Chronic lymphocytic leukemia (CLL) is a malignant type of cancer that involves white blood cells, or lymphocytes, in the bone marrow and then invades
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Approximately 15,000 people are diagnosed with the disease annually in the USA and about 5,000 will die from the disease. CLL is distinguished from CML, which involves myeloid white blood cells instead of lymphocytes. In both cases, one of the defining symptoms of the disease is an excess of white blood cells, either of the lymphocytes or myeloid cells. CLL can either be an excess of T-cell or B-cell lymphocytes, although 90-95% if cases involve B-cells.
Standard treatments for CLL usually includes chemotherapy such as fludarabine, cladribine, chlorumbucil, bendamustine, cyclophosphamide, doxorubicin or vincristine.
Several of these can be used in combination with monoclonal antibody therapy such as rituximab (Rituxan) or alemtuzumab (Campath), for example, sequential therapy using fludarabine, high-dose cyclophosphamide and rituximab. Alemtuzumab is often reserved for patients who have not responded to other treatments.
At the recent American Society of Hematology (ASH) meeting, a number of therapies emerged as potential new agents for the treatment of CLL.
One of these, fostamatinib, was presented in the plenary session. Friedberg described how inhibition of SYK by fostamatinib (R788, Rigel), an oral inhibitor, was well tolerated and demonstrated significant clinical activity. Trials are also ongoing in other B-cell related diseases such as NHL and rheumatoid arthritis. Data from the latter are expected in August/September this year and the company will seek a development partner.
Another interesting compound is ofatumumab (Arzerra), a humanised CD20 monoclonal antibody developed by Genmab and GSK similar to Genentech's rituximab. Phase III results are expected this year in refractory disease (to fludarabine) and front-line CLL. It is a biosimilar, but interestingly, Genmab prefer to describe it as a 'bio-better' i.e. greater potential efficacy and better safety/immunogenicity profile. This is a bit of fluff-puff though, because the golden rule of marketing is be first to market or be better, so one would hope that follow-on drugs to market would offer some meaningful differentiation rather than just being a me-too, otherwise why bother?
A number of marketed compounds are also completing trials in CLL in a bid to expand their franchise. These include lenalidomide (Revlimid) from Celgene, and rituximab (Rituxan) from Genentech. Lenalidomide data in CLL was presented at ASH. Most of the CLL patients were elderly, i.e. older than 70 at diagnosis. The protocol looked at continuous therapy with a starting dose of 5 mg, followed by slow dose escalation. Results showed an overall response rate of 54%, 40% had stable disease and 6% progressed on therapy. What was interesting was that 47% achieved a complete response (CR) and 38% a partial response (PR). Grade 3/4 adverse events included neutropenia/thrombopenia (26%). Infectious complications were seen in 3 patients. Overall, it looks as though Revlimid may be a reasonable well tolerated and effective drug in this patient population.
has proven to be a very effective therapy for NHL in combination with
standard chemotherapy (R-CHOP), so there was little surprise that data
were positive in front-line and refractory CLL in combination with FC
compared to FC alone. Although there appeared to be a slight increase
in adverse events such as febrile neutropenia, infections were
manageable and similar in both arms.
There are also a number of compounds in development for CLL that are not yet approved for any indication and most are still far too early in development (phase I or II) to determine whether they will be useful therapies yet or not. These include ABT-263 (Abbott), cenersen (Eleos), alvocidib (sanof-aventis), ALXN-6000 (Alexion), atacicept (EMD Serono), CAL-101 (Calistoga), CAT-8015 (MedImmune), cell permeation (MaxCyte), CNF-2024 (Biogen Idec), dacetuzumab (Genentech), forodosine (BioCryst), GCS-100 (Prospect), GS-9219 (Gilead), ISF35 (Memgen), lumiliximab (Biogen Idec), MDX-1342 (Medarex), milatuzumab (Immunomedics), obatoclax (Gemin X Biotechnologies), polyphenon E (Polyphenon), PRO-131921 (Genentech), SPC-2996 (Santaris), TRU-016 (Trubion) and motexafin gadolinium (Pharmacyclics).
Many of these small biotechs are, however, struggling to raise capital in the current economic climate and may struggle to develop the agents effectively unless they re-focus their efforts on the lead candidate.
Perhaps the most interesting compound in development is Allos Therapeutics pralatrexate, an anti-folate, which is expected to be filed for PTCL later this year under the FDA's Fast Track mechanism and is also potentially being developed in CTCL, NHL, NSCLC and transitory cell carcinoma of the urinary tract. Succesful data in NHL may also suggest a role in CLL, since therapies that are effective in one often work in the other tumour type too because of the role of B-cells and T-cells in the disease.