Invasive mold infections (IMIs) are an important cause of morbidity and mortality in patients who are undergoing bone marrow transplantation (BMT). To examine the epidemiology, risk factors, and outcome of IMIs in allogeneic BMT recipients, all cases of mold infection among 94 adult patients who underwent allogeneic BMT at this institution from 1 January 1997 through 31 December 1998 were reviewed retrospectively. Fifteen cases of IMI were identified; infection occurred a median of 102 days after BMT. Aspergillus species was the most common cause of disease, and species other than Aspergillus fumigatus were present in 53% of patients. By multivariate analysis, the variable associated with infection risk was systemic glucocorticosteroid use. Prophylactic antifungal therapy that was targeted to high-risk patients had little effect on disease incidence. These observations suggest that early identification of high-risk patients and better approaches to prevention should be explored, to reduce incidence and severity of disease in this population.

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The best endoscopic diagnostic strategy for gastrointestinal (GI) graft-versus-host disease (GVHD) is unknown. Over a 48-month period, all patients with unexplained diarrhea at risk for acute gastrointestinal GVHD were prospectively identified. Acute GVHD was defined as symptoms and histologic evidence of GVHD occurring within 100 days of transplant or donor lymphocyte infusion (DLI). Colonoscopy was performed with multiple biopsies of the ileum, right colon and rectosigmoid colon. Next, upper endoscopy with duodenal and random gastric biopsies of both antrum and body were performed. All biopsies were evaluated for GVHD by an experienced GI pathologist. Over the study period, 24 patients (mean age 37 years; 62.5% male) were evaluated. The median time from transplantation or DLI was 30.5 days. The biopsy site with the highest yield was the distal colon (82%). A combination of upper endoscopy with sigmoidoscopy and colonoscopy with ileal biopsies were equivalent (B94%). In patients with diarrhea at risk for GVHD, biopsies of the distal colon had the highest diagnostic yield suggesting the importance of sigmoidoscopy and biopsy. Colonoscopy and ileoscopy or flexible sigmoidoscopy plus upper endoscopy had the highest diagnostic yields.

BackgroundApproximately fifty percent of patients with acute myeloid leukemia can be cured with current therapeutic strategies which include, standard dose chemotherapy for patients at standard risk of relapse as assessed by cytogenetic and molecular analysis, or high-dose chemotherapy with allogeneic hematopoietic stem cell transplant for high-risk patients. Despite allogeneic hematopoietic stem cell transplant about 25% of patients still succumb to disease relapse, therefore, novel strategies are needed to improve the outcome of patients with acute myeloid leukemia.Methods and findingsWe developed an immunotherapeutic strategy targeting the CD33 myeloid antigen, expressed in ~ 85–90% of patients with acute myeloid leukemia, using chimeric antigen receptor redirected T-cells. Considering that administration of CAR T-cells has been associated with cytokine release syndrome and other potential off-tumor effects in patients, safety measures were here investigated and reported. We genetically modified human activated T-cells from healthy donors or patients with acute myeloid leukemia with retroviral supernatant encoding the inducible Caspase9 suicide gene, a ΔCD19 selectable marker, and a humanized third generation chimeric antigen receptor recognizing human CD33. ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells had a 75±3.8% (average ± standard error of the mean) chimeric antigen receptor expression, were able to specifically lyse CD33+ targets in vitro, including freshly isolated leukemic blasts from patients, produce significant amount of tumor-necrosis-factor-alpha and interferon-gamma, express the CD107a degranulation marker, and proliferate upon antigen specific stimulation. Challenging ΔCD19 selected inducible Caspase9-CAR.CD33 T-cells with programmed-death-ligand-1 enriched leukemia blasts resulted in significant killing like observed for the programmed-death-ligand-1 negative leukemic blasts fraction. Since the administration of 10 nanomolar of a non-therapeutic dimerizer to activate the suicide gene resulted in the elimination of only 76.4±2.0% gene modified cells in vitro, we found that co-administration of the dimerizer with either the BCL-2 inhibitor ABT-199, the pan-BCL inhibitor ABT-737, or mafosfamide, resulted in an additive effect up to complete cell elimination.ConclusionsThis strategy could be investigated for the safety of CAR T-cell applications, and targeting CD33 could be used as a ‘bridge” therapy for patients coming to allogeneic hematopoietic stem cell transplant, as anti-leukemia activity from infusing CAR.CD33 T-cells has been demonstrated in an ongoing clinical trial. Albeit never performed in the clinical setting, our future plan is to investigate the utility of iC9-CAR.CD33 T-cells as part of the conditioning therapy for an allogeneic hematopoietic stem cell transplant for acute myeloid leukemia, together with other myelosuppressive agents, whilst the activation of the inducible Caspase9 suicide gene would grant elimination of the infused gene modified T-cells prior to stem cell inf...

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