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Originally published as JCO Early Release 10.1200/JCO.2005.08.964 on March 14 2005 © 2005 American Society of Clinical Oncology.
Changing the Way We Think About Chronic Lymphocytic LeukemiaThe Ohio State University, Columbus, OH The treatment of chronic lymphocytic leukemia (CLL) has undergone a revolution during the past two decades. CLL was considered an indolent, incurable disease, and therapy consisted primarily of alkylator-based regimens. The introduction of the purine analogs fludarabine, pentostatin, and cladribine into clinical trials in the 1980s invigorated clinical research in CLL and dramatically changed the treatment of this disease. Studies using fludarabine as salvage therapy demonstrated that a small fraction (10% or less) of patients attained complete remission (CR),1,2 whereas up to a third of patients attained a CR with fludarabine as first-line therapy.3 Three large phase III trials in symptomatic, untreated CLL patients have confirmed the superiority of fludarabine, demonstrating advantages in response rate, CR rate, and progression-free survival (PFS) compared with alkylator-based regimens.4-6 However, no overall survival (OS) improvement was noted in these studies. A small incremental increase may not have been identified because of trial sample size or cross-over designs that allowed patients to receive fludarabine after progression on alkylator therapy. Given that we treat CLL at time of symptoms and given the ability of fludarabine to more effectively palliate disease-related manifestations and time of remission, fludarabine is considered by many, but not all, physicians as a better initial treatment than alkyators for CLL. Because of the ability of fludarabine to result in complete responses, this end point might serve as a surrogate marker for improved survival. This notion was derived from clinical experience in acute leukemia and non-Hodgkin's lymphoma (NHL), where CR correlates with long-term survival. In CLL, the relationship of CR to long-term survival is less clear. Long-term follow-up by the M.D. Anderson group with fludarabine monotherapy did not confirm this,7 and the randomized phase III studies of fludarabine did not identify a correlation between CR and long-term survival. However, attainment of CR in these studies was clinically defined or defined by a nonstringent morphology requirement of the NCI96 criteria, which permit considerable bone marrow involvement.8 In contrast, the experience with autologous and allogeneic stem-cell transplantation for CLL indicates that patients who become polymerase chain reaction (PCR) negative have prolonged PFS and OS.9 This body of work leads to the hypothesis that, if we could improve both the proportion of patients attaining CR and the quality of the remission as assessed by PCR (or other sensitive techniques), then we would improve the survival of patients with CLL. Subsequent research in CLL over the past decade has focused on development of combination regimens built on fludarabine or other nucleoside analogs, with the goal of improving CR and PFS and, ultimately, OS. The most promising of these regimens have been combinations of fludarabine with cyclophosphamide; pilot studies of two schedules demonstrated higher CR rates and overall response (OR) rates and increased frequency of flow cytometry–negative bone marrow biopsies at completion of therapy compared with historical results from fludarabine monotherapy trials.10-13 Concurrently, two important articles validated the importance of minimal residual disease assessment in relapsed CLL. The Barcelona group examined fludarabine, cyclophosphamide, and mitoxantrone in relapsed CLL patients and demonstrated that attaining either flow cytometry or PCR negativity is associated with improved OS.14 Similar findings were reported with alemtuzumab by the Leeds Group, using a highly sensitive flow cytometry assay.15 The Eastern Cooperative Oncology Group (ECOG), in conjunction with the US Intergroup (ECOG 2997 study), and the German CLL Study Group have initiated and completed two large phase III studies using combination regimens of fludarabine and cyclophosphamide. Both of these studies have been reported (in abstract form). The German CLL Study Group randomly assigned 375 previously untreated (209 assessable) CLL patients to either fludarabine and cyclophosphamide (using the M.D. Anderson regimen) or fludarabine monotherapy. This study demonstrated advantages for fludarabine and cyclophosphamide versus fludarabine alone in CR (20% v 9%, respectively) and PFS (28.2 v 22.8 months, respectively).16 The results of the experimental arm, although appearing positive, are similar to the results observed in each of the three previous randomized phase III studies performed with fludarabine alone.6 Virtually identical findings were observed in the ECOG study.17 Further follow-up of these two studies will be necessary before we can prove the added benefit of administering cyclophosphamide with fludarabine. In addition, it will be important to observe these patients for long-term toxicities because a higher incidence of treatment-related myelodysplastic syndrome and acute myeloid leukemia was noted in the combination of fludarabine and chlorambucil in the previous US Intergroup study 9011.18 The other approach in developing fludarabine-based combination regimens has focused on the addition of the monoclonal anti-CD20 antibody, rituximab. Rituximab has single-agent activity in CLL,19-21 modulates antiapoptotic proteins associated with fludarabine resistance,22,23 and is synergistic with a variety of chemotherapy agents in NHL models.24 Several groups have added rituximab to fludarabine-based cytotoxic regimens, with exciting results in phase II trials of untreated or previously treated CLL.25-27 Two of these reports by Keating et al28 and Wierda et al29 from the M.D. Anderson Cancer Center, which are in this issue of the Journal of Clinical Oncology, represent potentially important studies for the advancement of CLL treatment.
