NVP-LAQ824 is a novel potent hydroxamic acid-derived histone deacetylase inhibitor that induces apoptosis in nanomolar concentrations in myeloid leukemia cell lines and patient samples. Here we show the activity of NVP-LAQ824 in acute myeloid leukemia cells and BCR/ABL-expressing cells of mouse and human origin, both sensitive and resistant to imatinib mesylate (Gleevec, STI-571). Whereas imatinib inhibited overall cellular tyrosine phosphorylation in Ba/F3.p210 cells, NVP-LAQ824 did not inhibit tyrosine phosphorylation, and did not affect BCR/ABL or ABL protein expression. Neither compound was able to inhibit cellular tyrosine phosphorylation in the imatinib-resistant Ba/F3.p210-T315I cell line. These data taken together suggest that BCR/ABL kinase activity is not a direct target of NVP-LAQ824. Synergy between NVP-LAQ824 and imatinib was demonstrated against BCR/ABL-expressing K562 myeloid leukemia cell lines. In addition, we show that NVP-LAQ824 was well tolerated in vivo in a pre-clinical murine leukemia model, with antileukemia activity resulting in significant prolongation of the survival of mice when treated with NVP-LAQ824 compared to control mice. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in myeloid malignancies.

To the Editor: A 48-year-old woman being treated with lenalidomide for kappa light chain multiple myeloma presented with severe rash associated with urticaria, pruritus, and fever. The patient was initially diagnosed with Stage II breast cancer (ER/PR+ and HER-2neu negative) in 2003 and underwent treatment with lumpectomy followed by four cycles of Adriamycin and Cyclophosphamide followed by two cycles of Paclitaxel and then switched to an additional two cycles of Taxotere because of poor tolerance. This was followed by radiation therapy and hormonal therapy. Two years later she was diagnosed with multiple myeloma. As a result of her negative prior experience with chemotherapy and steroids she refused treatment with either and was therefore initially treated with single agent thalidomide. Thalidomide treatment had to be discontinued due to a similar reaction manifesting with severe rash, urticaria, and pruritus, which was thought to be a Type I (IgE mediated) hypersensitivity reaction. When lowered to 50 mg the patient continued to experience side effects necessitating its permanent discontinuation. She was subsequently treated with bortezomib which had to be discontinued secondary to increasing neuropathy. Lenalidomide treatment at the standard dose of 25 mg resulted in the reaction described above which was similar to the reaction she developed on thalidomide, which is not surprising given the structural similarities between the two drugs. The patient was subsequently referred to Allergy-Immunology for desensitization in August 2006. The patient was desensitized using the protocol shown in Table I. In brief, lenalidomide was dissolved in normal saline and diluted to concentrations of 0.025, 0.25, and 2.50 mg/ml. She was given gradually increasing strengths to take orally at 15-to 20-min interval. During the desensitization she had her blood pressure, heart rate, temperature, pulse oximetry, and peak flow monitored. She tolerated the escalating doses with no reaction and was subsequently begun on lenalidomide 15 mg daily, and continues to tolerate daily continuous dosing with no evidence of recurrent hypersensitivity. The patient remains asymptomatic in a PR as defined by the International Working Group Uniform Response Criteria, and also remains free from any evidence of recurrent breast cancer. This represents the first case of successful desensitization to lenalidomide that we are aware of. Since this drug has become an integral component of multiple myeloma therapy this represents an important option for patients who otherwise would not be able to tolerate lenalidomide.

Prolonged immunosuppression is generally associated with an increase in incidence of lymphoid cancers. Transplant recipients, primary or genetic immunodeficiencies and patients with the acquired immunodeficiency syndrome (AIDS) have a known increased incidence of lymphoproliferative disorders. Patients who develop hairy cell leukemia (HCL) also have impaired immune function at the T-cell level that is present before definitive therapy. The lack of T-cell responsiveness is due to a decrease in memory T helper cells, abnormal activation of spleen T lymphocytes that behave like tumor infiltrating cells, and selection of oligoclonal T-cell populations with a very restricted and skewed T-cell repertoire. Inadequate antigen presentation may also play a role due to monocytopenia and lack of CD 28 on T-cells. Treatment with purine analogs, particularly pentostatin and cladribine, targets both resting and proliferating lymphocytes. This further impairs immune function by producing a prolonged reduction of normal lymphocytes, mainly CD4 cells, for as long as two years. There are reports of lymphoproliferative disorders as a second malignancy after treatment for HCL. However, it is not clear if treatment with purine analogs can induce second malignancies due to immune suppression. We reviewed the literature for cases of secondary lymphoproliferative disorders in patients treated with and without purine analogues for HCL. Purine analogues do not appear to have an increased risk for a secondary lymphoproliferative disorder. However, a preexisting immunosuppressed state may exist that antecedes the treatment of HCL and predisposes some patients to secondary lymphoproliferative disorders. Secondary Lymphoproliferative Disorders in Patients Treated for Hairy Cell Leukemia (HCL) Prior Treatment for HCL Non Hodgkin’s Lymphoma Hodgkin’s Lymphoma Waldenstrom’s Macroglobulinemia Multiple Myeloma Purine Analogues 16 3 2 1 Other Systemic Therapies 7 2 0 1 No Systemic Therapy 10 0 0 0 Unknown 3 1 0 0