Monday, April 07, 2008

Drug-resistant chronic lymphocytic leukaemia

After successful induction therapy, relapse is almost inevitable if no consolidation takes place and is still possible if consolidation has been done. After long remissions, patients will usually respond again to the same type of treatment, but relapse after short-lived remissions and primary refractory disease needs a different approach.

In the relapsed and refractory setting,[157] and [158] fludarabine, cyclophosphamide, and rituximab can produce high response rates (73%) and complete remissions (25%). In a comparison with historical controls, results suggested that fludarabine, cyclophosphamide, and rituximab is superior to fludarabine plus cyclophosphamide or to fludarabine alone. However, although the multivariate analysis included concentrations in serum of β2 microglobulin, interphase cytogenetics and IGHV mutational status were not studied.

No phase III data on this comparison has yet been published, although the REACH trial is currently being evaluated. The first interim analysis early in 2008 did not react its projected end point and a final analysis will take place later this year.

Most effective treatments for chronic lymphocytic leukaemia need an intact TP53 pathway. Patients with advanced refractory chronic lymphocytic leukaemia treated with high-dose prednisolone had an overall response rate of 77%.[159] Alemtuzumab also produced high levels of response in TP53-deleted chronic lymphocytic leukaemia.[160] The combination of these agents gave a 100% response with 60% complete remission in a few patients with TP53 defects.[161]

The use of these agents in combination is very immunosuppressive and reactivation of CMV is a constant hazard. It is necessary to screen for this on a weekly basis, and to institute treatment with gancyclovir before symptoms occur is reactivation is seen.

Flavopiridol, a cyclin-dependent kinase inhibitor, has proved a very effective killer of TP53-deleted chronic lymphocytic leukaemia cells in vitro, but it was almost completely ineffective in vivo because it was so highly bound to human serum albumin. By altering the infusion schedule, partial remissions of long duration have been obtained in 42% of chronic lymphocytic leukaemias with TP53 deletions.[162]

Lenalidomide, is a derivative of thalidomide that is effective in the treatment of myeloma and myelodycplastic syndrome, especially cases with del 5q. It has been used in the treatment of CLL with moderate efficacy. Its mode of action is not completely clear, but it is believed to interfere with interactions between stromal cells and CLL cells in the tissues. Consequently it might have activity in patients with disease that is resistant to standard therapy.

The original phase II study from Roswell Park [163] reported on 45 patients with relapsed or refractory disease treated with 25mg/day for 21 days of a 28 day cycle. 9% achieved CRs and 38% PRs. 10 of the patients had ATM deletions and 6 p53 deletions. The response rate in those with ATM deletions was the same as in other cases, but they do not report what happened in patients with p53 deletions.

A second study from MD Anderson Cancer Center [163a] included a dose escalation phase, begining at 5mg/every day for 28 days, rising to a maximum of 25mg. 44 relapsed or refractory patients were studies. The CR rate was 7% and the PR rate 25%. Given the rather lower dose some patients received, this was in line with the Roswell Park findings. The response rate among del 11q patients was 39%, but among 8del 17p patients, only one responded. Lenalidomide is being touted as a useful drug in TP53 deleted patients; there is very little evidence to support this.

157 W Wierda, S O'Brien and S Wen et al., Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia, J Clin Oncol 23 (2005), pp. 4070–4078.

158 W Wierda, S O'Brien and S Faderl et al., A retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens, Cancer 106 (2006), pp. 337–345.

159 PD Thornton, E Matutes and AG Bosanquet et al., High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities, Ann Hematol 82 (2003), pp. 759–765.

160 NC Osuji, I Del Giudice, E Matutes, AC Wotherspoon, C Dearden and D Catovsky, The efficacy of alemtuzumab for refractory chronic lymphocytic leukemia in relation to cytogenetic abnormalities of p53, Haematologica 90 (2005), pp. 1435–1436.

161 AR Pettitt, E Matutes and D Oscier, Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects, Leukemia 20 (2006), pp. 1441–1445.

162 JC Byrd, TS Lin and JT Dalton et al., Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia, Blood 109 (2007), pp. 399–404.

163 A Chanan-Khan, KC Miller and L Musial et al., Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study, J Clin Oncol 24 (2006), pp. 5343–5349.

163a A Ferrajoli, L Bang-Ning, EJ Schlette et al. Lenalidomide induces compltee and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood (2008) published on-line March 11 doi:10.1182/blood-2007-12-130120

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