Publications by authors named "Christina Cho"

45 Publications

Development and validation of a disease risk stratification system for patients with haematological malignancies: a retrospective cohort study of the European Society for Blood and Marrow Transplantation registry.

Lancet Haematol 2021 Mar;8(3):e205-e215

Hematology Division, Chaim Sheba Medical Center, Tel Aviv University, Ramat Gan, Israel.

Background: Diagnosis and remission status at the time of allogeneic haematopoietic stem-cell transplantation (HSCT) are the principal determinants of overall survival following transplantation. We sought to develop a contemporary disease-risk stratification system (DRSS) that accounts for heterogeneous transplantation indications.

Methods: In this retrospective cohort study we included 55 histology and remission status combinations across haematological malignancies, including acute leukaemia, lymphoma, multiple myeloma, and myeloproliferative and myelodysplastic disorders. A total of 47 265 adult patients (aged ≥18 years) who received an allogeneic HSCT between Jan 1, 2012, and Dec 31, 2016, and were reported to the European Society for Blood and Marrow Transplantation registry were included. We divided EBMT patients into derivation (n=25 534), tuning (n=18 365), and geographical validation (n=3366) cohorts. Disease combinations were ranked in a multivariable Cox regression for overall survival in the derivation cohort, cutoff for risk groups were evaluated for the tuning cohort, and the selected system was tested on the geographical validation cohort. An independent single-centre US cohort of 660 patients transplanted between Jan 1, 2010, and Dec 31, 2015 was used to externally validate the results.

Findings: The DRSS model stratified patients in the derivation cohort (median follow-up was 2·1 years [IQR 1·0-3·2]) into five risk groups with increasing mortality risk: low risk (reference group), intermediate-1 (hazard ratio for overall survival 1·26 [95% CI 1·17-1·36], p<0·0001), intermediate-2 (1·53 [1·42-1·66], p<0·0001), high (2·03 [1·86-2·22], p<0·0001), and very high (2·87 [2·63-3·13], p<0·0001). DRSS levels were also associated with a stepwise increase in risk across the tuning and geographical validation cohort. In the external validation cohort (median follow-up was 5·7 years [IQR 4·5-7·1]), the DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34 [95% CI 1·04-1·74], p=0·025), high risk (HR 2·03 [95% CI 1·39-2·95], p=0·00023) and very-high risk (HR 2·26 [95% CI 1·62-3·15], p<0·0001) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14 041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% (95% CI 61·2-62·9) for these 14 041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4-54·0; very high risk patients) to 73·1% (70·1-76·2; low risk patients).

Interpretation: The DRSS is a novel risk stratification tool including disease features related to histology, genetic profile, and treatment response. The model should serve as a benchmark for future studies. This system facilitates the interpretation and analysis of studies with heterogeneous cohorts, promoting trial-design with more inclusive populations.

Funding: The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University.
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http://dx.doi.org/10.1016/S2352-3026(20)30394-XDOI Listing
March 2021

Post-error recruitment of frontal sensory cortical projections promotes attention in mice.

Neuron 2021 Feb 12. Epub 2021 Feb 12.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

The frontal cortex, especially the anterior cingulate cortex area (ACA), is essential for exerting cognitive control after errors, but the mechanisms that enable modulation of attention to improve performance after errors are poorly understood. Here we demonstrate that during a mouse visual attention task, ACA neurons projecting to the visual cortex (VIS; ACA neurons) are recruited selectively by recent errors. Optogenetic manipulations of this pathway collectively support the model that rhythmic modulation of ACA neurons in anticipation of visual stimuli is crucial for adjusting performance following errors. 30-Hz optogenetic stimulation of ACA neurons in anesthetized mice recapitulates the increased gamma and reduced theta VIS oscillatory changes that are associated with endogenous post-error performance during behavior and subsequently increased visually evoked spiking, a hallmark feature of visual attention. This frontal sensory neural circuit links error monitoring with implementing adjustments of attention to guide behavioral adaptation, pointing to a circuit-based mechanism for promoting cognitive control.
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http://dx.doi.org/10.1016/j.neuron.2021.02.001DOI Listing
February 2021

Reconstructed evolutionary history of the yeast septins Cdc11 and Shs1.

G3 (Bethesda) 2021 Jan;11(1)

Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA.

