[Show abstract][Hide abstract] ABSTRACT: Background:
Human rhinoviruses (HRVs) are common causes of upper respiratory tract infection (URTI) in hematologic malignancy (HM) patients. Predictors of lower respiratory tract infection (LRTI) including the impact of HRV species and types are poorly understood.
This study aims to describe the clinical and molecular epidemiology of HRV infections among HM patients.
From April 2012-March 2013, HRV-positive respiratory specimens from symptomatic HM patients were molecularly characterized by analysis of partial viral protein 1 (VP1) or VP4 gene sequence. HRV LRTI risk-factors and outcomes were analyzed using multivariable logistic regression.
One hundred and ten HM patients presented with HRV URTI (n=78) and HRV LRTI (n=32). Hypoalbuminemia (OR 3.0; 95% CI, 1.0-9.2; p=0.05) was independently associated with LRTI, but other clinical and laboratory markers of host immunity did not differ between patients with URTI versus LRTI. Detection of bacterial co-pathogens was common in LRTI cases (25%). Among 92 typeable respiratory specimens, there were 58 (64%) HRV-As, 12 (13%) HRV-Bs, and 21 (23%) HRV-Cs, and one Enterovirus 68. LRTI rates among HRV-A (29%), HRV-B (17%), and HRV-C (29%) were similar. HRV-A infections occurred year-round while HRV-B and HRV-C infections clustered in the late fall and winter.
HRVs are associated with LRTI in HM patients. Illness severity is not attributable to specific HRV species or types. The frequent detection of bacterial co-pathogens in HRV LRTIs further substantiates the hypothesis that HRVs predispose to bacterial superinfection of the lower airways, similar to that of other community-acquired respiratory viruses.
Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 09/2015; 71:51-8. DOI:10.1016/j.jcv.2015.07.309 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation.Bone Marrow Transplantation advance online publication, 8 June 2015; doi:10.1038/bmt.2015.133.
Bone marrow transplantation 06/2015; 50(9). DOI:10.1038/bmt.2015.133 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the past decade, haplo-cord stem cell transplantation (SCT) using myeloablative or reduced intensive conditioning regimens has been shown to result in reliable and fast engraftment of neutrophils and platelets comparable to HLA-matched donors and much faster than after cord stem cell transplant. Haplo-cord SCT also has a low incidence of early non-relapse mortality, low incidences of acute and chronic graft-vs-host disease (GVHD), and excellent graft-vs-leukemia (GVL) effects. Favorable long-term outcomes for high-risk patients with hematologic malignancies have been reported, including older patients. Haplo-cord SCT will likely overcome the limitations of cell dose during cord stem cell selection and might significantly expand the use of cord stem cell transplant in the adult population. The comparable survival outcomes of matched related donor (MRD), matched unrelated donor (MUD), and haplo-cord stem cell transplant strongly argue that haplo-cord SCT should be considered as effective alternative stem cell transplant for high-risk patients lacking standard donors. Further improvement in supportive care and incorporation of a better understanding of the human fetal immune development into the haplo-cord SCT are required to further improve this strategy.
[Show abstract][Hide abstract] ABSTRACT: New York Presbyterian Hospital [NYPH]/Weill Cornell and Memorial-Sloan Kettering Cancer Center [MSKCC], New York, NY
Background: Fulminant toxoplasmosis is a rare and difficult to diagnose complication after HSCT. Disseminated toxoplasmosis has a reported incidence of 0.1 to 6% in allogeneic transplants and is often fatal.
Methods: We report a cluster of 6 cases of fulminant toxoplasmosis, diagnosed within a 1-year period, at 2 neighboring transplant centers in NYC. Toxoplasmosis was diagnosed by positive serum PCR or at autopsy.
