Therapies of the Third

3.5.1. Fludarabine

The modern era of CLL also saw the introduction of a new drug into the treatment armamentarium. In the post-chlorambucil period, numerous studies has searched for multidrug regimens

No. at Risk

Fludarabine 107 78 Chlorambucil 67 34

48 13

29 4

10 0

Fig. 38. Proportion of patients with an initial response to fludarabine or chlorambucil who continued in remission. Shown are the proportions of the 107 patients assigned to fludarabine and the 67 assigned to chlorambucil who had a response to treatment and remained in complete or partial remission. In both groups combined, 78% of patients (135 of 174) had relapses. The median duration of the response was significantly longer in the fludarabine group than in the chlorambucil group (25 vs. 14 mo,p < 0.001). (From ref. 47, Rai et al., 2000, Fig. 1. Copyright © 2000 Massachusetts Medical Society. All rights reserved.)

that would be more effective in CLL. Unfortunately, the toxicity associated with multiple drug regimens did not result in increased survival. Then, a new class of drugs emerged, the nucleoside analogs: fludarabine, 2-chlorodeoxyadenosine (CdA), and 2'-deoxycoformycin (pentostatin, or DCF). The definitive fludarabine study by Rai et al. in 2000 (47) is of importance for several reasons. First clinical responsiveness was based upon published NCI guidelines (120). Second, there was a comparative control arm for chlorambucil treatment by itself, and third, there was a third arm that compared the combination of fludarabine and chlorambucil. The findings of this study were striking. First of all, the combined arm of fludarabine and chlorambucil was terminated early owing to excessive toxicity. Second the overall response rate was superior for fludarabine vs chlorambucil with complete response (CR) and partial response (PR) of 20 and 43% for fludarabine and 4 and 33% for chlorambucil. Toxicity was greater for the fludarabine-treated patients and consisted of infections, neutropenia, and thromboyctopenia. However, there was no survival difference when fludarabine was compared with chlorambucil, yet because of its superior CR rate, overall response rate, and duration of response, fludarabine is now considered the first-line choice for untreated CLL. Figure 38 shows the initial response for fludarabine- and chlorambucil-treated patients who continued in remission (25 vs 14 mo). Figure 39 compares patients without disease progression (20 vs 14 mo). Figure 40 compares overall survival (66 vs 56 mo).

3 4 5 Years

3 4 5 Years

No. at Risk

Fludarabine 172 116 74 Chlorambucil 183 99 44

43 17

27 7

13 2

Fig. 39. Proportion of patients without disease progression, according to treatment group. Shown are the proportions of the 172 patients assigned to fludarabine and the 183 assigned to chlorambucil in whom disease progression could be evaluated who did not have progression of disease from the time of entry into the study. The disease progressed in 79 and 81% of the patients in the two groups, respectively. The median time to progression was significantly longer in the fludarabine group than in the chlorambucil group (20 vs. 14 mo, p < 0.001). (From ref. 47, Rai et al., 2000, Fig. 2. Copyright © 2000 Massachusetts Medical Society. All rights reserved.)

3.5.2. Monoclonal Antibody Therapy

Recently the chimeric monoclonal antibody to CD20, rituximab or rituxan, has been approved for use in the treatment of CLL (FDA Approval Letter Nov. 26, 1997). Although initial responses were low and consisted only of PRs and no CR, interest has continued in its use in CLL (121-123). The original studies used 375 mg/m2 once a week for 4 wk. Subsequent studies have suggested that this same dose three times a week for 4 wk for a total of12 doses instead of 4 doses has resulted in better overall responses (124,125). Also, early data suggest that the CR is increased by the addition of Rituxan to fludarabine, but survival data are not yet available. Campath (anti-CD52) has also been recently approved for use in CLL patients refractory to alkylating agents and fludarabine (FDA Approval Letter of May 7, 2001). The FDA approved a novel treatment regime for one type of non-Hodgkin's lymphoma that for the first time includes a monoclonal antibody combined with a radioactive chemical (FDA Approval Letter of Feb. 20, 2002). The product, zevalin, must be used along with rituxan.

