Histoplasma capsulatum Infection in an Allogeneic Hematopoietic Stem Cell Transplant Patient Receiving Voriconazole Prophylaxis

Histoplasma capsulatum infection is a rare complication in the allogeneic stem cell transplant patients. Minimal guidance exists on how to appropriately manage histoplasmosis in these patients. We report a patient who developed Histoplasma pneumonia while receiving voriconazole prophylaxis at a therapeutic trough level. The patient experienced significant clinical improvement after initiation of itraconazole pharmacotherapy. We recommend a lower threshold for evaluation for histoplasmosis in allogeneic hematopoietic stem cell transplant recipients who live in endemic regions, regardless of their antifungal prophylactic regimen

THE OUTCOME OF ATG ON THE STEM CELL TRANSPLANTS FROM MATCHED UNRELATED DONOR, A SINGLE INSTITUTE EXPERIENCE

poster abstractBACKGROUND: Antithymocyte globulin (ATG) was found to decrease the morbidity of stem cell transplant (SCT) from matched unrelated donor (MUD) by decreasing the incidence of chronic graft vs host disease cGvHD, and at high doses, acute GvHD. We reviewed our results of MUD transplants where ATG was incorporated into the preparative regimen, and compared the results to patients prior to September 2006 where ATG was not used. The primary endpoints were the effect on GvHD and lethal infectious complications. Method: All stem cell transplants from MUD performed after 2000 at IU hospital for treatment of hematological malignancies using a myelo-ablative regimen were retrospectively reviewed. Result: between 1/2000 and 3/2009 seventy nine stem cell transplants were conducted using stem cells from MUD. 28 patients received ATG at a total dose of 7.5mg/kg vs 51 patients who did not receive ATG. Both groups were matched in term of age, sex, underline malignancies, degree of HLA-match, CMV serology, and conditioning regimens. Ninety-six percent of patient in ATG group received prophylaxis for GvHD using FK506/Sirolimus vs 14% in the no ATG group where a methotrexate based treatment was used (P<0.0001). The rate of Grade II-VI acute GVHD at day 100 was significantly lower in the ATG group compare to no ATG (14% vs 39%, P =0.011). Although however, the rate of chronic GVHD at 1 year was higher in ATG group than in the no ATG group, this was statistically not significant (43% and 23%; P=0.2). The rates of overall fungal infections and lethal fungal infections were comparable (14% and 10%) for ATG vs (17% and 11%) for no ATG (p =0.70). The rate of primary CMV infection (i.e., in patient not receiving corticosteroid treatment for GVHD) was higher in ATG group, although not statistically significant (31% vs 17%, P=0.27). Day 100 mortality was 15% and 25% in ATG and no ATG group respectively, overall survival at 1 and 2 years was 47% and 31% for ATG group vs 49% and 36% for no ATG group (P>0.05), Median time to death was 8.6 months (CI95%, 1.8-15.4) and 11.9 months (CI95%, 8-15.7) with P=0.7. The mortality from GVHD at 4 months was 0% in ATG group vs 12% in no ATG group (P =0.08).While the mortality rate from bacterial infection and sepsis were equivalent, more patients in the ATG group who did not receiving corticosteroid treatment for aGVHD died from viral and fungal infection (15% vs 0% at 8 months, P=0.013). Summary: While ATG was associated with a trend toward lower mortality rate at day 100 due to statistically significant decrease in incidence and mortality of aGVHD, it was associated with increase rate of delayed-onset acute GVHD and statistically significant high rate of lethal viral and fungal infection leading to similar overall survival at 1 and 2 years. This study demonstrates the lack of overall benefit of ATG at dose of 7.5mg/kg. Further study to investigate the outcome of using lower doses of ATG to lower the rate of lethal infections while still reducing the risk of GvHD is recommended

The novel histone deacetylase inhibitor, AR-42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate-derived histone deacetylase inhibitor, AR-42, in primary human myeloma cells and cell lines. AR-42 was cytotoxic to MM cells at a mean LC(50) of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR-42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT-3 pathway. AR-42 also inhibited interleukin (IL)-6-induced STAT3 activation, which could not be overcome by exogenous IL-6. AR-42 also downregulated the expression of STAT3-regulated targets, including Bcl-xL and cyclin D1. Overexpression of Bcl-xL by a lentivirus construct partly protected against cell death induced by AR-42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR-42, which together with a decrease in cyclin D1, resulted in G(1) and G(2) cell cycle arrest. In conclusion, AR-42 has potent cytotoxicity against MM cells mainly through gp130/STAT-3 pathway. The results provide rationale for clinical investigation of AR-42 in MM

Effect of family cohesion on symptom distress during hematopoietic stem cell transplantation

Purpose Family may play an important role in hematopoietic stem cell transplantation (HSCT) recovery; however, little is known about the effect of family functioning on an individual’s health. The purpose of this study was to examine the effect of family cohesion (family functioning) on the trajectory of HSCT recipients’ symptom distress (symptom frequency and symptom bother) before, during, and after HSCT. Methods Secondary analysis was conducted using data collected from178 individuals who underwent HSCT. Longitudinal parallel process (LPP) modeling was used to examine how family cohesion and HSCT-associated symptoms (symptom frequency and symptom bother) change over time, and how these longitudinal changes relate to each other. Results The trajectory of family cohesion predicted the trajectories of HSCT-associated symptom frequency and bother. HSCT recipients who experienced higher family cohesion at baseline (T1) showed lower symptom frequency (p < .01) as well as symptom bother (p < .01) at T1. This trajectory analysis also showed that HSCT recipients who had improved family cohesion over time reported decrease in symptom frequency (p < .01) as well as bother (p < .01) over time. Conclusion Findings indicate that higher family cohesion predicts decrease in symptom distress over the HSCT trajectory. Interventions aimed at enhancing family cohesion have the potential to lower HSCT recipients’ symptom distress. Further research is needed to understand the critical role of family cohesion and family functioning and their relationship with HSCT symptom distress prevention, early detection, and risk stratification

