Haematological Malignancies
Figure 2: Schematic Demonstrating the Aims of Treatment and Treatment Options for Patients with Chronic Lymphocytic Leukaemia Depending on their Level of Fitness
Aim of treatment
Minimal residual disease /
overall survival
Improved CR/PFS Durable remission Symptom control / palliation
go) patients. At the other end of the CLL patient spectrum, best supportive care (BSC) is appropriate for the control and palliation of symptoms in unfit (no go) patients (see Figure 2). However, questions remain about which treatment is the most appropriate for patients between these two extremes (slow go), as well as how physicians should identify/categorise these patients.5
There is also uncertainty as
to whether the goals of treatment should be the same for this group of patients than for their fitter counterparts. For example, is MRD negativity a realistic treatment goal?
FCR ‘Fit’ (go go) BEN +/– R
(not so go go) (not so slow go)
CLB +/– R BEN +/– R FCR lite
(slow go) BSC
‘Unfit’ (no go)
BEN = bendamustine; BSC = best supportive care; CLB = chlorambucil; CR = complete response; FCR = fludarabine–cyclophosphamide–rituximab; PFS = progression-free survival; R = rituximab.
The Phase III Study of the effectiveness & safety of lenalidomide versus chlorambucil as first-line therapy for elderly patients with B-cell CLL (ORIGIN trial), which is currently recruiting, is evaluating chlorambucil versus lenalidomide as first-line therapy in elderly (i.e., ≥65 years) patients with CLL.28 the trial is due to end in 2013.
The primary endpoint is PFS and
Using a ‘pick the winner’ design, a future French intergroup trial, the Groupe ouest est leucémies aiguës myéloblastiques (GOELAM) [West–East acute myeloblastic leukaemias group] trial, due to start in March 2012, will evaluate five therapies in previously untreated patients >65 years, with co-morbidities as defined by a Cumulative Illness Rating Scale (CIRS) score >6 and <10. This trial will involve 140 patients and will compare chlorambucil alone with ofatumumab (a fully human anti-CD20 monoclonal antibody) alone, fludarabine plus ofatumumab, bendamustine plus ofatumumab, and FC-lite, in an attempt to gauge which is the best first-line regimen.
Finally, two trials are ongoing with ofatumumab. The ofatumumab plus chlorambucil vs chlorambucil monotherapy in previously untreated patients with CLL (COMPLEMENT-1) trial is comparing chlorambucil monotherapy with chlorambucil plus ofatumumab in previously untreated patients who are considered inappropriate for fludarabine-based therapy.29
The trial has completed recruitment and is expected to report data in 2013.
Following on from the COMPLEMENT-1 trial, the Randomised investigation of alternative ofatumumab-based regimens for less fit patients with CLL (RIAltO) will compare ofatumumab plus chlorambucil with ofatumumab plus bendamustine in patients not considered fit enough for FCR.30
This trial will begin enrolling shortly.
Thus, over the next few years, we should have high-quality, reliable results from clinical trials demonstrating the relative efficacy and safety of a variety of novel combination regimens in elderly, co-morbid and previously untreated patients with CLL.
Improving Patient Selection and Treatment Choices – Fitness and Co-morbidity Scales At one end of the CLL patient spectrum, it is clear that FCR is an effective treatment option to induce MRD and improve OS in the fit (go
56
For the aforementioned reasons, we propose that sub-groups (‘not so go go’ and ‘not so slow go’) are adopted to provide a tailor-made approach to treatment selection for the individual patient. A version of the CIRS modified for geriatric patients (CIRS-G) may be another useful measure of fitness in elderly CLL patients.33
Another useful method of classifying co-morbid conditions is the Charlson score, a weighted index that takes into account the number and severity of co-morbid diseases.34
It is a simple EUROPEAN ONCOLOGY & HAEMATOLOGY
What is currently lacking from routine clinical practice is a simple tool for accurately gauging fitness and co-morbidity to facilitate optimal treatment decision-making for the majority of CLL patients, who lie between the extremes of the fit and the unfit. The rationale for including a sub-group zone of 'not so slow go' patients (see figure 2) results from our clinical observations that a proportion of 'slow go' patients are able to tolerate stronger treatments to achieve improved CR and prolonged PFS. In a recent survey conducted at the European Hematology Association (EHA) Annual Meeting 2011, 65 % of haemato-oncologists confirmed that they used their clinical judgement alone to gauge a patient’s fitness and suitability for a particular treatment regimen.
In an attempt to improve clinical judgement and make the treatment of the majority of CLL patients more consistent and systematic, a number of scales have been investigated. The GCLLSG has adopted the CIRS to distinguish between physically fit and unfit patients.31 scale is divided into three groups:
The
• ‘go-go’ patients, who are independent, have no co-morbidity, have a normal life expectancy and are considered suitable for treatment with FCR;
• •
‘no-go’ patients, who are severely handicapped, with a high level of co-morbidities and reduced life expectancy – these patients would typically receive best supportive care for palliation of their symptoms; and
in between the two preceding groups lies the 'slow go' patient cohort who present with some co-morbidities, impaired organ function and reduced performance status. However the patients within this large cohort are extremely heterogeneous. The approach to treatment therefore should be further sub-divided in order to tailor therapy. Currently the European Society for Medical Oncology (ESMO) suggests chlorambucil as the SOC for 'slow go' patients, however as mentioned earlier we have observed that a proportion of these patients are able to tolerate a stronger therapy regime such as bendamustine. In addition we postulate that there exists a proportion of 'go go' patients that would benefit from bendamustine, as an alternative to FCR. We have therefore indicated a 'twilight zone' in figure 2, denoted by a grey rectangle, which we propose to represent 'not so go go' and 'not so slow go' patients for whom therapy could be improved.5,31,32
Proportion of patients
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