3.5.3. Growth Factors

In 1995 Pangalis et al. (126) reported that 8/9 CLL patients responded to recombinant human erythropoietin (r-HuEPO) treatment regardless of the pretreatment serum EPO level. A slower response was attributed to a "packed marrow." In 1988 Casadevall (127) reviewed a multicenter study of 146 patients by Cazzaola et al. (128) and 121 patients reported by Osterborg et al. (129).

chlorambucil

to ql

Fludarabine Chlorambucil Fludarabine plus chlorambucil

to ql

No. at Risk

Fludarabine 178 155 140 124 95 60 24 9

Chlorambucil 193 172 147 132 101 52 21 6

Fludarabine plus 136 117 106 94 70 44 19 5 chlorambucil

Fig. 40. Overall survival according to treatment group. Shown are the proportions of 178 patients assigned to fludarabine, the 193 assigned to chlorambucil, and the 136 assigned to fludarabine plus chlorambucil who were still alive during follow-up. Forty-seven percent, 57%, and 56% of the patients in the three groups, respectively, died. There was no statistically significant difference in overall survival among the three groups (median, 66, 56, and 55 mo, respectively;p = 0.21). (From ref. 47, Rai et al., 2000, Fig. 3. Copyright © 2000 Massachusetts Medical Society. All rights reserved.)

Both reports concerned patients with non-Hodgkin's lymphoma and multiple myeloma. The probability of a response in the first study (increase > 2 g Hgb) reached 62% in the group treated with 10,000 IU daily after 8 wk. In the second study a cumulative response frequency of 60% for the fixed dose and variable stepwise dose was seen. In both of these studies, Hgb levels could be corrected without obvious side effects.

Casadevall (127) also reviewed two reports evaluating the effects of epoetin-a therapy in anemic CLL patients. The first report is unfortunately only an abstract from Rose et al. (130), who treated 221 anemic CLL patients and evaluated them for hematologic parameters and health status. They reported that 47% of treated patients had an increase of at least six points in the Hct over baseline values unrelated to transfusions, compared with 15% in the placebo group (p > 0.001). The second article on the treatment of anemic CLL patients with EPO reviewed by Casadevall is the aforementioned report of Pangalis et al. (126).

Russo et al. (131) make a cogent argument for the combined use of granulocyte/macrophage colony stimulating factor (GM-CSF) and EPO in the refractory, chemotherapy nonresponsive patient. The antileukemic and antitumor effect is of interest in these four patients.

The most interesting paper is by Siakantaris et al. (132) and represents an expansion of the earlier 1995 study by Pangalis et al. (126). For this study, 22 patients with CLL, 5 patients with SLL, and 6 patients with lymphoplasmocytic lymphoma (LPL)—all with anemia (Hct < 32%)—

were treated three times weekly with 50 U/kg for 3 mo. After 1.5 mo, the dose was incrementally increased to a maximum of 300 U/kg if the response was unsatisfactory. Of these patients, 50% had a complete response (Hct > 38%) and an overall response rate of 80% (PR = Hct increase of 6% over baseline). All patients on maintenance therapy have a continuous response. There was no correlation with low or high pretreatment EPO serum levels, ongoing chemotherapy, presence or absence of B-cell symptoms, diffuse or nondiffuse bone marrow pattern, or the presence or absence of splenomegaly. Of further interest, 14 CLL Rai stage III patients were downstaged after treatment with r-HuEPO: 11 became Rai stage II, 2 became Rai stage I, and 1 became Rai stage 0 (see Table III of that report). They apparently did not see any reduction in absolute lymphocyte count, as noted by Russo et al. (131), suggesting that the combined use of cytokine growth factors may be required for the antileukemic effect.

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