Pretransplant HLA typing revealed loss of heterozygosity in the major histocompatibility complex in a patient with acute myeloid leukemia

Introduction Chromosomal abnormalities are frequent events in hematological malignancies. The degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. Purpose of the study In this report, we describe an acute myeloid leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. Materials and methods HLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. Results Typing results on PB sample collected during blast crisis demonstrated homozygosity at the -A, -B, -C, -DR, and -DQ loci. A BS sample demonstrated heterozygosity at all loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during and after blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 35.9 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. Conclusions LOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved

Modeling Sitagliptin Effect on Dipeptidyl Peptidase 4 (DPP4) Activity in Adults with Hematological Malignancies After Umbilical Cord Blood (UCB) Hematopoietic Cell Transplant (HCT)

Background and Objectives— Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of hematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has shown to be a promising approach in adults with hematological malignancies after umbilical cord blood (UCB) hematopoietic cell transplant (HCT). Based on data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with hematological malignancies after a single-unit UCB HCT. Methods— The clinical study included 24 patients that received myeloablative conditioning followed by 4 oral sitagliptin 600mg with single-unit UCB HCT. Using a nonlinear mixed effects approach, a semi-mechanistic pharmacokinetic/pharmacodynamic model was developed to describe DPP4 activity from this trial data using NONMEM 7.2. The model was used to drive Monte-Carlo simulations to probe various dosage schedules and the attendant DPP4 response. Results— The disposition of sitagliptin in plasma was best described by a 2-compartment model. The relationship between sitagliptin concentration and DPP4 activity was best described by an indirect response model with a negative feedback loop. Simulations showed that twice a day or three times a day dosage schedules were superior to once daily schedule for maximal DPP4 inhibition at the lowest sitagliptin exposure. Conclusion— This study provides the first pharmacokinetic/pharmacodynamic model of sitagliptin in the context of HCT, and provides a valuable tool for exploration of optimal dosing regimens, critical for improving time to engraftment in patients after UCB HCT

Large-Scale Bioinformatics Analysis of Bacillus Genomes Uncovers Conserved Roles of Natural Products in Bacterial Physiology

ABSTRACT Bacteria possess an amazing capacity to synthesize a diverse range of structurally complex, bioactive natural products known as specialized (or secondary) metabolites. Many of these specialized metabolites are used as clinical therapeutics, while others have important ecological roles in microbial communities. The biosynthetic gene clusters (BGCs) that generate these metabolites can be identified in bacterial genome sequences using their highly conserved genetic features. We analyzed an unprecedented 1,566 bacterial genomes from Bacillus species and identified nearly 20,000 BGCs. By comparing these BGCs to one another as well as a curated set of known specialized metabolite BGCs, we discovered that the majority of Bacillus natural products are comprised of a small set of highly conserved, well-distributed, known natural product compounds. Most of these metabolites have important roles influencing the physiology and development of Bacillus species. We identified, in addition to these characterized compounds, many unique, weakly conserved BGCs scattered across the genus that are predicted to encode unknown natural products. Many of these “singleton” BGCs appear to have been acquired via horizontal gene transfer. Based on this large-scale characterization of metabolite production in the Bacilli , we go on to connect the alkylpyrones, natural products that are highly conserved but previously biologically uncharacterized, to a role in Bacillus physiology: inhibiting spore development. IMPORTANCE Bacilli are capable of producing a diverse array of specialized metabolites, many of which have gained attention for their roles as signals that affect bacterial physiology and development. Up to this point, however, the Bacillus genus’s metabolic capacity has been underexplored. We undertook a deep genomic analysis of 1,566 Bacillus genomes to understand the full spectrum of metabolites that this bacterial group can make. We discovered that the majority of the specialized metabolites produced by Bacillus species are highly conserved, known compounds with important signaling roles in the physiology and development of this bacterium. Additionally, there is significant unique biosynthetic machinery distributed across the genus that might lead to new, unknown metabolites with diverse biological functions. Inspired by the findings of our genomic analysis, we speculate that the highly conserved alkylpyrones might have an important biological activity within this genus. We go on to validate this prediction by demonstrating that these natural products are developmental signals in Bacillus and act by inhibiting sporulation

The Brain: Is it a Next Frontier to Better Understand the Regulation and Control of Hematopoiesis for Future Modulation and Treatment?

We wish to suggest the possibility there is a link between the brain and hematopoiesis in the bone marrow and that in the future it may be possible to use such information for better understanding of the regulation of hematopoiesis, and for efficacious treatment of hematopoietic disorders

A phase I trial of Flavopiridol in relapsed multiple myeloma

PURPOSE: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. METHODS: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. RESULTS: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. CONCLUSIONS: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myelom