Treatment of Advanced CLL

Early treatment is prescribed for most patients with advanced forms of CLL, including (1) classical chemotherapeutic regimens, (2) purine analogs, (3) monoclonal antibodies, (4) autologous or allogeneic bone marrow transplantation, and (5) other treatments.

2.3.1. Classical Chemotherapeutic Regimens

CB alone or associated with corticosteroids using a daily or intermittent schedule has been traditionally used to treat CLL. Ten randomized trials (14), involving 2035 patients mostly with Binet stage B or C or following the Rai staging system in some, compared CB with polychemotherapy regimens [cyclophosphamide, oncovin, and prednisone (COP) in four, cyclo-phosphamide, hydroxydaunomycin, oncovin, and prednisone (ChOP) in five, and CB plus epirubicin in the remaining one]. The CLL-80 trial from the French Cooperative Group compared daily continuous CB with 12 monthly COP regimens (one each during the first 6 mo and one every 3 mo during 18 mo) in 291 previously untreated stage B patients. Long-term results from this trial failed to demonstrate any benefit in response and survival using the COP regimen compared with

CB (29). Similar results were observed in an MRC trial in which 234 patients were randomly allocated to receive CB or COP (30). In addition, a Spanish trial (58 patients) (31) and an Eastern Cooperative Oncology Group trial (99 patients) (32) compared intermittent CB associated with prednisone with the COP regimen and failed to find any difference in terms of survival.

Five different trials compared the ChOP regimen with CB in advanced symptomatic CLL patients (Binet stages B and/or C and Rai stages III and IV) and failed to find differences in terms of survival, although better responses, which did not translate into survival advantage, were observed for the ChOP regimen in all these trials (33-37). Only the International Society for Chemo-Immunotherapy (ISCI) trial found a significant difference in response, which also translated into a survival advantage favoring high-dose CB (37). However, these results have not yet been reproduced and need to be confirmed. In the CL-L80 trial, the French Cooperative Group on CLL randomized 70 stage C patients between COP and ChOP (COP plus doxorubicin 25 mg/m2 iv d 1) (38-40). Median survival was 22 mo with COP and 62 mo with ChOP, supporting a beneficial effect of low-dose doxorubicin for stage C patients. However, Jaksic et al. (37) recently found a better overall response in "advanced CLL" with high dose CLB when compared with ChOP, and the Eastern Cooperative Oncology Group has reported a median survival of 49 mo in stage C patients treated by chlorambucil + prednisone (CLB + PRD) or COP, which did not significantly differ from the survival observed in the CLL-80 ChOP arm of the French Cooperative Trial (32). The ChOP regimen has been compared with CLB + PRD in advanced CLL in randomized trials by the Danish and Swedish groups, and no survival difference could be found (35,36). Although higher responses with ChOP were observed in all these trials, they failed to translate into survival advantage.

To analyze the interest of ChOP compared with standard treatments, data from these different groups were pooled for meta-analysis study (14). These series had long follow-ups and included advanced stage patients not always defined by the same staging system. Although the initial trial from the French Cooperative Group as well as other groups employing anthracycline-containing regimens generated the hypothesis that ChOP was a better treatment, the following trials have not supported it. Overall, the pooling of the data does not show evidence that ChOP actually prolongs survival compared with standard treatment. When excluding deaths not caused by CLL, ChOP might be better, but definitely not significantly. Since the French study was confined to stage C patients, analysis within subgroups was also carried out, and again there was no evidence of a different effect. Although the French trial was correctly designed and carried out and its statistical significance is clear, meta-analysis studies did not confirm these initial results. Alternatively, the possibility exists that the higher dose of cyclophosphamide used in the French ChOP study compared with classical ChOP could have an influence on these results. Recent results from the CLL-90 study, in which this schedule was found to be superior to the classical cyclophosphamide, adriamycin, and cisplatin (CAP) regimen (41), might favor this view.

In nonrandomized trials, others combinations have given results generally identical to those obtained with CLB, including mechlorethamine, oncovin, procarbazine, and prednisone (MOPP) (42), vincristine, BCNU, cyclophosphamide, melphalan, and prednisone (M2) (43), CAP (33), cyclophosphmide, adriamycin, cytosine-arabinoside, vincristine, and prednisone (POACH) (34).

