Junko Jimbo

Severe Hepatic Injury Caused by Imatinib Mesylate Administered for the Treatment of Chronic Myeloid Leukemia and the Efficacy of Prednisolone for its Management

Imatinib mesylate is a specific inhibitor of BCR-ABL tyrosine kinase, which is now widely used for the treatment of chronic myeloid leukemia (CML) with a high efficacy. Although severe hepatic injury caused by imatinib mesylate is rare, such a side effect may force patients to discontinue taking imatinib mesylate. In the present paper, we report on the case of a 51-year-old woman with CML who experienced hepatic injury with severe hyperbilirubinemia caused by imatinib mesylate. The findings from a liver biopsy specimen and her clinical course suggested the hepatic injury to presumably have been caused by an allergic mechanism. The co-administration of prednisolone was thus tried, and she has been able to continue imatinib mesylate administration without any liver dysfunction and finally was able to obtain a complete cytogenetic response. We therefore recommend that prednisolone should be tried when severe hepatic injury caused by imatinib mesylate is observed, since it might enable such patients to continue imatinib mesylate treatment and thereby improve the prognosis in such cases.

Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70

Cancer immunotherapy using heat shock protein (HSP) derived from autologous tumor requires cluster of differentiation (CD)4+ as well as CD8+ T‐cells for the prolongation of patient survival, suggesting that a humoral immune response through CD4+ T‐cells is important in addition to cellular immunity. However, the role of humoral responses in HSP‐based autologous tumor immunotherapy remains unclear. In the present study, we investigated whether leukemia‐specific antibodies and antibody‐mediated cytotoxicity against autologous leukemia cells have a crucial role in a mouse A20 leukemia model by immunizing A20‐derived HSP70. Immunization with A20‐derived HSP70 induced the production of anti‐A20‐antibodies and the antibodies recognized HSP70‐binding peptides derived from A20. One of those was a major histocompatibility complex (MHC) class‐I binding peptide, which has been clarified as the target peptide of CD8+ cytotoxic T‐cells (CTL) against A20. The anti‐A20‐antibodies produced by immunization with A20‐derived HSP70 induced complement‐dependent cytotoxicity (CDC) against A20 in vitro. In addition, immunization with A20‐derived HSP70 increased intracellular interleukin‐4 (IL4)‐production of CD4+ T‐cells, confirming the activation of type‐2 helper T‐cells. Taken together, immunization with leukemia‐cell‐derived HSP70 induces antibodies against leukemia‐cell‐specific peptides and might play a crucial role in the eradication of leukemia cells by CDC in mice. These findings will enable future establishment of a novel therapeutic strategy using antileukemia antibodies in HSP‐based autologous tumor immunotherapy. (Cancer Sci 2008; 99: 1427–1434)

A novel five-way chromosomal translocation observed in chronic myelogenous leukemia

Most patients with chronic myelogenous leukemia (CML) show a Philadelphia (Ph) chromosome with a characteristic translocation between chromosomes 9 and 22. However, there are variant complex translocations involving other chromosomes in addition to the standard translocation. We describe a case of CML showing a complex and novel chromosomal translocation involving five chromosomes, t(4;12;7;9;22).

Two cases of mycosis fungoides treated by reduced‐intensity cord blood transplantation

Mycosis fungoides is a cutaneous T‐cell lymphoma, which is clinically divided into three stages: patch, plaque and tumor. Despite a variety of treatments the prognosis is poor in advanced mycosis fungoides. Recently, allogeneic hematopoietic stem cell transplantation has been successfully applied for such cases. We performed reduced‐intensity umbilical cord blood transplantation for two advanced mycosis fungoides patients. Case 1 was a 56‐year‐old man and case 2 was a 30‐year‐old woman. Tumors of each case were refractory to conventional chemotherapy. Although radiation therapy was considerably effective, tumors relapsed after several months. Reduced‐intensity umbilical cord blood transplantation was performed because case 1 had no human leukocyte antigen‐identical siblings and the sibling of case 2 did not agree to be the donor. The male patient died of pulmonary failure 23 days after reduced‐intensity umbilical cord blood transplantation. The case 2 patient succeeded in reduced‐intensity umbilical cord blood transplantation and remained in complete/partial remission for 13 months. However, chemotherapy‐resistant tumors relapsed, and allogeneic hematopoietic stem cell transplantation was performed at 17 months. She died of cerebral hemorrhage 23 days after the procedure. Reduced‐intensity umbilical cord blood transplantation may be included in the treatments for advanced mycosis fungoides, where graft‐versus‐lymphoma effect seems to be a significant factor for the success of the treatment.

Combined use of dendritic cells enhances specific antileukemia immunity by leukemia cell-derived heat shock protein 70 in a mouse model with minimal residual leukemia cells.

We have reported that immunotherapy using leukemia cell-derived heat shock proteins (HSPs) is effective against minimal residual disease (MRD) after syngeneic stem cell transplantation (SCT) in mice. However, leukemia patients after SCT are usually immunocompromised and immunologically tolerant to leukemia cells.We investigated whether the use of dendritic cells (DCs) in combination with HSP70 enhances cytotoxicity against B-cell leukemia cell line A20 in mice after syngeneic SCT. All unimmunized mice died of leukemia early after A20 cell inoculation, whereas mice immunized with HSP70 or HSP70-pulsed DCs survived significantly longer. Although only 60% of the HSP70-immunized mice survived, all mice immunized with HSP70-pulsed DCs survived without MRD. In addition, the cytotoxicities against A20 cells for splenocytes from mice immunized with HSP70-pulsed DCs were significantly higher than those of HSP70-immunized mice, and the cytotoxicities against A20 cells were significantly blocked by anti-CD8 antibody and by major histocompatibility complex class I antibody, but not by anti-CD4 antibody. Moreover, abnormalities were detected in neither the biochemical data nor the histopathologic findings. These findings indicate that the combined use of DCs and leukemia cell-derived HSP70 enhances the antileukemia effect by inducing the specific cytotoxicities of CD8+ cytotoxic T-cells, thereby eradicating MRD effectively and safely, even in an immunocompromised state after syngeneic SCT. This approach may thus be useful for further application of HSP in leukemia patients after autologous SCT.