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    Drug combination for non-Hodgkin lymphoma produces fewer side effects


    John T. Sandlund, MD

    A new combination of anti-cancer drugs, when integrated into an existing treatment for non-Hodgkin lymphoma, causes reduced risk for side effects in children than the conventional regimen, St. Jude researchers have found.

    The new combination is just as effective as the conventional regimen and gives clinicians a new treatment option for children who have significant potential for the side effects—heart dysfunction and infertility.

    “The new combination offers a foundation for improving treatment further by adding to the drug cocktail so-called monoclonal antibodies, which are immune proteins designed to target cancer cells,” said John Sandlund, MD, Oncology. “Such targeted antibodies are in contrast to conventional chemotherapy drugs that affect a spectrum of actively growing cells, and not just cancer cells.” Sandlund is the first author of a paper on this work that appears in the August 15 issue of the journal Cancer.

    The drug combination the researchers tested consisted of dexamethasone, cytarabine and carboplatin. All three are widely used anti-cancer drugs, but researchers find that combinations of such drugs can constitute a one-two-three punch against cancer that is more effective than the individual drugs.

    The researchers’ aim in using the regimen they dubbed “DAC” was to achieve both an improved effectiveness over conventional therapy and to reduce that therapy’s dosage of two anti-cancer drugs—doxorubicin and cyclophosphamide—that are more likely to produce cardiac problems and infertility.

    Previous studies had shown that DAC worked in patients who had relapsed, Sandlund said. The investigators sought to determine whether DAC could be used as an initial therapy in children who had newly diagnosed non-Hodgkin lymphoma. The researchers treated 25 patients with DAC as the initial treatment in the chemotherapy course, which lasted about 10 months. The trial was conducted between 1991 and 1997, and the researchers have followed the patients since then to determine long-term side effects.

    The researchers found that 22 of the 25 patients responded to the drug combination, and about 64 percent showed a long-term, five-year event-free survival. This effectiveness is about the same as with the conventional regimen that included doxorubicin and cyclophosphamide. However, the researchers reported that the risk for side effects of DAC were significantly lower.

    “We were not satisfied with this result in terms of the therapeutic effectiveness of the combination,” Sandlund said. “We had hoped that we could improve upon that effectiveness. However, we were gratified to see the reduced risk for worrisome side effects.

    “Such side effects are a significant consideration in treatment,” he said. “When we talk about the outcome for children being treated for different cancers, certainly the first thing one thinks about is controlling the disease—making it go away and never come back. But sometimes when people talk about treatment outcome, it can often be forgotten that part of the outcome is the long-term side effects of the therapy as these children grow.”

    DAC and other drug treatment strategies will be improved upon, thanks to advances since the 1990s—when the children in the study were treated—in distinguishing different subtypes of lymphoma according to their biology, Sandlund added.

    Until about the late 1990s, patients were distinguished only generally as having histological subtypes of non-Hodgkin lymphoma, in which white blood cells called lymphocytes were proliferating uncontrollably. However, after that time clinicians began to distinguish the cancers based on which type of lymphocyte—B cells or T cells—were responsible for the uncontrolled proliferation of the cancer.

    “Now children with mature B-cell disease are treated with intensive regimens specific for that type of lymphoma,” Sandlund said. “And while the optimal therapy for children with mature T-cell disease is still under investigation, there is promise of more targeted treatments for those diseases as well. We believe that DAC will provide one of the backbone therapies to which antibodies or other new active agents can be added to improve the outcome further.”

    St. Jude researchers are now conducting initial clinical trials of antibody therapies in patients with T cell lymphomas who have suffered relapse.

    Other St. Jude authors of this paper include Victor Santana, MD, Melissa Hudson, MD, Raul Ribeiro, MD, Renee Rencher and Ching-Hon Pui, MD, all of Oncology; Mihaela Onciu, MD, of Pathology; Dana Wallace, of Biostatistics; and David Head and Daryl Murry (formerly of St. Jude).

    This research was supported in part by the National Cancer Institute, the State of Tennessee and ALSAC.

    October 2008