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31st Annual Meeting Association des médecins hématologues et oncologues du Québec

Vaudreuil, Quebec / April 20-23, 2006

According to Dr. Anders Österborg, Professor of Oncology, Karolinska Institute and Hospital, Stockholm, Sweden, the biology and epidemiology of B-cell chronic lymphocytic leukemia (CLL), the most common form of leukemia in adults, have undergone evolution. These developments call for a change in perspective on and a more optimistic, proactive approach to the diagnosis, prognostic staging and treatment of the disease. “During the last few years, CLL has become very interesting because of the new biological aspects and because of many new therapeutic possibilities,” he told the audience.

Until recently, it was believed that CLL resulted almost exclusively from an accumulation of a malignant B-cell clone in bone marrow, blood, lymph tissue and organs. These B-cell clones were characterized by an inherent defect in apoptotic capacity. Over the last decade, new evidence has shown that CLL is derived from antigen-experienced B-cells that do not only have an intrinsic defect in apoptosis but are also influenced by a variety of regulatory signals from bystander cells in the bone marrow micromilieu. In addition, CLL cells seem to exhibit a higher capacity to proliferate than was once understood. Many patients have cell clones with identical Ig heavy-chain gene rearrangements, a situation which points to one or more common antigens that still remain mainly unidentified. However, it has been long recognized that the clinical course of the disease can vary widely from patient to patient. It is believed that this heterogeneity is due partly to differences in B-cell maturation and activation, gene profile and mutations in immunoglobulin heavy-chain variable-region (VH) genes. These new findings on the disease process have substantial implications for current and future therapeutic approaches, indicated Dr. Österborg.

CLL was perceived for a long time as a relatively benign and indolent disease affecting primarily the elderly and for which treatment could reasonably be delayed until disease progression occurred. However, between 20 and 30% of cases of CLL occur in individuals under 55 years old and the incidence in this age group is on the rise. In younger adults, the diagnosis is more devastating and aggressive treatment may be more appropriate. In addition, overall survival after failure of standard therapies (such as alkylating agents and fludarabine) is often less than one year. “There is an urgent medical need to do something for these patients who have failed standard therapy,” Dr. Österborg emphasized.

Contribution of New Prognostic Factors

Clinical staging systems, disease patterns and other factors (Table 1) are typically employed to aid decisions on initiation of CLL therapy but many of these cannot predict a patient’s clinical course when the disease is still in its earliest stages. Emerging biologic markers enhance clinical staging by allowing earlier classification of probable disease course and prognosis, and support the concept of risk-adapted therapeutic decision-making, Dr. Österborg indicated. Some of these biologic factors might also be potential molecular targets for therapy, he added.

Table 1. Current and Proposed Prognostic Factors

The mutation status of VH genes in leukemic lymphocytes has been shown by several research groups to be a reliable prognostic indicator. Mutated CLL, defined as disease including leukemic cells with at least 2% VH mutations as compared with corresponding genes in the germ line, is associated with a much better median survival than unmutated cell phenotypes, Dr. Österborg explained. For example, in research by Hamblin et al. (Blood 1999; 94(6):1848-54), median survival in patients with mutated vs. unmutated CLL was 293 vs. 117 months. “That is, to me, not only a significant but a clinically meaningful difference, indicating that perhaps [patients with the unmutated form of CLL] are a group for whom we need to have a closer look at what we could do in terms of therapy,” Dr. Österborg indicated.

Because mutation analysis is time-consuming and costly, investigators are continuing to assess other potential biologic factors that—–together or separately—may offer similar prognostic information. One relatively simple test that has generated enthusiasm among hematopathologists is flow cytometry analysis of the expression of zeta-associated protein (ZAP)-70, an intracellular protein that disseminates activation signals and which is not expressed by normal B-cells. ZAP-70 is typically associated with an unmutated cell phenotype, and patients who are ZAP-70-positive have a poorer prognosis than those whose test is negative (Orchard et al. Lancet 2004;363(9403):105-11). Some recent evidence suggests that ZAP-70 analysis may even be a stronger prognostic indicator than mutation analysis. Still, it is widely believed to be too early to rely on this test as a prognostic marker outside the research setting, Dr. Österborg cautioned. “The problem is that this is complicated in terms of reproducibility. It still needs to be standardized and validated across different hematopathology laboratories.”