Septins are GTP-binding proteins conserved across metazoans. They can polymerize into extended filaments and, hence, are considered a component of the cytoskeleton. The number of individual septins varies across the tree of life-yeast (Saccharomyces cerevisiae) has seven distinct subunits, a nematode (Caenorhabditis elegans) has two, and humans have 13. However, the overall geometric unit (an apolar hetero-octameric protomer and filaments assembled there from) has been conserved. To understand septin evolutionary variation, we focused on a related pair of yeast subunits (Cdc11 and Shs1) that appear to have arisen from gene duplication within the fungal clade. Either Cdc11 or Shs1 occupies the terminal position within a hetero-octamer, yet Cdc11 is essential for septin function and cell viability, whereas Shs1 is not. To discern the molecular basis of this divergence, we utilized ancestral gene reconstruction to predict, synthesize, and experimentally examine the most recent common ancestor ("Anc.11-S") of Cdc11 and Shs1. Anc.11-S was able to occupy the terminal position within an octamer, just like the modern subunits. Although Anc.11-S supplied many of the known functions of Cdc11, it was unable to replace the distinct function(s) of Shs1. To further evaluate the history of Shs1, additional intermediates along a proposed trajectory from Anc.11-S to yeast Shs1 were generated and tested. We demonstrate that multiple events contributed to the current properties of Shs1: (1) loss of Shs1-Shs1 self-association early after duplication, (2) co-evolution of heterotypic Cdc11-Shs1 interaction between neighboring hetero-octamers, and (3) eventual repurposing and acquisition of novel function(s) for its C-terminal extension domain. Thus, a pair of duplicated proteins, despite constraints imposed by assembly into a highly conserved multi-subunit structure, could evolve new functionality via a complex evolutionary pathway.
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http://dx.doi.org/10.1093/g3journal/jkaa006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849910PMC
January 2021

Perianal cutaneous malakoplakia in an allogeneic stem cell transplant recipient.

J Cutan Pathol 2021 Jan 20. Epub 2021 Jan 20.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

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http://dx.doi.org/10.1111/cup.13761DOI Listing
January 2021

Corrosion of Polished Cobalt-Chrome Stems Presenting as Cobalt Encephalopathy.

Arthroplast Today 2020 Dec 2;6(4):1022-1027. Epub 2020 Dec 2.

Tower Orthopedic and Joint Replacement Clinic, Anchorage, AK, USA.

Adverse reactions to metallic debris from corrosion of polished cobalt-chromium-cemented femoral stems are reported. Cobaltism (systemic cobalt poisoning) has not been reported from this phenomenon. Three patients presented to their surgeon for ongoing care 10-20 years after primary metal-on-plastic hip arthroplasty with the same polished cobalt-chromium-cemented femoral stems (Heritage, Zimmer). Urine cobalt was elevated, and the patients had symptoms consistent with cobaltism. Quantitative-FDG-PET-CT brain imaging was performed showing generalized and focal brain hypometabolism consistent with cobalt encephalopathy. At revision, all stems were well fixed and grossly corroded. At 1 year after revision, cobalturia and cognitive symptoms were resolved or improved. Mechanically assisted crevice corrosion at the polymethylmethacrylate interface is a complication of polished cobalt-chromium-cemented stems that can result in systemic cobalt exposure and toxic encephalopathy. Our cases had only minor periprosthetic symptoms. Patients implanted with polished cobalt-chromium-cemented stems warrant monitoring with urine cobalt. Patients with cobaltemia warrant an evaluation for toxic encephalopathy.
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http://dx.doi.org/10.1016/j.artd.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772456PMC
December 2020

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults.

