A whole range of new therapeutic agents is in development, some of which are already in the clinic. Lenalidomide [163] might act by interfering with the tumour/stroma interaction. Ofatumumab is a fully humanised CD20 monoclonal antibody with reputed advantages over rituximab because of a slower off-rate.[164] Lumiliximab—a primatised anti-CD23—is entering clinical trials in patients with chronic lymphocytic leukaemia.[165] Chronic lymphocytic leukaemia cells with deletions at 11q23 seem to be especially sensitive to the orally available poly (ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalamide.[166] ATM-deletion-mediated drug resistance might also be overcome with Nutlin 3a.[167] Finally, acadesine seems to be a new chemotherapeutic agent capable of killing chronic lymphocytic leukaemia cells yet leaving T cells unharmed.[168]
References
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.
164 JL Teeling, WJ Mackus and LJ Wiegman et al., The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20, J Immunol 177 (2006), pp. 362–371.
165 BD Cheson, Monoclonal antibody therapy of chronic lymphocytic leukemia, Cancer Immunol Immunother 55 (2006), pp. 188–196.
166 HE Bryant and T Helleday, Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair, Nucleic Acids Res 34 (2006), pp. 1685–1691.
167 K Kojima, M Konopleva, T McQueen, S O'Brien, W Plunkett and M Andreeff, Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia, Blood 108 (2006), pp. 993–1000.
168 C Campas, JM Lopez and AF Santidrian et al., Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes, Blood 101 (2003), pp. 3674–3680.
3 comments:
I'm not sure that any of these agents has been approved by the FDA, save Revlimid, and that was for MDS if memory serves me correctly, not CLL.
Ofatumumab is still in trials and probably won't get FDA approval until 2009 or 2010.
Lumiliximab is still in trials with no anticipated FDA approval date. It probably wouldn't be used except in combination with existing chemotherapy drugs.
4-Amino-1,8-naphthalimide is a PARP inhibitor. One PARP inhibitor is in one clinical trial for CLL. That phase I trial is expected to end in 2009. It is too early to tell if the drug will met its goals.
Nutlin 3a has yet to enter clinical trials.
Acadesine is in one phase I trial in CLL. It is a purine nucleoside analog similar to fludarabine.
That's why I put them in this section
Revlimid is in trial at this time for CLL at a few clinics. My husband starts the MDAnderson revlimid trial on May 28, 2008. Their protocol is 10mg a day for 3 months with no off days.
Jenny Lou Park
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