|
|
Chronic lymphocytic leukemia (CLL), the most common type of leukemia, with nearly 10,000 new cases per year in the US alone, is not curable with current therapies, but options exist for high-quality, long-term remission, according to Andrew D. Zelenetz, MD, PhD, of Memorial Sloan-Kettering Cancer Center in New York City. Often asymptomatic, CLL is common in the elderly, with a median patient age in the 70s.
 |
| Dr. Zelenetz |
Patients with stages 0 or I/II disease without adverse risk factors such as massive splenomegaly, diffuse adenopathy, elevated b2-microglobulin levels, or a short (< 12 months) lymphocyte doubling time can be followed with observation, whereas treatment is recommended for patients with stage I/II disease who have one or more of these adverse risk factors and for those with advanced-stage disease. In addition to these traditional high-risk factors, Dr. Zelenetz mentioned that “modern” risk parameters include the mutational status of the immunoglobulin heavy chain variable gene (IGHV), with its potential surrogate measures of CD38 and ZAP-70, as well as the fluorescence in situ hybridization (FISH) status of select cytogenetic abnormalities. For instance, IGHV mutation was a tremendous predictor for outcome in a previous study, according to Dr. Zelen-etz, and “patients with unmutated immunoglobulin variable genes have a much poorer outcome.”
Another cytogenetic abnormality that may be a prognostic feature for outcome of patients with CLL is deletion of 17p, which is associated with the loss of p53, the gene coding for the tumor protein p53. According to a study by Dohner et al (Blood 1995;85:1580–1589), treatment with fludarabine or pentostatin (Nipent) was influenced by p53 deletion status; 56% of patients with B-cell CLL and wild-type p53 responded to therapy, whereas 0% of those with a p53 deletion responded to therapy. These findings suggest that cytogenetic factors may influence both the timing and choice of treatment.
Fludarabine is considered one of the most active single agents for CLL. In a Cancer and Leukemia Group B study (CALGB 9011), a comparison of fludarabine and chlorambucil (Leukeran) revealed that fludarabine produced significantly higher overall and complete response rates, which led to a major improvement in the duration of response, reported Dr. Zelenetz. Although there was no overall survival advantage to using fludarabine, the crossover design of the study may have compromised the analysis of overall survival, he added.
Another study, performed by the Eastern Cooperative Oncology
Group (ECOG E2997), showed definitive evidence supporting a combination regimen
of fludarabine and cyclophosphamide for patients with previously untreated CLL.
“A significant improvement in overall and complete response rates on the
combined fludarabine/cyclophosphamide arm compared with fludarabine alone
translated to an improvement in progression-free survival,” Dr. Zelenetz
reported. The median time to disease progression was 41.4 months for the 125
patients who were given the combination versus 17.7 months for the 121 patients
who received fludarabine alone. Furthermore, the fludarabine/cyclophosphamide
regimen did not appear to increase toxicity substantially compared with
fludarabine monotherapy.
Although rituximab (Rituxan) has limited activity as monotherapy in CLL, its use in combination with fludarabine and other conventional chemotherapeutic agents achieved superior results. In a retrospective comparative analysis of CALGB 9712 and CALGB 9011 (Byrd JC et al. Blood 2005;105:49–53), investigators discovered that untreated patients with B-cell CLL who received fludarabine and rituximab had significantly better progression-free (P < 0.0001) and overall (P = 0.006) survival than did patients receiving fludarabine alone. However, these findings require confirmation in a prospective randomized trial, warned Dr. Zelenetz.
A chemoimmunotherapy program consisting of fludarabine, cyclophosphamide, and rituximab (FCR regimen) for untreated patients with CLL was studied by Keating and colleagues at The University of Texas M. D. Anderson Cancer Center in Houston (Keating MJ et al. J Clin Oncol 2005;23:4079–4088). Of the 224 patients treated, 95% had an overall response, and 70% had a complete response. Most patients had no detectable disease on flow cytometry at the end of therapy.
In an historic comparison of single-agent fludarabine, fludarabine/cyclophosphamide, and FCR performed by the same group, the FCR regimen yielded a steady improvement in response rates, time to treatment failure, and overall survival. However, like the Byrd comparison, this is a retrospective study, Dr. Zelenetz emphasized, and validation of these findings in a prospective randomized trial is necessary.
Unfortunately, relapse is almost inevitable in patients with CLL, Dr. Zelenetz stated. In addition to the previously discussed regimens, alemtuzumab (Campath) and pentostatin represent active alternatives for patients who require additional therapy.
Alemtuzumab, a potent humanized monoclonal antibody, has shown activity in both previously treated and untreated patients with CLL, according to preliminary findings. “Alemtuzumab is a very toxic drug,” said Dr. Zelenetz, “so you have to select patients carefully.” (see table) One of the most troubling complications is the reactivation of CMV, and Dr. Zelenetz recommended treatment if rising antigenemia is detected. “Never wait for a symptom,” he cautioned.
Subcutaneous administration of alemtuzumab, which Dr.
Zelenetz reported appears to be equally efficacious as intravenous dosing, has
been advocated in an attempt to avoid the infusional toxicity associated with
intravenous dosing. Early findings indicate that subcutaneous alemtuzumab may
be a feasible second-line option in the outpatient setting for high-risk,
fludarabine-refractory patients, particularly those with p53 mutations,
according to Dr. Zelenetz.
The combination of FCR and alemtuzumab (CFAR) was assessed in 66 heavily pretreated patients with relapsed CLL (Wierda W et al. Blood 2005;106[11]:719). Although distinguishing the actual effect of alemtuzumab from that of the FCR regimen alone is difficult, Dr. Zelenetz admitted, “the complete response rate of 22% is higher than one would expect.” At this point, CFAR appears to be an active, albeit highly myelosuppressive, regimen in this population.
Finally, pentostatin-based regimens may be effective in treating patients with relapsed CLL. In a retrospective analysis performed by Dr. Zelenetz and colleagues at Memorial Sloan-Kettering (Lamanna N et al. J Clin Oncol 2006;24:1575–1578), pentostatin (a less myelotoxic agent than fludarabine) was added to cyclophosphamide (PC) and also to cyclophosphamide/rituximab (PCR). Although both regimens yielded similar response rates in 32 patients with previously treated CLL, there was a dramatic and statistically significant improvement in the median duration of response in the PCR arm (25 months vs 9 months). The regimen was well tolerated with few infectious complications, the investigators revealed, and 72% of patients received the planned treatment at full dose. The use of PCR as initial therapy for patients with CLL is currently being studied.
“These patients were actually well matched for prognostic factors, so this appears to be a real difference,” Dr. Zelenetz affirmed. However, “this is a retrospective historic comparison, not a prospective randomized trial, which needs to be done,” he concluded.