Rie Kojima

Antithymocyte globulin affects the occurrence of acute and chronic graft-versus-host disease after a reduced-intensity conditioning regimen by modulating mixed chimerism induction and immune reconstitution

Background. There have been no detailed analyses of the induction of donor cell–type chimerism, the onset and incidence of acute and chronic graft-versus-host disease (GVHD), and the immune recovery kinetics after reduced-intensity stem cell transplantation (RIST). Methods. To address these, with particular emphasis on the impact of the use of antithymocyte globulin (ATG) in RIST, we compared 39 consecutively registered patients who underwent RIST from an HLA-matched related donor and 33 patients who underwent conventional marrow-ablative transplantation. Results. The incidences of grades II to IV acute and chronic GVHD tended to be less in RIST with ATG than in either RIST without ATG or conventional marrow-ablative transplantation. In a multivariate analysis, the predictive factors for acute and chronic GVHD included, respectively, ATG and grades II to IV acute GVHD. In a chimerism analysis, the achievement of complete donor chimera in T-cell lineage was delayed in RIST without ATG compared with RIST with ATG (P =0.038), which might explain the observed delayed onset of acute GVHD in RIST with ATG compared with the other two regimens. The ratio of type 1 and 2 dendritic cells did not affect the development of GVHD, whereas the number of naive CD4+ T cells did. No difference was observed in the incidence of clinically definitive infection, including cytomegalovirus, among the three cohorts, regardless of the use of ATG. Conclusions. We suggest that the conditioning regimen and immunosuppressive strategy after RIST should be carefully balanced against the risk of GVHD and of relapse of the basic disorder caused by the lack of a graft-versus-leukemia benefit.

TRALI after the infusion of marrow cells in a patient with acute lymphoblastic leukemia

BACKGROUND:  TRALI is one of the most serious, life‐threatening complications after blood transfusion. Antibodies against neutrophils or HLA molecules from the donor are thought to be the primary causative agents. Rarely, antibodies in the recipient may react with transfused neutrophils and initiate the same events, which raises the possibility that TRALI may also occur in an allogeneic PBPC transplantation setting.

A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease.

This prospective study evaluates the safety and efficacy of pravastatin for the treatment of chronic graft-versus-host disease (GVHD). We included 18 patients with refractory chronic GVHD. Oral pravastatin was started at 10 mg/day, and the dose was increased up to 40 mg/day in 4 weeks. This maximum dose was administered over 8 weeks. There were no severe adverse events caused by pravastatin. A clinical response was observed in the skin score in two patients, mouth score in five patients, eye score in two patients, liver score in three patients, platelet count score in one patient, and weight loss in two patients. The overall response rate was 28%. Immunophenotypic analyses showed that T-helper (Th)1 cells were dominant in all but one patient before treatment and that the Th1/Th2 ratio tended to be lower in the responders than in the nonresponders. A randomized controlled trial is warranted to evaluate the efficacy of pravastatin against chronic GVHD.

Reduced-intensity allogeneic hematopoietic stem-cell transplantation as an immunotherapy for metastatic colorectal Cancer

Background. Allogeneic stem-cell transplantation (allo-SCT) can induce curative graft-versus-leukemia reactions for hematologic malignancies through allogeneic immunity. Because the gastrointestinal tract is a target of graft-versus-host disease (GvHD), colorectal cancer might be a candidate for allo-SCT. Methods. Four patients with metastatic colorectal cancer underwent reduced-intensity stem-cell transplantation (RIST) in the National Cancer Center Hospital between July 2002 and February 2003. Three patients received transplants from an human leukocyte antigen (HLA)-identical related donor, and the remaining patient received selected CD34-positive cells from a two-loci HLA-mismatched donor. The basis of preparative regimen was busulfan 4 mg/kg for 2 days and fludarabine 25 mg/kg for 6 days. Results. All the patients tolerated the preparative regimen and achieved engraftment without significant toxicities. All developed acute or chronic GvHD. Although serum levels of CA19–9 and carcinoembryonic antigen were transiently elevated after RIST in all the patients, the levels subsequently decreased below the levels from before RIST in all but one patient. Three had measurable lesions before RIST, one achieved partial response, and the others stable disease, which was durable for 120 and 60 days. Three patients died; the causes of death were progressive disease, GvHD, and accident. Postmortem examination was obtained for two patients; in one patient, the peritoneal metastatic lesions macroscopically disappeared, and in the other patient, the supraclavicular lymph node disappeared while the other measurable lesions remained stable. Conclusions. All the patients showed some evidence suggesting the presence of a graft-versus-tumor effect for colorectal cancer, which should be confirmed in a future prospective trial.