2.3.2. Purine Analogs

During the late 1980s, purine analogs emerged as major drugs in CLL and generated tremendous interest (44-49). They were first used in progressive and refractory CLL patients. Long-term, single-institution nonrandomized studies indicate that fludarabine (FDB), alone or associated with prednisone, is able to induce 30% of true clinical, hematological, and bone marrow biopsy-confirmed complete remission, as well as an overall response rate of about 78%, whereas resistance to FDB is observed in 22% (48). Once complete remission is obtained, the median time to progression is around 30 mo. The vast majority of patients appear to be relapsing, but there is a small subset of 10-15% long-term responders; recurrence can also be anticipated for them. The median survival of these patients is close to 5 yr, which is no different from previous reports in CLL. In regard to relapsing patients, about 60% of these can be rescued with FDB, although the expected duration of response is on the order of 15 mo, compared with 30 mo for initial responders (48). Overall, these results indicate that FDB as a single agent or combined with corticosteroids is not curative. The association with corticosteroids is probably disadvantageous (47).

Among the agents tested so far in combination with FDB, cyclophosphamide has led to the most impressive results, with overall response rates of up to 90% and a complete remission rate around 40% in previously untreated patients (48,50-52) and as salvage treatment (53,54). However, the superiority of this combination over FDB alone has not been validated through a randomized trial. The French Cooperative Group on CLL has recently completed a phase II trial of oral FDB and cyclophosphamide in previously untreated B-CLL patients. The preliminary results of this study support the high activity of this combination (52).

The historical series of the Scripps clinic experience on the use of 2-chloro-deoxyadenosine (CDA) in the treatment of alkylator failure CLL showed that 4% of these patients obtained a complete remission and 50% a partial remission, for an overall response rate of 54% (55). In previously untreated patients, an overall response rate of 85% and a 60% complete remission rate were observed (56). When the different nonrandomized studies were pooled (N = 102), 37% obtained a complete remission using the National Cancer Institute (NCI) criteria (57), and 39% obtained partial response (56). Overall, CDA has potent activity in CLL. Myelosuppression and infection are the major toxicities; the long-term impact on progression-free and overall survival remains to be elucidated. Determination of the relative effectiveness of CDA compared with FDB for front-line therapy of CLL will ultimately require a randomized study. These initial results derived from nonrandomized trials seem to be indicating that purine analogs may play an important role in CLL treatment, either in front-line therapy or in salvage therapy.

To define whether these drugs are able to improve survival in CLL, two randomized trials compared FDB to anthracyclin-containing regimens (41,58), two compared FDB with CB using a classical schedule (56,57), and compared FDB with high-dose CB. A European trial (58) compared FDB therapy with the CAP regimen for treatment of CLL in a randomized, multicenter prospective trial, including 100 previously untreated stage B + C patients and 96 pretreated patients with CB or similar nonanthracycline-containing regimens. Patients were randomly assigned to six courses of either FDB (25 mg/m2/d on d 1-5) or CAP (cyclophosphamide 750 mg/m2/d and doxorubicin 50 mg/m2/d on d 1, and prednisone 40 mg/m2/d on d 1-5). Remission rates were significantly higher after FDB than after CAP, with overall response rates of 60 and 44%, respectively (p = 0.023). A higher response rate to fludarabine was observed in both untreated (71 vs 60%, p = 0.26) and pretreated (48 vs 27%, p = 0.036) patients, although the difference was statistically significant only in pretreated cases. In the latter group, remission duration and survival did not differ between treatment groups with a median remission duration of 324 d after FDB and 179 d after CAP (p = 0.22) and median survival times of 728 d and 731 d, respectively. In untreated cases, on the other hand, FDB induced significantly longer remissions than CAP (p < 0.001), although this difference did not translate into survival advantage. Treatment-associated side effects consisted in both regimens were predominantly myelosup-

pression and in particular granulocytopenia. CAP-treated patients had a higher frequency and severity of nausea and vomiting (25 vs 5%,p < 0.001) and alopecia (65 vs 2%,p < 0.001). These results indicate that FDB compared favorably with CAP in terms of response, although this difference did not induce a survival improvement.

