The incidence of Gram-negative bacteremia has increased in hematopoietic stem cell transplant (HSCT) recipients. We prospectively collected data from 13 Brazilian HSCT centers to characterize the epidemiology of bacteremia occurring early post transplant, and to identify factors associated with infection due to multi-drug-resistant (MDR) Gram-negative isolates. MDR was defined as an isolate with resistance to at least two of the following: third-or fourth-generation cephalosporins, carbapenems or piperacillin-tazobactam. Among 411 HSCT, fever occurred in 333, and 91 developed bacteremia (118 isolates): 47% owing to Gram-positive, 37% owing to Gram-negative, and 16% caused by Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa (22%), Klebsiella pneumoniae (19%) and Escherichia coli (17%) accounted for the majority of Gram-negative isolates, and 37% were MDR. These isolates were recovered from 20 patients, representing 5% of all 411 HSCT and 22% of the episodes with bacteremia. By multivariate analysis, treatment with third-generation cephalosporins (odds ratio (OR) 10.65, 95% confidence interval (CI) 3. 75-30.27) and being at one of the hospitals (OR 9.47, 95% CI 2.60-34.40) were associated with infection due to MDR Gram-negative isolates. These findings may have important clinical implications in the decision of giving prophylaxis and selecting the empiric antibiotic regimen.

Hematopoietic stem cell transplantation (HSCT) is an important therapeutic option for some hematological diseases. However, patients who undergo HSCT acquire a state of immunodeficiency that causes significant mortality. Reconstitution of thymic function is needed to support the immune system. One way to measure thymic function is through T-cell receptor excision circle (TREC) quantification. TRECs are generated by T-cell receptor gene rearrangements during T-cell maturation in the thymus and represent a reliable marker for thymic output. In this study, we aimed to assess aging and malignant hematological diseases as two important factors that may influence thymic output before HSCT. We observed that patients before HSCT presented signal joint TREC (sjTREC) numbers lower than 606.55 copies/μg DNA (low values) compared with healthy individuals, with an odds ratio (OR) of 12.88 [95% confidence interval (CI): 5.26–31.53; p < 0.001]. Our results showed that a group of older individuals (≥50 years old), comprising both healthy individuals and patients, had an OR of 10.07 (95% CI: 2.80–36.20) for low sjTREC values compared with younger individuals (≤24 years old; p < 0.001). Multiple logistic regression analysis confirmed that both older age (≥50 years old) and malignant hematological diseases and their treatments were important and independent risk factors related to thymic function impairment (p < 0.001). The median sjTREC value for patients of all ages was significantly lower than the sjTREC median for the subgroup of older healthy individuals (≥50 years old; p < 0.001). These data suggested that patients before HSCT and healthy individuals exhibited age-dependent thymic impairment, and that prior treatment for hematological diseases may exacerbate aging-related deterioration of natural thymic function. Furthermore, we analyzed these patients 9 months post-HSCT and compared patients who underwent autologous HSCT with those who underwent allogeneic HSCT. Both groups of patients achieved sjTREC copy numbers similar to those of healthy individuals. We did not find a close relationship between impaired thymic function prior to HSCT and worse thymic recovery after HSCT.

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Fludarabine in combination with intravenous Busulfan has been used to reduce treatment related mortality (TRM) in allogeneic stem cell transplantation (SCT). Considering that busulfan has erratic bioavailability and unpredictable intestinal absorption, previous investigations have used intravenous busulfan with plasma-targeted levels dosing. In Brazil neither intravenous Busulfan nor routine plasma level measurement of Busulfan are available. In this report we retrospectively analyze 74 patients (median age 32 y.o.) submitted to SCT using a Fludarabine and oral Busulfan based conditioning regimen. Forty three patients had acute myeloid leukaemia (AML, age range 5 to 58) and 31 patients chronic myeloid leukemia (CML, age range 19 to 58). Among the AML patients, 44% were in first remission (CR1), 23% in second remission (CR2) and 33% patients had active disease (AD) at the time of transplant. Among CML patients, 65% were in chronic phase (CML-CP), 29% in accelerated phase (CML-AP) and 6% in blast crisis (CML-BC). Fludarabine 30 mg/m2 and oral Busulfan 4 mg/kg was given for 4 days with Cyclosporine A and Methotrexate GVHD prophylaxis. For patients with unrelated donors, ATG were added. All patients engrafted (median 14 days). At a median follow up time of 180 days non-relapse mortality was 5%. Seventeen patients (23%) died (12 AML and 5 CML patients). Among survivors (57 patients), 56 remain in complete remission. One patient with a refractory AML and a complex karyotype relapsed on day +90. One patient died of severe sinusoidal obstruction syndrome (SOS). Acute GVHD occurred in 14 (19%) patients (10 AML and 4 CML) none of them grade III or IV. Chronic GVHD occurred in 11 patients so far, being the cause of death in 2 patients. Major cause of death was relapse of disease in patients transplanted with active disease. Only three AML patients in CR1 died (chronic GVHD, sepsis and fulminant hepatic failure) in contrast to 60% of patients with active disease (88% relapsed). One patient with CML-CP died with a relapse in CML-BC, the remaining 19 (92%) patients are alive in complete remission. One patient transplanted in CML-AP died (cGVHD and zygomykosis) and all patients transplanted in BC died of their disease. Actuarial 1-year overall survival for CML is 92% and 54% (CP and AP/BC respectively, p=0,04) and for AML 72% and 23% (CR1/CR2 and AD, respectively, p=0,005). These preliminary data show that oral Busulfan and Fludarabine can safely be used without plasma level monitoring. The follow up time is short and the effect on the control of CML cannot be concluded. However AML has been effectively controlled as far as patients were transplanted in remission (AML-CR1 and CR2). For patients in more advanced disease stages this regimen is not optimal. However, this regimen is safe and may improve the results in early stages of AML and CML even in countries with limited resources in health care.