The study of cytogenetics also offers useful prognostic clues. Likely the most relevant genetic lesions discovered to date are deletions at 11q or 17p, which are chromosomes involved in regulation of apoptosis and resistance to chemotherapy. These genetic aberrations also appear to correlate with unmutated CLL and poor outcome (Dohner et al. New Engl J Med 2000;343(26):1910-6). “[Patients with these deletions] did much worse than [those with] all other cytogenetic abnormalities. This is the first time where we see something that could influence our clinical decision-making, because we also know from recent trials that these patients will respond very poorly to chlorambucil, not very well to fludarabine, but apparently better to CD52-targeted antibody therapy,” Dr. Österborg stated.

Additional information on CLL prognosis has emerged from studies of telomere length, telomerase activity and VH family gene subtyping, he added.

Initial and Subsequent Treatment

Once the decision has been made to offer cytotoxic therapy, numerous practical considerations can help guide the choice of treatment. According to Dr.Österborg, chlorambucil is still the preferred first-line agent for elderly patients for whom symptomatic relief is a reasonable goal. The combination of fludarabine and cyclophosphamide (FC) is emerging as the first-line standard therapy in younger patients or those with more advanced disease (e.g. those presenting with anemia or thrombocytopenia). Two prospective, randomized controlled trials (Eichhorst et al. Blood 2006;107(3):885-91 and Catovsky et al. American Society of Hematology 2005 meeting; abstract 716) have now demonstrated that this combination resulted in higher rates of complete response (CR) and overall response rate (ORR) than fludarabine alone. With FC treatment, patients gained a longer progression-free survival period (48 vs. 20 months) and the combination was associated with a lower risk of autoimmune hemolysis. It also allows fludarabine to be given for three days per treatment cycle rather than five, which could reduce treatment costs, Dr. Österborg observed.

In Europe, it is now standard practice to administer alemtuzumab, a monoclonal antibody targeting the cell surface protein CD52, upon failure of chemotherapy. Dr. Österborg noted that in several studies, response rates to single-agent alemtuzumab in patients with advanced CLL have ranged from 33% to close to 50%, and response duration from eight to 12 months. In the pivotal trial of this agent (Keating et al. Blood 2002;99(10):3554-61), survival in responders was approximately double that of the intent-to-treat (ITT) population and triple that of historical controls (Figure 1). In a phase II study in which alemtuzumab was employed first-line, more than 80% of patients had a remission (Lundin et al. Blood 2002;100:(3)768-73). “[Using alemtuzumab as first-line CLL therapy] is something that should not yet be done outside clinical trials, but these data show that in trial settings, perhaps, we should move it from last-line to second- or first-line therapy, especially as part of a combination therapy,” Dr. Österborg suggested.

Figure 1. Pivo
mab: Overall Survival

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Immunosuppression is a key concern with CD52-targeted therapy. Alemtuzumab produces long-lasting suppression of CD4 and CD8 cells (Lundin et al. Leukemia 2004;18(3):484-90). “That’s why it’s critically important to have all the patients on antiviral and antibiotic prophylaxis,” Dr. Österborg stressed. The currently recommended preventive regimen is acyclovir and cotrimoxazole until six months’post-alemtuzumab therapy (antifungal prophylaxis is not recommended). Clinical reactivation of cytomegalovirus (CMV) is considered the most significant risk with alemtuzumab-related immunosuppression. “If a patient [presents with] low-degree fever, rising C-reactive protein and fatigue, we immediately do a CMV PCR [polymerase chain reaction] analysis to check for CMV reactivation. If it’s positive, we [stop alemtuzumab and] start ganciclovir therapy right away. It’s possible to restart alemtuzumab afterwards in most patients,” he told delegates.

Tolerability of intravenously administered alemtuzumab may also be an issue. According to Dr. Österborg, tolerability can be substantially improved if the agent is administered via subcutaneous rather than intravenous injection. (Currently, this practice is officially recommended only for patients in whom venous access is a problem.) “Using it intravenously, it will lead to rigour in close to 80% of the patients, and rash, nausea or vomiting also in a high proportion. It has been shown that alemtuzumab is about equally effective given subcutaneously and has almost none of the first-dose reactions.” Subcutaneous injection may produce local skin reactions but these tend to be transient and seldom require interruption in therapy in patients who have received prior treatment with chemotherapy.

Clinical Pearls on Use

An important finding in previous trials of alemtuzumab is that a response is most likely and toxicity and tolerability issues are less likely to be problematic in patients with good performance status, Dr. Österborg observed. He noted that many clinicians have tended to delay administering the monoclonal antibody because of toxicity concerns and, despite poor prior results, opt to administer another course of chemotherapy. “We must keep in mind that once we start to find that fludarabine is no longer effective, that is the time point to shift toward antibody therapy—treat the patient while they are still in a relatively good condition.”