Intensive multimodality therapy including paclitaxel and reduced-intensity allogeneic hematopoietic stem cell transplantation in the treatment of adrenal cancer with multiple metastases

Adrenocortical carcinoma is a rare malignancy in adolescents and young adults. The prognosis of unresectable/metastatic adrenocortical carcinoma remains very poor because the rarity of the tumor has made it difficult to establish treatment guidelines, and diagnosis and the resultant treatment can be greatly delayed. We treated a 24-year-old woman who was diagnosed with adrenocortical carcinoma of the right adrenal gland which extended to the inferior vena cava. Although she underwent surgical resection of the extensive tumor as the primary treatment, the disease recurred in the lung and liver as multiple metastases shortly after surgery. She received intensive multimodality therapy, including chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP regimen), embolization of the feeding arteries, and proton irradiation for the liver mass. Finally, she underwent reduced-intensity allogeneic hematopoietic stem cell transplantation from an HLA 1-locus-mismatched sibling donor. A prolonged survival of 39 months after the onset of the disease was achieved. Although this experience is limited, we suggest that TIP chemotherapy was effective for adrenocortical carcinoma, and a graft-versus-tumor effect after reduced-intensity stem cell transplantation may have contributed to the prolonged survival.

Life-threatening hypothyroidism associated with administration of cyclosporine in a patient treated with reduced-intensity hematopoietic stem-cell transplantation for metastatic renal-cell carcinoma.

Thyroid dysfunction as a late complication of bone-marrow transplantation has been recognized (1). In regards to early onset posttransplant thyroid dysfunction, little information is available (2). Here, we report a case of hypothalamic hypothyroidism, in the early phase of reduced-intensity hematopoietic stem-cell transplantation (RIST), which can be attributed to cyclosporine. A 26-year-old female with metastatic renal-cell carcinoma underwent RIST from a human–leukocyte-antigen (HLA)-identical sibling at our institute. Preceding therapies included right nephrectomy, pelvic radiotherapy, and interferon, and none of these was known to be related to thyroid dysfunction. The conditioning regimen consisted of busulfan, fludarabine, and antithymocyte globulin (3). Cyclosporine of 3 mg/kg was administered as graft-versushost disease (GvHD) prophylaxis. Her posttransplant course was uneventful until cyclosporine was tapered off by day 45 to induce graft-versus-tumor effect (4), and grade II acute GvHD occurred on day 54. Intravenous cyclosporine at 2 mg/kg was promptly initiated, and, thereafter, she developed severe malaise and hepatorenal dysfunction. Cyclosporine was discontinued on day 62, and her symptoms completely disappeared. Oral cyclosporine was resumed at 2 mg/kg on day 69 in attempt to induce graft-versus-tumor effect. Then she again complained of generalized fatigue, followed by paralytic ileus and lethargy on day 71. Cyclosporine was suspected to be the culprit and was discontinued. Her clinical conditions immediately improved. Her thyroid function was normal before transplantation. Surprisingly, on day 72, serum thyroid-stimulating hormone, free triiodothyronine, and free thyroxine were below detectable levels (Fig. 1). A thyrotropin-releasing hormone loading test showed a low and delayed response, which is compatible with secondary hypothalamic dysfunction. Other anterior pituitary functions remained normal. Although metastatic pituitary tumor and microadenoma are known to cause secondary disorders of the thyroid, magnetic resonance imaging of the brain performed at the onset of thyroid dysfunction failed to show any organic lesions (Fig. 2), neither hypothalamic nor pituitary occupying lesions. In addition, none of the preceding treatment administered before transplantation appeared to contribute to thyroid dysfunction. In consideration of the close chronological relationship between the emergence or disappearance of symptoms and the use of cyclosporine, it is likely that her hypothalamic hypothyroidism was best attributed to the medication. Although cyclosporine toxicities on the central nervous system (5) including cyclosporine-induced encephalopathy are well known, neither thyroid nor hypothalamic dysfunc-