In 1990, the French Cooperative Group (41) activated a trial in which previously untreated patients with stage B or C CLL were randomly allocated to receive six monthly courses of either FDB 25 mg/m2 iv daily for 5 d or cyclophosphamide 750 mg/m2 iv on d 1, doxorubicin 50 mg/ m2 iv on d 1 and prednisone 40 mg/m2 orally on d 1-5 (CAP) or to the mini-ChOP regimen previously used by this group, consisting of iv vincristin 1 mg/m2 and doxorubicin 25 mg/m2 on d 1, plus cyclophosphamide 300 mg/m2 and prednisone 40 mg/m2 given orally on d 1-5. Endpoints were treatment response, overall survival and tolerance. From June 1, 1990 to April 15, 1998, 938 patients (651 stage B and 287 stage C) were randomized in 73 centers. Compared with ChOP and FDB, CAP induced lower overall remission rates (58.2%; ChOP, 71.5%; FDB; 71.1%; p < 0.0001 for each), including lower clinical remission rates (CAP, 15.2%; ChOP, 29.6%; FDB, 40.1%; p = 0.003).

On the basis of these results (observed in a previous interim analysis held in September 1996), it was decided to discontinue accrual in this group. As expected, median survival was better for stage B (81 mo) than for stage C patients (60 mo). Causes of death were related to CLL in 75% of cases, and overall survival did not differ among the three arms (67, 70, and 69 mo in the ChOP, CAP, and FDB groups, respectively). Incidences of infections (< 5%) and autoimmune hemolytic anemia (< 2%) during the six courses were similar in the randomized groups, whereas FDB, compared with ChOP and CAP, induced more frequent protracted thrombocytopenia (p = 0.003) and less frequent nausea/vomiting (p = 0.003) and hair loss (p < 0.0001). For patients with stage B and C CLL, first-line FDB and ChOP regimens both provided similar overall survival and response rates at closing and better results than CAP. However, there was an increase in clinical remission rate and a trend toward a better tolerance of FDB over ChOP that may influence the choice between these regimens as front-line treatments in patients with CLL (41).

In a randomized study, Rai et al. aimed to compare FDB and CB for patients with previously untreated CLL with active disease (59). Eligible patients were all high-risk or those intermediate-risk patients who had active disease and all were previously untreated, with a performance status of less than 3. Between October 1990 and December 1994, 544 previously untreated CLL patients with active disease were randomized to receive FDB (25 mg/m2 iv daily for 5 d) or CB (40 mg/m2 po on d 1) or a combination of FDB + CB (20 mg/m2 of each drug) q4 wk for up to 12 mo. Nonresponders or responders in FDB-alone and CB-alone arms whose CLL progressed within 6 mo of treatment were crossed over to the other arm. Survival analysis for this report was based on 385 patients.

A significantly higher overall response rate of 70% was obtained among 167 evaluable patients on FDB [27% complete response (CR) + 43% partial response (PR)] compared with 45% (3% CR + 42% PR) among 173 patients on CB (p = 0.0001). Among 119 patients on FDB + CB, 65% overall responses were noted (25% CR + 40% PR). Response duration following FDB was significantly longer than with CB: 117 patients with either CR or PR on FDB had a median duration of response of 32 mo vs 18 mo among 73 patients on CB (p = 0.0002). Similarly, the median progression-free survival (time from study entry to disease progression or death from any cause) was 27 mo for patients receiving FDB vs 17 mo for patients on CB (p < 0.0001). With a median follow-up of 30 mo, there was no difference in the overall survival (p = 0.49), although this comparison is complicated by the crossover design of the study. An estimated 62% of patients on both arms survived for at least 4 yr. Seventy-four patients initially treated with CB received FDB, with only 29 crossovers from FDB to CB. Both drugs were well tolerated, with similar toxicity profiles, except for a 20% grade 3 + grade 4 leukopenia with FDB vs 7% with CB (p = 0.001). However, toxicities were significantly worse for the combination arm, which displayed 42 and 45% thrombocytopenia and neutropenia of grade 3 and grade 4 level and approximately twice the frequency of serious grade 3 and 4 infections than the individual one-arm protocols. These results caused the combination arm to be stopped somewhat sooner than the total protocol.