The first report by Keating et al28 summarizes the results of fludarabine, cyclophosphamide, and rituximab (FCR) in 224 previously untreated CLL patients. Extraordinary clinical activity was observed, with CR in 70% of patients, nodular partial response (NPR) in 15% of patients, and partial response (PR) in 15% of patients. The OR rate was 95%, though the percentage of stage I and II patients was higher than in most earlier studies. It is unclear what proportion of these early-stage patients had symptoms. Two-color flow cytometry studies showed that 103 (71%) of 145 patients achieved a flow-negative marrow, as defined by less than 1% CD5- and CD19-positive cells. These flow-negative patients had a significantly lower relapse rate (3.6%) than patients who had 1% to 4.9% or Given the questionable benefit of adding an alkylator to fludarabine monotherapy at this point, one could question whether a similar randomized study adding an alkylator to fludarabine and rituximab is needed. The Cancer and Leukemia Group B (CALGB) has reported a randomized phase II study of 104 previously untreated CLL patients,25,26 demonstrating that concurrent administration of fludarabine and rituximab achieved a 47% CR rate compared with a 28% CR rate when the two agents were given sequentially.26 A recent retrospective review of the CALGB 9011 and 9712 trials revealed that previously untreated CLL patients who received fludarabine and rituximab, whether concurrently or sequentially, compared with patients who received fludarabine alone, experienced significantly improved rates of OR (84% v 63%, respectively), CR (38% v 20%, respectively), 2-year PFS (67% v 45%, respectively), and 2-year OS (93% v 81%, respectively).25 Although the CR rate (70%) was higher in the M.D. Anderson study published in this issue,28 PFS and OS with short follow-up seem to be similar when fludarabine and rituximab or FCR are administered as initial therapy. Thus, we are left with the following question: should FCR, fludarabine and rituximab, fludarabine and cyclophosphamide, or monotherapy with fludarabine now be the standard of care for up-front treatment of CLL? Although the M.D. Anderson report by Keating et al28 and the CALGB comparison study26 both report highly encouraging results, one must remember that these findings still represent phase II, noncomparative data. The difference in patient demographics between these two studies, with younger, earlier-stage patients being enrolled onto the M.D. Anderson study, could be a major contributing reason for the difference in complete response rates between these two studies. At the present time, PFS between these two studies seems to be similar. With respect to both trials, one only needs to recall the excitement generated by highly aggressive combination treatments in the treatment of aggressive NHL in the 1980s. Similarly distinguished institutions reported phase II results that seemed superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), yet a phase III study by the Southwest Oncology Group showed that all three regimens were no better than CHOP.30 The value of multi-institutional, prospective, randomized phase III studies should never be underestimated. Although recent research has made great strides in identifying prognostic markers, such as ß2-microglobulin, CD38 expression, p53 dysfunction, interphase cytogenetics, immunoglobulin VH mutational status, ZAP-70 expression, mcl-1 protein expression and mcl-1 promoter insertion, a prognostic scoring system, such as the International Prognostic Index for aggressive NHL, does not yet exist for CLL. Thus, it remains difficult to compare CLL patients in one phase II study to patients in another phase II study. Because CLL is a heterogeneous disease, one must exercise great care when comparing results from phase II trials. Identification of the critical prognostic factors necessary for risk stratification of CLL patients is a major area of ongoing research. In the meantime, however, there is no substitute for well-designed, prospective, randomized clinical trials. How, then, do we treat symptomatic, previously untreated CLL patients? It is with great anticipation that clinicians await the results of an ongoing randomized phase III study by the German CLL Study Group comparing fludarabine and cyclophosphamide with FCR. Concurrently, a randomized phase II US Intergroup study will examine the following different combinations of chemoimmunotherapy: FCR, fludarabine and rituximab, fludarabine and rituximab followed by maintenance rituximab, and fludarabine and rituximab followed by consolidation alemtuzumab (and potentially, at a later date, other consolidation therapies such as flavopiridol). This study will examine 2-year PFS as the primary end point based on VH mutational subtype. This trial will