, but that its efficacy remains to be determined.[62]
Other Antibodies
Several antibodies have been generated that recognize CLL antigens; these are currently under investigation. Link and colleagues reported preliminary results of a phase II study utilizing apolizumab (Hu1D10, Remitogen), a monoclonal antibody generated against HLA-DR expressed on normal and malignant B cells. Patients received the antibody at 0.5 or 1.5 mg/kg once weekly for 4 consecutive weeks.[63] At the time of the report 21 patients were treated, five of whom had small lymphocytic histology. Although response data were not available, the authors commented on the feasibility of administration and on the limited side effects that were essentially related to infusion- related symptoms. An anti-CD23 agent is currently under development as well.
Conclusions
As we enter the new millennium, targeted therapy with monoclonal antibodies has revolutionized the approach to select malignant disorders. These antibodies are, in general, better tolerated than conventional chemotherapy, and can be combined together and with other agents. The ability of administering these antibodies to older patients who are heavily pretreated will hopefully allow for improved outcomes in treating challenging entities such as refractory CLL. Although CLL generally remains an incurable disease, these new therapeutic options reflect the dawn of a new era and the potential for more effective control of this devastating disease.