Results: Between December 2012 and September 2013, six patients were diagnosed with fulminant toxoplasmosis at MSKCC (4 cases) and NYPH/Weill Cornell (2 cases). The incidence of cases, preceding this study, was 1-2 cases per year at MSKCC and zero over the prior 5 years at NYP/Weill Cornell. Underlying diagnosis were acute lymphoblastic leukemia (2), acute myeloid leukemia, myeloma, lymphoma and myelodysplastic syndrome (1 each). Patients received ex-vivo T-cell depleted peripheral blood stem cell (TCD-PBSC) allograft (3) or umbilical cord + TCD-PBSC allografts (3). Five patients received anti-thymocyte globulin during their conditioning regimen. Five of 6 patients had positive Toxoplasma IgG prior to transplant. All patients presented with fevers prior to developing respiratory failure and death. Median days from transplant to death was 37 days (range 23-135 days). Diagnosis of toxoplasmosis was made by serum PCR (n=4 patients, range 45,100-4,900,000 copies/ml) or at autopsy (n=2 patients). None of the patients were taking prophylaxis with activity against toxoplasma prior to diagnosis. No epidemiologic risk factors to explain the increased incidence were identified.
Conclusion: We report an unexplained cluster of 6 cases of fulminant and fatal toxoplasmosis, occurring within a 1 year period, in TCD and UCB recipients at 2 centers in NYC. No common epidemiologic link was identified. We urge a high index of suspicion for toxoplasmosis, and prompt investigation using toxoplasma serum PCR, for severely immunosuppressed HSCT recipients who are toxoplasma seropositive and present with unexplained fevers.
IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
[Show abstract][Hide abstract] ABSTRACT: Transplant-associated thrombotic microangiopathy (TA-TMA) refers to inflammatory and thrombotic diseases of the microvasculature characterized by hemolytic anemia, thrombocytopenia, and evidence of organ damage, particularly acute renal failure. This syndrome occurs in 10% to 20% of patients with allogeneic hematopoietic stem cell transplants (HSCTs). It is much less frequent in the autologous setting. TA-TMAs present diagnostic challenges because they may not clearly fall into one of the categories of the 2 major TMAs: atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). In addition, complications of the transplant itself, including infection, graft-versus-host disease, and disseminated intravascular coagulation, as well as the side effects of immunosuppressive drugs, can mimic a TMA. Because the pathophysiology of TA-TMA is poorly understood, current treatment options are suboptimal, and the condition carries a very high mortality rate. In 3 recent case summaries, the median acute response rate to plasma exchange was as high as 55%, but this therapy failed to alter underlying disease pathology and had little impact on overall mortality, which was approximately 80%. Indeed, the vast majority of TA-TMA patients lack suppression of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity to less than 5% to 10% of normal and do not have a complete response to plasma exchange, characteristics indicating that a TTP-like disorder is not involved. Recent advances in the treatment of aHUS may offer a therapeutic option in the aHUS-like TMAs associated with HSCTs. These issues are discussed in the context of a patient recently evaluated and treated at our institution; the case serves to illustrate the difficulties associated with the diagnosis and treatment of TA-TMA.
Clinical advances in hematology & oncology: H&O 09/2014; 12(9):565-73.
[Show abstract][Hide abstract] ABSTRACT: The treatment of multiple myeloma (MM) has dramatically changed in the last decade due to the introduction of the immunomodulatory drugs (IMIDs) and proteasome inhibitors, otherwise known as the novel agents. Prior to the advent of the novel agents, the gold standard of treatment had been high-dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) for eligible candidates. Given the remarkable activity of the novel agents, and the significant morbidity of HDT/ASCT, the role of stem cell transplantation has now come into question. In this review, we explore the benefits and drawbacks to HDT/ASCT in the era of the novel therapies.