hopefully identify therapies most appropriate for lower risk (VH mutated) and higher risk (VH unmutated) CLL patients and form the basis for a future randomized phase III study in which treatment is decided prospectively by genetic risk. Inclusion of patients onto this or other clinical trials remains the most appropriate option for symptomatic, previously untreated CLL patients. The second report by Wierda et al29 summarizes the M.D. Anderson experience with this same FCR regimen in 177 previously treated patients, 82% of whom had relapsed after prior fludarabine-based therapy. The subgroup of patients who had previously received fludarabine and cyclophosphamide (n = 34) and the total population had similar CR (24% v 25%, respectively) and OR rates (74% v 73%, respectively) to FCR. However, patients who failed to achieve at least a 6-month response to initial fludarabine-based therapy (n = 33), compared with patients who were previously sensitive to fludarabine, had markedly inferior CR (6% v 33%, respectively) and OR rates (58% v 77%, respectively). PFS and OS were primarily influenced by at least a partial response to therapy, ß2-microglobulin level, and normal chromosomes or del(13)(q14) abnormality by metaphase cytogenetics. Thus, although the addition of rituximab may improve outcome, it preliminarily seems to have limited long-term ability to overcome inherent tumor resistance to fludarabine or high-risk karyotypes. Indeed, the frequency of p53 mutations or deletions is 42% in this patient group,31 possibly explaining why remissions are compromised. Alemtuzumab32 or investigational therapies for patients with fludarabine-refractory disease should be considered as an alternative to FCR. Of additional early concern is the occurrence of five cases of treatment-related acute myeloid leukemia or myelodysplastic syndrome in this study. Nonetheless, these articles28,29 clearly demonstrate that CLL patients who have experienced treatment failure with cytotoxic chemotherapy or rituximab therapy may still respond to a combination of cytotoxic therapy and rituximab. As labeled by the M.D. Anderson group in the titles of both articles,28,29 "chemoimmunotherapy" may achieve clinical activity when chemotherapy or immunotherapy alone may not; these articles do establish that the two treatment modalities together may be effective in this clinical setting. In summary, the two articles28,29 by the M.D. Anderson CLL group demonstrate that chemoimmunotherapy has considerable activity in clinical practice and that such combination therapy can achieve high rates of hematologic, flow cytometric, and molecular responses in CLL. Although curative therapy may not yet exist for CLL, these reports show that aggressive therapy can yield PFS of significant duration and lay the groundwork for further clinical research into combination therapy in CLL. As new monoclonal antibodies and other novel agents are introduced into clinical trials, a major challenge of CLL research will be determining the optimal manner in which these agents should be clinically incorporated into fludarabine-containing regimens. Additionally, it will be important to understand how different genetic subsets respond to these therapies because it is likely that we will increasingly treat future CLL patients based on their genetic risk stratification. Great strides in the treatment of CLL have been made in the last 20 years, and the next two decades promise that further advancements in CLL therapy will be achieved. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. 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29. Wierda W, O'Brien S, Wen S, et al: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 23:4070-4078, 2005
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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5% tumor cells by flow cytometry (20% and 43%, respectively). In contrast to previous reports, this study demonstrated that flow cytometry–negative or minimally positive (< 5%) bone marrow at completion of therapy correlated with improved OS. PCR-based studies, using a new method not validated against standard assays, demonstrated parallel findings to the flow cytometry studies. In contrast, no difference in relapse rate was noted between the NPR (35%) and PR (27%) groups, raising the question whether NPR should be considered a separate category from PR. For the practicing physician, these results indicate that persistent residual disease detected by two-color flow cytometry (a test performed by most flow laboratories) predicts for an increased risk of relapse and inferior survival with combination therapy. Additional prospective studies using quantitative assays for minimal residual disease will be needed to determine whether there is a threshold of disease that predicts relapse. 
