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Chronic lymphocytic leukemia: recent advances in biology and therapy

Although chronic lymphocytic leukemia (CLL) has existed for millennia the first report in medical literature was by Velpeau in 1827 who described Monseiur Vernis, a 63 year old Parisian lemonade vendor, formerly a florist. Vernis was a carefree person with an eye for the ladies who, although he managed to avoid syphilis, was struck down by CLL. About 25 years later Virchow, Craigie and Bennett helped distinguish CLL from other leukemias. For the next 100 years there was little progress in our understanding of CLL. Even then, movement was glacial. In the 1950s, several modestly-effective drugs such as chlorambucil, melphalan, mechlorethamine and corticosteroids were introduced along with some forms of radiation therapy. However, the dominant clinical philosophy was do no harm. Although the immune deficiency inherent to CLL was defined at this time, there was little understanding of CLL development. In the 1970s, the Rai and Binet staging systems were introduced. These facilitated reasonably accurate prediction of survival for cohorts of subjects but less so for individuals with CLL. Prediction triggered the notion we should intervene promptly in persons with high-risk CLL who might do poorly with a watch and wait strategy. However, early interventions proved mostly ineffective or even counter-productive. Other prognostic variables were soon identified including cytogenetics (albeit devilishly tricky in CLL), IGH mutation state and others. Now we could more precisely identify persons with CLL with a poor prognosis. Enter fludarabine, cyclophosphamide and later rituxumab and variations thereof, interferon and auto- and allotransplants. These interventions seemed to alter the natural history of high-risk CLL but a cure remained, and still remains, elusive. This is not terrible in a disease whose median age of onset is over 70 years but is disturbing in a 40 year old with high-risk CLL. Fortunately, other drugs were added such as bendamustine and alemtuzumab. Very recently there has been a flurry of new, effective drugs including ofatumumab, obinutuzumab, ibrutinib and idelalisib. There has also been substantial progress in our understanding of the molecular and biological bases of CLL and in our ability to monitor disease levels, so-called measureable residual disease. Will these advances help us to cure CLL? Time will tell.

In this special supplement to Leukemia we present several recently published reports which highlight where CLL research is headed. Unfortunately we could include only a fraction of the excellent reports on CLL published in Leukemia over recent years, but we hope this supplement will increase the visibility of research being done and encourage further studies. This is an exciting time for CLL researchers

Robert Peter Gale MD, PhD, DSc(hc), FACP 
Andreas Hochhaus MD

We are glad to acknowledge the support of Janssen Pharmaceuticals Companies of Johnson & Johnson in producing this collection. Nature Publishing Group carries sole responsibility for the editorial content.