tretinoin and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

We report the development of therapy-related early pre-B acute lymphoblastic leukemia in a patient administered a topoisomerase II inhibitor, etoposide, a consolidation therapy agent for acute promyelocytic leukemia. Our case is of interest because of simultaneous relapse of the original leukemia and onset of therapy-related leukemia and relatively rare t(1;11)(p32;q23) translocation with confirmed MLL/AF-1p fusion. This case suggests that careful monitoring for MLL gene rearrangements is necessary after administration of topoisomerase II inhibitors.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 11; Cytarabine; Daunorubicin; Enzyme Inhibitors; Etoposide; Fatal Outcome; Humans; Idarubicin; In Situ Hybridization, Fluorescence; Leukemia, Promyelocytic, Acute; Male; Middle Aged; Mitoxantrone; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Neoplasms, Second Primary; Oncogene Proteins, Fusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Topoisomerase II Inhibitors; Translocation, Genetic; Tretinoin

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.

Topics: Adjuvants, Immunologic; Alitretinoin; Antineoplastic Agents; B-Lymphocytes; Bexarotene; Diphtheria Toxin; Gene Expression Regulation; Humans; Interleukin-2; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Interleukin-2; Receptors, Retinoic Acid; Recombinant Fusion Proteins; Retinoid X Receptors; Retinoids; T-Lymphocytes; Tetrahydronaphthalenes; Transcription Factors; Tretinoin; Tumor Cells, Cultured