Blood Adv 2020 Dec;4(23):6064-6076

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Cord blood transplantation (CBT) after high intensity or nonmyeloablative conditioning has limitations. We investigated cyclosporine-A/mycophenolate mofetil-based intermediate intensity (cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, total body irradiation 400 cGy) unmanipulated double-unit CBT (dCBT) with prioritization of unit quality and CD34+ cell dose in graft selection. Ninety adults (median age, 47 years [range, 21-63]; median hematopoietic cell transplantation comorbidity index, 2 [range, 0-8]; 61 [68%] acute leukemia) received double-unit grafts (median CD34+ cell dose, 1.3 × 105/kg per unit [range, 0.2-8.3]; median donor-recipient human leukocyte antigen (HLA) match, 5/8 [range 3-7/8]). The cumulative incidences of sustained CB engraftment, day 180 grade III-IV acute, and 3-year chronic graft-versus-host disease were 99%, 24%, and 7%, respectively. Three-year transplant-related mortality (TRM) and relapse incidences were 15% and 9%, respectively. Three-year overall survival (OS) is 82%, and progression-free survival (PFS) is 76%. Younger age and higher engrafting unit CD34+ cell dose both improved TRM and OS, although neither impacted PFS. Engrafting unit-recipient HLA match was not associated with any outcome with a 3-year PFS of 79% in 39 patients engrafting with 3-4/8 HLA-matched units. In 52 remission acute leukemia patients, there was no association between minimal residual disease (MRD) and 3-year PFS: MRD negative of 88% vs MRD positive of 77% (P = .375). Intermediate intensity dCBT is associated with high PFS. Use of highly HLA mismatched and unmanipulated grafts permits wide application of this therapy, and the low relapse rates support robust graft-versus-leukemia effects even in patients with MRD.
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http://dx.doi.org/10.1182/bloodadvances.2020003371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724901PMC
December 2020

Noradrenergic Activity in the Olfactory Bulb Is a Key Element for the Stability of Olfactory Memory.

J Neurosci 2020 11 23;40(48):9260-9271. Epub 2020 Oct 23.

Institut National de la Santé et de la Recherche Médicale U1028, CNRS UMR 5292, and Neuroplasticity and Neuropathology of Olfactory Perception Team, Lyon Neuroscience Research Center, University of Lyon, F-69000 Lyon, France.

Memory stability is essential for animal survival when environment and behavioral state change over short or long time spans. The stability of a memory can be expressed by its duration, its perseverance when conditions change as well as its specificity to the learned stimulus. Using optogenetic and pharmacological manipulations in male mice, we show that the presence of noradrenaline in the olfactory bulb during acquisition renders olfactory memories more stable. We show that while inhibition of noradrenaline transmission during an odor-reward acquisition has no acute effects, it alters perseverance, duration, and specificity of the memory. We use a computational approach to propose a proof of concept model showing that a single, simple network effect of noradrenaline on olfactory bulb dynamics can underlie these seemingly different behavioral effects. Our results show that acute changes in network dynamics can have long-term effects that extend beyond the network that was manipulated. Olfaction guides the behavior of animals. For successful survival, animals have to remember previously learned information and at the same time be able to acquire new memories. We show here that noradrenaline in the olfactory bulb, the first cortical relay of the olfactory information, is important for creating stable and specific olfactory memories. Memory stability, as expressed in perseverance, duration and specificity of the memory, is enhanced when noradrenergic inputs to the olfactory bulb are unaltered. We show that, computationally, our diverse behavioral results can be ascribed to noradrenaline-driven changes in neural dynamics. These results shed light on how very temporary changes in neuromodulation can have a variety of long-lasting effects on neural processing and behavior.
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http://dx.doi.org/10.1523/JNEUROSCI.1769-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687066PMC
November 2020

Letermovir for Prevention of Cytomegalovirus Reactivation in Haploidentical and Mismatched Adult Donor Allogeneic Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis.

Biol Blood Marrow Transplant 2020 Oct 11. Epub 2020 Oct 11.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

Cytomegalovirus (CMV) is serious viral infection in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. November 2017, the novel CMV DNA terminase complex inhibitor letermovir was approved for prophylaxis of CMV infection in CMV-seropositive allo-HCT recipients. Here we sought to determine the effectiveness of letermovir in preventing CMV infection in CMV-seropositive patients undergoing haploidentical or mismatched adult unrelated donor allo-HCT using post-transplantation cyclophosphamide-based graft-versus host-disease prophylaxis. Sixty-four patients underwent transplantation between 2014 and 2019, of whom 32 received letermovir and 32 did not receive letermovir. The day 180 cumulative incidence of CMV infection requiring therapy was 45.3% (95% confidence interval [CI], 32.7% to 57.1%) in the entire cohort, 68.8% (95% CI, 48.9% to 82.2%) in the patients who did not receive letermovir, and 21.9% (95% CI, 9.5% to 37.6%; P < .001) in patients who received letermovir. Adjusting for regimen intensity, disease histology, and age, the hazard ratio for CMV infection was .19 (95% CI, .08 to .47; P < .001) in patients who received primary prophylaxis with letermovir. The 1-year cumulative incidence of treatment- related mortality was similar between patients with and without letermovir treatment (16.9% versus 18.9%), as was overall survival (64.0% versus 49.0%). Persistent CMV infection requiring >28 days of therapy was more common in patients who did not receive letermovir (31.2% versus 6.2%; P = .02). In summary, letermovir was effective in preventing CMV infection in this high-risk population of HLA-mismatched allo-HCT recipients.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.009DOI Listing
October 2020