Certain patient subgroups are more likely to respond to the monoclonal antibody than to other agents, and the goal of therapy for individual patients may also play a role in treatment selection. “It appears quite clearly from a number of recent trials that patients with 17p deletion—who typically respond quite poorly to fludarabine and have a poor prognosis—respond well to alemtuzumab. So this is a subgroup for which I think we should consider targeting CD52 quite early,” he stated.

In early trials of this monoclonal antibody as a therapy for low-grade lymphoma, response rates were only around 14%. However, despite progressive growth of their lymph nodes, many of those patients experienced disease remission in blood and bone marrow. According to Dr. Österborg, “Our experience suggests if a CLL patient has large lymph nodes and a major goal of therapy is to shrink that load, then in that case, alemtuzumab is not a very good option. But if bone marrow remission is important in a patient who has relatively large lymph nodes, then this agent is still something to consider.” The monoclonal antibody may also be beneficial in patients with severe bone marrow suppression due to heavily infiltrated bone marrow or previous chemotherapy, and its immunosuppressive effects may be useful in those with autoimmune hemolytic anemia or autoimmune thrombocytopenia, he added (Lundin et al. Med Oncol 2006; 23(1):137-40).

Minimal Residual Disease Elimination

Some evidence indicates antibody therapy in general may be most relevant in patients with small tumour volumes. This notion may also apply to CLL: elimination of minimal residual disease (MRD) may prove an appropriate goal of monoclonal antibody therapy if it can be shown it produces a survival advantage, stated Dr. Österborg. “There are a number of trials indicating that the better the quality of the remission in the CLL patient, the better their overall survival might be.” UK investigators recently showed in a retrospective analysis of 91 patients treated with alemtuzumab that MRD negativity was associated with a longer survival than was observed in patients who did not achieve MRD negativity (Moreton et al. J Clin Oncol 2005;23(13):2971-9). Results from a small prospective trial, in which the monoclonal antibody was administered immediately after fludarabine, further support this finding (Wendtner et al. Leukemia 2004;(6):1093-101). Unfortunately, perhaps due to an inadequate washout period before initiation of the monoclonal antibody or to a high dose, toxicity was an issue in this German trial. However, the investigators did find that time to treatment failure was significantly longer in the experimental treatment group than in the observation group. Additional trials with carefully designed treatment schedules and dosing are warranted, Dr. Österborg suggested.

Combination Therapies for CLL

Combining conventional chemotherapy and antibody treatment in CLL makes sense if the aim is to achieve long-lasting molecular remission, Dr. Österborg stated. Combination therapy may be effective both via synergistic effects and because alemtuzumab may sensitize tumour cells to chemotherapy. However, evidence on such combinations remains largely limited to non-randomized and/or single-centre studies. According to data gathered from 177 patients with relapsed CLL, the combination of fludarabine, cyclophosphamide and rituximab (FCR) leads to an ORR of 73%, although it is less effective in those with poor cytogenetic findings (Wierda et al. JCO 2005;23(18):4070-8); used first-line in a single-arm study, the same combination produced a CR of 70% (Keating et al. JCO 2005; 23(18):4079-88). Confirmation of these data may come from a large, recently closed, prospective, randomized study of FCR vs. FC as first-line therapy and results are expected shortly.

One group has determined that co-administration of fludarabine and rituximab is more effective than fludarabine followed by rituximab, as measured by ORR 90% vs. 77%, CR 47% vs. 28% and improved survival over fludarabine alone (Byrd et al. Blood 2003;101(1):6-14 and Byrd et al. Blood 2005;105(1):49-53). In a phase II study, the combination of fludarabine and alemtuzumab has been shown to be safe and effective. Findings indicated an ORR of 83%, CR 30% and overall time to treatment failure 13 months. Two of 36 patients experienced subclinical CMV reactivations (Elter et al. JCO 2005;23:7024-31). Investigators are now evaluating the efficacy of this combination vs. fludarabine alone. A large international phase III trial now underway will compare FC vs. FC plus alemtuzumab as first-line therapy in patients aged under 65 who are at high risk due to either unmutated disease or unfavourable cytogenetic findings. “It will be of major interest to see if alemtuzumab will add something significant in this situation,” noted Dr. Österborg.

While compelling data on these combinations are awaited, new prognostic assessments—especially mutation analysis and cytogenetics—and timely treatment with proven therapies can help clinicians optimize treatment timing and outcomes for patients with CLL.