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Blood, 15 February 2008, Vol. 111, No. 4, pp. 1757. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dyer, M. J. S. Search for Related Content PubMed Articles by Dyer, M. J. S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL OBSERVATIONS Comment on Dearden et al, page 1820 DAT ± AHA = bad CLL Martin J. S. Dyer MEDICAL RESEARCH COUNCIL TOXICOLOGY UNIT Autoimmune complications arise commonly in chronic lymphocytic leukemia and may become life-threatening. Dearden and colleagues have analyzed the results of the UK Leukaemia Research CLL4 clinical trial and have come up with some interesting and unanticipated conclusions. The benefits of public transportation may not always be apparent. Robin Coombs conceived the basis of the direct antiglobulin test (DAT) while traveling back to Cambridge on a slow, blacked-out train during the Second World War.1 Armed with this test, it became apparent that a positive DAT and overt autoimmune hemolytic anemia (AHA) occurred in many cases of chronic lymphocytic leukemia (CLL).2 Subsequently, AHA was shown to be more common in advanced than in stable disease, and could be evoked by either drugs or irradiation. AHA following fludarabine can often be difficult, sometimes impossible, to control. Autoimmune complications can therefore pose a significant problem in the management of CLL. Since fludarabine-based combination che-motherapy has now become the standard of care for most patients with CLL, the observations in this issue of Blood by Dearden and colleagues, along with existing results from the UK Leukaemia Research CLL4 trial,3 on the incidence and significance of a positive DAT and the development of AHA in 777 previously untreated patients are of considerable clinical interest. In this trial, patients were randomized to receive either single-agent chlorambucil or fludarabine, or fludarabine and cyclophosphamide (FC) in combination. By every criterion, FC appeared to be superior. The lowest incidence of AHA development during treatment was with FC (5% of patients), compared with 11% receiving chlorambucil and 9% receiving fludarabine. The number of DAT-positive patients with-out AHA fell with FC, but in contrast, rose with single-agent fludarabine. It is particularly noteworthy that the severity of AHA appeared to be worst in patients receiving fludarabine alone; all 4 deaths from AHA occurred in such patients. All things considered, there now appears to be little justification for using fludarabine monotherapy in CLL. Development of AHA was associated with DAT positivity, clinical stage, treatment, age, and serum β2-microglobulin levels. Five-year overall survival was adversely affected by AHA (58% vs 37%), which may reflect that these patients received less chemotherapy. However, it is fascinating that DAT positivity itself, before treatment and in the absence of AHA, was also an independent poor prognostic marker in terms of both progression-free and overall survival. Why this should be remains unknown. Both DAT positivity and AHA are therefore markers of poor-risk CLL. How such autoimmune complications of CLL arise, in a disease otherwise characterized by progressive immunoparesis, remains uncertain. AHA in CLL usually represents the development of high-affinity IgG anti–red-cell autoantibodies by residual normal B cells. How these develop is not clear, but presumably such development represents a failure of normal T-cell regulatory mechanisms that accompany progressive CLL and its treatment. It will be interesting to assess the development of AHA in relation to IGHV mutational status; these data will be available from the CLL4 trial. Whether use of rituximab during induction chemotherapy will alter the frequency and severity of autoimmune complications in CLL remains to be determined. We can anticipate more interesting clinical data to emerge shortly from this randomized trial. Footnotes Conflict-of-interest disclosure: The author declares no competing financial interests. REFERENCES Coombs RRA, Mourant AE, Race RR. Detection of weak and incomplete Rh agglutinins: a new test. Lancet 1945; 92:15–16.[CrossRef] Rosenthal MC, Pisciotta AV, Komninos ZD, Goldenberg H, Dameshek W. The auto-immune hemolytic anemia of malignant lymphocytic disease. Blood 1955; 10:197–227.[Abstract/Free Full Text] Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007; 370:230–239.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia Claire Dearden, Rachel Wade, Monica Else, Sue Richards, Don Milligan, Terry Hamblin, and Daniel Catovsky, for the UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group and NCRI CLL Working Group Blood 2008 111: 1820-1826. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Dyer, M. J. S. Search for Related Content PubMed Articles by Dyer, M. J. S. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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