Improving quality of life in chronic lymphocytic leukemia

Patients with chronic lymphocytic leukemia (CLL) can have impaired quality of life (QoL) because of progressive disease and complications including anemia, fatigue, infections and second malignancies [1,2]. QoL can be further impaired by disease associated anxiety [3] and therapy for CLL [4]. Because CLL is a chronic disorder that is incurable with conventional therapy, optimizing QoL is a major goal of management. Initial treatments for CLL with chemoimmunotherapy (CIT) regimens including purine analogs and rituximab have improved overall and complete response, duration of response and survival [5–7]. However, this progress has come at the cost of increased treatment related toxicity. The challenge is to determine whether these non-curative therapies result in sufficient long-term improvement of QoL to justify their toxicity.

Accurate, reproducible and consistent determination of QoL in CLL can be challenging. CLL progression is often insidious, and patients can have difficulty judging the magnitude and causation of disease associated changes, a problem that can be exacerbated by the effects of comorbidities [8]. In studies of QoL in trials of initial therapy for progressive CLL, an additional challenge is the need to collect a complete and accurate data set over many years.

Patients with CLL are often treated for progressive disease because of consequences of their disease such as anemia and fatigue that can cause a profound decrease in QoL [9]. Initiation of treatment results in disruptions of patients’ normal routines and the realization that the disease has entered a more threatening stage. The resultant anxiety and depression can have significant effects on QoL [2]. Initial treatment of progressive CLL can thus have both positive and negative effects on QoL, depending on the pretreatment morbidity and the efficacy and toxicity of therapy. Effective therapy can rapidly reverse CLL induced fatigue and result in recovery from symptomatic anemia, but is unlikely to markedly increase QoL in patients treated for asymptomatic disease progression. In contrast, all treatments can result in complications that decrease the QoL.

In this issue of Leukemia and Lymphoma, Else et al. report the results of a long-term study of QoL in patients treated for progressive CLL in the British CLL4 trial [10]. CLL4, which was reported in 2007, enrolled 777 patients who were randomized to treatment with chlorambucil, fludarabine or fludarabine and cyclophosphamide (FC) between 1999 and 2004 [4]. FC achieved the highest response rate and duration of response, but did not improve overall survival and was the most toxic therapy [4]. Patients receiving fludarabine or FC had a significantly greater deterioration in QoL compared to those receiving chlorambucil during treatment, but QoL after completion of therapy was similar between the groups. However, patients with sustained remissions had the best QoL. Given that FC treatment resulted in more and longer remission, these findings appear discordant.

There are several possible reasons for this apparent discrepancy. QoL studies rely on patients’ subjective assessments, and accurate comprehensive data can be very difficult to obtain. Considerable bias can occur because of incomplete or missing evaluations which are more frequent in patients who are older, have more severe disease or have disease progression. In addition, the data sets for patients who die are incomplete. Despite the development of methods to correct these problems, residual bias can persist. An additional obstacle to assessing whether more efficacious treatment resulted in improved QoL was that the majority (67%) of the patients studied did not have appreciably decreased QoL before initiation of therapy, and thus had limited potential for improvement in QoL [2]. The study used a standardized and well-validated QoL questionnaire, but this was not designed for CLL studies, and could thus have been less sensitive to CLL specific features such as drenching night sweats, anemia and fatigue that impact on QoL. An additional concern is that this study was designed and conducted in the pre-CIT era using therapies that are all significantly less effective than those currently used. While some of these limitations are intrinsic to any studies of QoL or CLL, others are remedial, and this report is thus important for the design of future studies. However, the current data are not sufficient to determine conclusively whether the more effective and more toxic therapies now available for CLL improve overall QoL compared to less effective treatments.

Can the results of this study be applied to current patient management? The finding that patients with progressive CLL who respond to therapy have a significantly improved QoL supports the use of effective therapy, and is similar to the result of a previous German led study [11]. Although not proven, these data suggest that the more efficacious but more toxic therapy (FC) is likely to result in improved long-term QoL in CLL. Following the documentation of improved overall survival with initial treatment of progressive CLL with fludarabine, cyclophosphamide and rituximab (FCR) [5], it would be valuable to have data from patients treated with FCR to determine its impact on long-term QoL. In the interim, the currently available data suggest that the initial treatment of progressive CLL with the most efficacious CIT that patients are likely to tolerate is the best way to optimize their QoL.

Potential conflict of interest

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