An Italian trial (60) compared FDB using classical schedule to intermittent CB associated with prednisone in 150 advanced CLL patients. Response rates were very close in both arms, possibly because this study was employing CB at higher dosage than in the American trial. Response duration was longer in the FDB arm, and toxicity was comparable.

The European Organization for Research and Treatment of Cancer (EORTC) started a randomized trial aiming to compare high-dose continuous CB (10 mg/m2) with FDB at classical dosage (25 mg/m2 on d 1-5 every 3 wk). This treatment was administered for 18 wk (61). Eighty-four patients have been enrolled so far in this trial, and response evaluation was available for 74 patients with a median follow-up of 33 mo. Response rates, overall survival, and progression-free survival were comparable in both arms. The German CLL Study Group (51) compared (in younger patients resistant to alkylating agents) high-dose CB (0.2 mg/kg/d) given continuously for 6 mo with FDB (25 mg/m2 on d 1-3 every 28 d) plus cyclophosphamide (250 mg/m2 on d 1-3 every 28 d). A higher response rate (88 vs 67%) and lower toxicity was observed for the association of FDB and cyclophosphamide.

The Polish Leukemia Study Group (62) compared CDA plus prednisone (CDA at 0.12 mg/kg/ d and prednisone at 30 mg/m2 during five consecutive days each month) with a classical intermittent CB plus prednisone schedule, in 229 previously untreated advanced CLL patients. Although the CDA-containing regimen obtained a significantly higher response rate (86% overall response vs 59% for the CB-containing regimen; p < 0.002), again, better response did not translate into survival advantage.

2.3.3. Monoclonal Antibodies

The humanized monoclonal antibody Campath 1H (alemtuzumab) directed against the CD52 antigen has shown important activity against B-CLL cells. CD52 is abundantly expressed on the surface of virtually all peripheral B- and T-lymphocytes, on monocytes but not granulocytes, red blood cells, and on platelets. The mechanism of action described for Campath 1H is the ability to induce cell lysis using host effector mechanisms such as complement fixation and antibody-dependent cell cytotoxicity (ADCC) and a direct effect through the induction of apoptosis (reviewed in refs. 63 and 64). Several studies showed the effectiveness of Campath 1H in patients with either previously untreated or relapsed/refractory B-CLL patients (65,66). Clearing of blood lymphoid tumor cells was observed in virtually all patients, and clearing of bone marrow B-CLL cells was seen in 30-40% of previously treated patients and up to 70% of naive patients. However, only a minority of patients had a complete response in regard to the lymph node component of the disease.

Campath 1H has been tested as consolidation therapy after chemotherapy in a short series of six patients with relapsed B-CLL; partial to complete response was seen in five patients (67). This finding suggests that Campath 1H may be effective in eliminating residual disease after conventional chemotherapy. In these trials, Campath 1H was usually applied at a dose of 30 mg iv three times a week for a maximum of 12 wk. Premedication with diphenhydramine and acetaminophen as well as prophylaxis against opportunistic infections is required. The main toxicities were mild infusion-related side effects such as rigor, fever, nausea, vomiting, rash, and fatigue, which mostly occurred during the first week of therapy. About half of the patients with previously treated CLL developed transient thrombocytopenia, neutropenia, or infections, which were severe [World Health Organization (WHO) grade 3 and 4] in approx 20% (68). These results suggest that the best indication for Campath would be as a treatment for CLL patients without bulky tumoral disease or for residual disease. They also indicate that Campath is effective as a second-line therapy in patients refractory to alkylant drugs and purine analogs. Interestingly, this drug can be also subcutaneously scheduled (69).

