Sunday, April 06, 2008

CLL: Consolidation therapy

Consolidation of remission aims to eliminate all detectable disease from the patient. In assessing the success of such attempts, the sensitivity of the method used to detect minimal residual disease is crucial. Unlike, many other haematological cancers, there is no characteristic chromosomal translocation to detect. Detection methods use either PCR to identify a unique tumour-associated sequence or flow cytometry to find an exclusive set of tumour antigens. The most sensitive assay uses PCR to detect a specific clonotypic sequence. This technique can ascertain 1 in 100 000 cells,[138] but the IGHV gene needs to have been sequenced before treatment. Use of consensus primers to detect monoclonal immunoglobulin is much less sensitive, being only able to identify 1 in 1000 cells.[139] Rawstron and colleagues [140] have developed a four-colour flow technique capable of detecting 1 in 50 000 cells, and this method has been refined further by an international group for use when anti-CD20 form part of the treatment strategy.[141]

Remissions are traditionally consolidated with high-dose chemotherapy, sometimes with autologous stem-cell rescue. With this approach, a German research group could eliminate minimal residual disease and produce prolonged remissions in patients whose chronic lymphocytic leukaemia had mutated IGHV genes; however, for those with unmutated IGHV genes, molecular relapse was inevitable, and clinical relapse almost so, by 4 years' follow up.[142] However, even this less-than-encouraging outcome might be better than what is achievable with conventional chemotherapy, according to findings of a comparison in matched historical controls.[143] Moreover, stem-cell harvest is only possible in about two-thirds of patients with chronic lymphocytic leukaemia, and there is a worryingly high prevalence of secondary myelodysplastic syndrome.[144] and [145]

Stem-cell allografts have been used in an attempt to capitalise on the graft-versus-leukaemia effect to eliminate minimal residual disease. In a largely elderly population, myeloablative conditioning leads to high treatment-related mortality of 40–50%.[145], [146] and [147] To combat this toxic effect, allotransplantation with reduced intensity conditioning, often followed by donor lymphocyte infusion, has become popular. Early results do not yet show an improvement in event-free survival compared with myeloablative transplants.[148], [149] and [150] In every series, a high frequency of chronic graft-versus-host disease is noted. Nevertheless, in patients with poor-risk prognostic markers, and especially those with 17p13 deletions, sustained remissions without molecular relapse are achievable.[151]

Potentially less hazardous are attempts to consolidate remission with monoclonal antibodies. Alemtuzumab is especially suited because it can kill chronic lymphocytic leukaemia cells in a caspase-independent manner that is not inhibited by loss of TP53 protein [152] and is, therefore, able to eliminate chemotherapy-resistant cells.[153] In a study of 91 previously treated patients,[154] 44 of whom were refractory to purine analogues, complete remissions as defined by the US National Cancer Institute [121] were achieved in 32%. In these individuals, a four-colour flow technique for detection of minimal residual disease did not identify disease in 56%.[140] Patients who became negative for minimal residual disease had significantly longer treatment-free and overall survival than those who did not.

In a prospective phase III study in Germany,[155] patients were randomly allocated either no treatment or alemtuzumab 30 mg intravenously three times a week for 12 weeks, beginning a median of 67 days after the last dose of induction chemotherapy (fludarabine with or without cyclophosphamide). Although recruitment to this trial was halted at 21 patients because of severe infections in the alemtuzumab group, those allocated alemtuzumab had significantly longer progression-free survival than those assigned no treatment. Using a very sensitive PCR-based assay with sequence-specific primers to detect minimal residual disease, five of six patients tested became negative for minimal residual disease. Findings of a phase II study156 of alemtuzumab given in doses of 10 mg subcutaneously three times a week for 6 weeks, beginning not less than 8 weeks after discontinuation of fludarabine induction chemotherapy, proved that this regimen was safe and able to turn partial remissions into complete remissions. A PCR technique with consensus primers (a less sensitive method than that used in the phase III study) was used to detect minimal residual disease; patients with mutated IGHV genes were more likely to become negative for minimal residual disease than were those with unmutated IGHV genes. Reactivation of cytomegalovirus happened in 53% but was successfully treated with oral ganciclovir. 53% of patients successfully underwent autologous stem-cell transplantation, but no follow-up information is available. At present, immunological consolidation with alemtuzumab after chemotherapy seems safer than with allogeneic transplantation, but we await a comparison of efficacy.


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140 AC Rawstron, B Kennedy and PA Evans et al., Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy, Blood 98 (2001), pp. 29–35.
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