Experience enhances certainty about olfactory stimuli under bulbar cholinergic control.

Learn Mem 2020 10 15;27(10):414-417. Epub 2020 Sep 15.

Computational Physiology Lab, Department of Neurobiology and Behavior, Cornell University, Ithaca, New York 14850, USA.

We present evidence that experience and cholinergic modulation in an early sensory network interact to improve certainty about olfactory stimuli. The data we present are in agreement with existing theoretical ideas about the functional role of acetylcholine but highlight the importance of early sensory networks in addition to cortical networks. We use a simple behavioral paradigm in mice which allows us to measure certainty about a stimulus via the response amplitude to a condition and novel stimuli. We conclude that additional learning increases certainty and that the slope of this relationship can be modulated by activation of muscarinic cholinergic receptors in the olfactory bulb.
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http://dx.doi.org/10.1101/lm.051854.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497109PMC
October 2020

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation.

J Clin Invest 2020 12;130(12):6656-6667

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

BACKGROUNDUnderstanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations.METHODSWe retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available.RESULTSWe identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354-1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients.CONCLUSIONIn this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.FUNDINGNIH grant P01 CA23766 and NIH/National Cancer Institute grant P30 CA008748.
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http://dx.doi.org/10.1172/JCI141777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685738PMC
December 2020

Cancer-associated fibroblasts downregulate type I interferon receptor to stimulate intratumoral stromagenesis.

Oncogene 2020 09 17;39(38):6129-6137. Epub 2020 Aug 17.

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Activation of cancer-associated fibroblasts (CAFs) and ensuing desmoplasia play an important role in the growth and progression of solid tumors. Here we demonstrate that, within colon and pancreatic ductal adenocarcinoma tumors, efficient stromagenesis relies on downregulation of the IFNAR1 chain of the type I interferon (IFN1) receptor. Expression of the fibroblast activation protein (FAP) and accumulation of the extracellular matrix (ECM) was notably impaired in tumors grown in the Ifnar1 (SA) knock-in mice, which are deficient in IFNAR1 downregulation. Primary fibroblasts from these mice exhibited elevated levels of Smad7, a negative regulator of the transforming growth factor-β (TGFβ) pathway. Knockdown of Smad7 alleviated deficient ECM production in SA fibroblasts in response to TGFβ. Analysis of human colorectal cancers revealed an inverse correlation between IFNAR1 and FAP levels. Whereas growth of tumors in SA mice was stimulated by co-injection of wild type but not SA fibroblasts, genetic ablation of IFNAR1 in fibroblasts also accelerated tumor growth. We discuss how inactivation of IFNAR1 in CAFs acts to stimulate stromagenesis and tumor growth.
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http://dx.doi.org/10.1038/s41388-020-01424-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502515PMC
September 2020

The microbe-derived short-chain fatty acids butyrate and propionate are associated with protection from chronic GVHD.

Blood 2020 07;136(1):130-136

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.
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http://dx.doi.org/10.1182/blood.2019003369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332893PMC
July 2020

Fibronectin in the Tumor Microenvironment Activates a TLR4-dependent Inflammatory Response in Lung Cancer Cells.

J Cancer 2020 4;11(11):3099-3105. Epub 2020 Mar 4.

Department of Regenerative & Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208-3479.