Owing to the weak expression of CD20 by CLL B-cells and to initial poor results in CD5+ lymphocytic lymphoma (70), anti-CD20 antibody has been less evaluated in CLL. Because of these data, rituximab was expected to play an adjuvant role after a debulking treatment, for example, as an in vivo purging agent before stem cell collection and transplantation, or as a potentiator of chemotherapy with FDB and cyclophosphamide. However, phase I/II studies with anti-CD20 in CLL have shown that the drug could be active at least on blood lymphocytosis, but either at very high doses, or with a three weekly schedule and then at a high cost (71,72). Radiolabeled anti-CD20 antibodies (yttrium 90 or iodine 131), currently being investigated in low-grade lymphoma, have been less explored in CLL (73). Two limitations to its use are anticipated: a consummation of the product both by blood lymphocytes, which have to be reduced with other drugs first, and, given its constant lymphocyte infiltration, by bone marrow irradiation related to the targeting of the radiolabeled drug. As expected, preliminary trials in lymphoma have confirmed hematological toxicity, with a risk of myelodysplastic syndromes, especially in patients previously treated with alkylating drugs. Finally, recent work from the M.D. Anderson Cancer Center, has shown that the association of FDB, rituximab, and Campath is able to achieve a significant number of complete remissions, including complete molecular remissions (74).

2.3.4. Autologous and Allogeneic Bone Marrow Transplantation

The rationale for intensive treatment is based on the speculation that increasing the quality of response should provide a longer time to progression interval and the assumption that it is the best way to increase overall survival. Moreover, allogenic transplant has been demonstrated to cure some patients through the graft vs leukemia effect.

Myeloablative treatments followed by autologous or allogenic stem cell rescue were first proposed as palliation intent for patients with advanced disease that was resistant or relapsing after standard treatments (75-80). A large European retrospective survey of stem cell transplantation in CLL has recently summarized the available data and outcome from 413 patients (79). Despite great differences in previous treatments, patient selection, source and treatment of stem cells, conditioning regimens, age, and status at transplantation, these data suggest that autologous stem cell transplantation compares favorably with allogenic transplantation in terms of treatment-related toxicity, mortality, and overall survival. Results of the autotransplantation procedure are better when performed soon in the course of the disease (< 36 mo) and when peripheral stem cells are used; cell manipulation, either positive (CD34) or negative (B-cell purging), does not translate into improved survival. However, a lower incidence of relapse is observed with allotransplants, suggesting a graft vs leukemia allogenic effect and the possibility that some of these patients might have achieved cure (79).

Autologous stem cell transplantation (ASCT) has also been investigated in younger patients with refractory/relapsed B-CLL or in first remission, leading to high response rate and prolonged progression-free survival (79-81). Although it has been suggested that previous treatment with FDB could impair the harvest of peripheral stem cells, ASCT could be performed in most patients after fludarabine therapy (79). Performed early in first remission, ASCT has showed promising results, with an impressive rate of complete response at the molecular level (25). Through assessment of the residual disease after the transplant procedure with sensitive clone-specific methods, it has been shown that patients who became polymerase chain reaction (PCR) negative after transplantation (either allogenic or autologous) experienced long-term disease-free survival (81,82), whereas the persistence or recurrence of the clone-specific signal predicted relapse (81,82). Since only patients demonstrating chemosensitivity are selected for a transplant program and since these patients are known by their long-term outcome, the place of ASCT in front-line treatment of younger B-CLL patients should be prospectively investigated. PCR negaitivity in residual disease has been obtained for the first time in CLL, which constitutes an important step in the strategy leading to cure (81). The time has come to evaluate more precisely the place of intensive treatment, either as part of the initial strategy (especially in "young" patients) or as salvage treatment for poor responders after first-line treatment. In this setting, first-line chemotherapy preceding intensive treatment should combine a maximal antitumor effect and a low stem cell toxicity to avoid difficulties of stem cell collection.

Stem cell allotransplantation in CLL is often limited by the patient's age and donor availability (75-77). Only 10% of patients with advanced stage CLL, and fulfilling the eligibility for this treatment, actually undergo allotransplantation (97). The procedure is associated with a high treatment-related mortality (40%) and a 20% relapse rate at 3 yr. Quality of life after allotransplantation is often a matter of concern. Some groups have developed an alternative method using less toxic, non myeloablative regimens (83,84), which has been proposed in patients with CLL until they are 65-70 yr old (85). This perspective deserves further study.

Another approach toward eliminating residual disease is postremission treatment with monoclonal antibodies like Campath or anti-CD20. Both have been demonstrated by clone-specific molecular probes to induce complete molecular remission following an initial chemotherapy regimen. In the case of anti-CD20, a higher response rate could be achieved by increasing either the dose (71) or the frequency of administration (72) of rituximab.

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