[Show abstract][Hide abstract] ABSTRACT: Abstract From June 5(th) to 7(th) the 12(th) Annual International Cord Blood Symposium was held in San Francisco. The meeting was devoted to advances in umbilical cord blood research with a major focus on translational and clinical results in cord blood transplantation and in regenerative medicine. Over three days, a comprehensive summary of the state of the art was provided. We have summarized the most important data, organized around the following themes: use of umbilical cord blood for tissue repair - new indications for CBU SCT - enhancing count recovery after CBU SCT - improving outcomes - product quality - financial and cost considerations.
Leukemia and Lymphoma 07/2014; 56(4):1-21. DOI:10.3109/10428194.2014.947980 · 2.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Allogeneic hematopoietic cell transplantation is increasingly utilized in older adults. This study prospectively evaluated the prognostic utility of geriatric assessment domains prior to allogeneic transplantation in recipients 50 years and older. Geriatric assessment was performed prior to transplant, and included validated measures across domains of function and disability, comorbidity, frailty, mental health, nutritional status, and systemic inflammation. 203 patients completed geriatric assessment and underwent transplant. The median age was 58 years (range, 50-73). After adjusting for established prognostic factors, limitations in instrumental activities of daily living (HR 2.38, 95% CI 1.59-3.56; P < .001), slow walk speed (HR 1.80, 95% CI 1.14-2.83; P = .01), high comorbidity by hematopoietic cell transplantation-specific comorbidity index (HR 1.56, 95% CI 1.07-2.28; P = .02), low mental health by short-form-36 mental component summary (HR 1.67, 95% CI 1.13-2.48; P = .01), and elevated serum C-reactive protein (HR 2.51, 95% CI 1.54-4.09; P < .001) were significantly associated with inferior overall survival. These associations were more pronounced in the cohort 60 years and older. Geriatric assessment measures confer independent prognostic utility in older allogeneic transplant recipients. Implementation of geriatric assessment prior to allogeneic transplantation may aid in appropriate selection of older adults.
[Show abstract][Hide abstract] ABSTRACT: Microchimerism represents a condition where one individual harbors genetically distinct cell populations, and the chimeric population constitutes<1% of the total number of cells. The most common natural source of microchimerism is pregnancy. The reciprocal cell exchange between a mother and her child often leads to the stable engraftment of hematopoietic and non-hematopoietic stem cells in both parties. Interaction between cells from the mother and those from the child may result in maternal immune cells becoming sensitized to inherited paternal alloantigens of the child, which are not expressed by the mother herself. Vice versa, immune cells of the child may become sensitized toward the non-inherited maternal alloantigens of the mother. The extent of microchimerism, its anatomical location, and the sensitivity of the techniques used for detecting its presence collectively determine whether microchimerism can be detected in an individual. In this review, we focus on the clinical consequences of microchimerism in solid organ and hematopoietic stem cell transplantation, and propose concepts derived from data of epidemiologic studies. Next, we elaborate on the latest molecular methodology, including digital PCR, for determining in a reliable and sensitive way the extent of microchimerism. For the first time, tools have become available to isolate viable chimeric cells from a host background, so that the challenges of establishing the biologic mechanisms and function of these cells may finally be tackled.
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT We examined clofarabine pharmacokinetics and association with renal toxicity in 62 patients participating in a phase I-II study of clofarabine-melphalan-alemtuzumab conditioning for hematopoietic stem cell transplantation (HSCT). Pharmacokinetic parameters, including clofarabine area under the concentration-time curve (AUC), maximum concentration and clearance, were measured and patients were monitored for renal injury. All patients had normal pre-treatment creatinine values, but over half (55%) experienced acute kidney injury (AKI) after clofarabine administration. Age was the strongest predictor of AKI, with older patients at greater risk (p = 0.002). Clofarabine AUC was higher in patients who developed AKI, and patients with the highest dose-normalized AUCs experienced the most severe grades of AKI (p = 0.01). Lower baseline renal function, even when normal, was associated with lower clofarabine clearance (p = 0.008). These data suggest that renal-adjustment of clofarabine dosing should be considered for older and at-risk patients even when renal function is ostensibly normal.