thioguanine-anhydrous and Aspergillosis

Azathioprine and mercaptopurine are widely used in the treatment of inflammatory bowel disease. However, its use is limited by adverse drug event related to the relatively narrow therapeutic index of the active metabolites. Several patients discontinue treatment because of intolerable adverse events or toxicity such as leucopenia and hepatotoxicity. High 6-thioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels are associated with toxicity. Variations in the thiopurine S-methyltransferase (TPMT) gene can lead to diminished TPMT enzyme activity and to an increased incidence of myelotoxicity due to high 6-methylmercaptopurine ribonucleotides levels after treatment with azathioprine and mercaptopurine. Unlike azathioprine and mercaptopurine, thioguanine is more directly metabolized to the active metabolites without formation of the toxic 6-methylmercaptopurine ribonucleotides. Taking this into account, it seems likely that thioguanine is less associated with myelotoxicity due to TPMT deficiency. However, we report the case of a Crohn's disease patient with life-threatening complications on 6TG treatment due to TPMT deficiency. Our patient developed a severe pancytopenia on thioguanine therapy, with 6-thioguanine nucleotides levels more than 10 times higher than the upper limit of the therapeutic window and was found to be a TPMT poor metabolizer (TPMT *3A/*3A). This case strongly illustrates that knowledge of TPMT enzyme activity is very important in the use of all thiopurines, including thioguanine. In conclusion, clinicians should be aware of the impact of TPMT deficiency on the metabolism of thioguanine and should consider performing preemptive TPMT genotyping in combination with frequent blood test monitoring when using thiopurines in general.

Topics: Aspergillosis; Drug Hypersensitivity; Female; Humans; Inflammatory Bowel Diseases; Middle Aged; Pancytopenia; Purine-Pyrimidine Metabolism, Inborn Errors; Severity of Illness Index; Thioguanine

Splenic rupture is a rare but well-recognized complication of hematological malignancies. Here, we present the case of a 22-year-old woman with the diagnosis of acute myeloid leukemia who was undergoing peripheral blood stem cell transplantation. On day + 10 she developed a hypovolemic shock due to rupture of her spleen and went to emergency laparotomy. This is the first report of splenic rupture during peripheral blood stem cell transplantation.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Combined Modality Therapy; Cytarabine; Doxorubicin; Fatal Outcome; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematoma; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Puerperal Disorders; Remission Induction; Rupture, Spontaneous; Shock; Splenic Rupture; Thioguanine

The clinical courses of 54 consecutive adult patients with acute myelogenous leukemia (AML) who underwent 67 courses of intensive remission induction therapy were analyzed to assess factors associated with development of serious fungal and bacterial infections. Fever developed in 65 of 67 remission induction attempts and was due to bacterial, bacterial-fungal, and fungal etiologies in 49%, 14%, and 9% of cases, respectively. No etiology of fever was found in 28% of cases. Bacteremia occurred in 54% of remission induction attempts. Invasive fungal disease (IFD) occurred in 22% of cases with an overall mortality of 60%, including 45% of the patients who died during treatment. Using multivariate logistic regression analysis, a mathematical model was constructed which correlated with the risk of IFD. Major factors associated with patients who ultimately develop IFD included the duration of chemotherapy, the number of sites colonized with fungi and the number of fungal species isolated on certain surveillance cultures, particularly Aspergillus species. These studies define characteristics of patients at high risk for development of IFD for whom early initiation of empiric antifungal therapy is strongly recommended.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspergillosis; Cytarabine; Daunorubicin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mycoses; Risk; Sepsis; Statistics as Topic; Thioguanine

A patient with relapse of acute granulocytic leukemia developed an Aspergillus infection along the subcutaneous tract of a silicone rubber indwelling central venous catheter. The infection invaded the brachial plexus resulting in paralysis of the right upper extremity and subsequently invaded a major artery of the arm resulting in the demise of the patient. Both an infectious brachial plexus neuritis and fatal hemorrhage secondary to a Hickman catheter are apparently rare.

Topics: Antineoplastic Agents; Aspergillosis; Brachial Plexus; Catheters, Indwelling; Cytarabine; Female; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Middle Aged; Neuritis; Thioguanine