The microenvironment of solid tumors plays an essential role in tumor progression. In lung cancer, the stromal cells produce a fibronectin rich extracellular matrix which is known to contribute to both tumor metastasis and drug resistance. Due to its conformational lability, fibronectin is considerably remodeled by the contractile forces of the fibrotic microenvironment within the tumor stroma. As a result, the secondary structure of fibronectin's Type III domains is disrupted and the molecule becomes highly stretched. The contribution/impact of these strained forms of fibronectin on tumor growth and metastasis is not known. In the current study we show that the partially unfolded first Type III domain of fibronectin, III-1c, activates a toll-receptor/NF-κB pathway leading to an increase in the expression of IL-8. Using a 3-D model of tumor-associated extracellular matrix, we demonstrate that lung cancer cells seeded onto this matrix activate a TLR4/NF-κB signaling pathway leading to a robust increase in the release of IL-8. Cytokine release by these cells is completely dependent on the presence of fibronectin in the extracellular matrix. These findings suggest that paracrine signaling between the tumor and the stromal myofibroblasts causes a remodeling of the matrix fibronectin into a strained conformation which supports the activation of a TLR4/NF-κB signaling pathway resulting in the upregulation of fibro-inflammatory cytokines.
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http://dx.doi.org/10.7150/jca.39771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097952PMC
March 2020

The geriatric syndrome of sarcopenia impacts allogeneic hematopoietic cell transplantation outcomes in older lymphoma patients.

Leuk Lymphoma 2020 08 31;61(8):1833-1841. Epub 2020 Mar 31.

Department of Medicine, Weill Cornell Medical College, New York, NY, USA.

Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.
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http://dx.doi.org/10.1080/10428194.2020.1742909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429343PMC
August 2020

Characteristics and Impact of Post-Transplant Interdisciplinary Palliative Care Consultation in Older Allogeneic Hematopoietic Cell Transplant Recipients.

J Palliat Med 2020 Dec 27;23(12):1653-1657. Epub 2020 Mar 27.

Supportive Care Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

The myriad of benefits of early palliative care (PC) integration in oncology are well established, and emerging evidence suggests that PC improves symptom burden, mood, and quality of life for hematopoietic cell transplant (HCT) recipients. Specific impact of PC consultation on outcomes of older allogeneic HCT (allo-HCT) recipients, a historically high-risk population vulnerable to transplant-related complications and mortality, has not been explored. In this single institution, retrospective analysis of 527 first allo-HCT recipients aged ≥60 years, we characterized 75 patients who had received post-HCT PC consultation and its association with geriatric vulnerabilities identified by pre-HCT geriatric assessment. We also examined end-of-life care outcomes among patients who died within one-year of allo-hematopoietic cell transplantation. In multivariate analysis, higher disease risk, female gender, and, importantly, pre-HCT functional limitation (hazard ratio 2.35, 95% confidence interval, 1.35-4.09,  = 0.003) were associated with post-HCT PC utilization. Within one-year of hematopoietic cell transplantation, 127 patients died; among those, recipients of early PC consultation had significantly higher rates of hospice enrollment (25% vs. 9%,  = 0.019) and lower rates of hospital death (71% vs. 90%,  = 0.013), intensive care unit admission (44% vs. 75%,  = 0.001), and high-intensity medical care in last 30 days of life (46% vs. 77%,  = 0.001). Our results highlight important pre-HCT risk factors associated with increased PC needs posthematopoietic cell transplantation and benefits of PC involvement for older allo-HCT recipients at the end of life. Prospective studies should examine the optimal timing of PC consultation and its multidimensional benefits for older allo-HCT patients.
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http://dx.doi.org/10.1089/jpm.2019.0611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698973PMC
December 2020

Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

N Engl J Med 2020 02;382(9):822-834

From the Adult Bone Marrow Transplantation Service (J.U.P., M.M., A.G.C., K.A.M., N.K., D.G.B., M.S.-E., N.C.F., A.A.T., R.J.L., L.Y.S.S., G.L.S., C.C., M.S., I.P., B.G., D.M.P., J.N.B., M.-A.P., S.A.G., M.R.M.B.) and the Infectious Disease Service (Y.T., E.F., L.A.A., R.J.W., E.G.P.), Department of Medicine, the Department of Epidemiology and Biostatistics (S.M.D.), the Department of Immunology, Sloan Kettering Institute (A.L.C.G., E.R.L., A.E.S., J.B.S., C.K.S.-T., M.D.D., M.B.S., G.K.A., Y.S., M.R.M.B.), and the Program for Computational and Systems Biology (J.B.X.), Memorial Sloan Kettering Cancer Center, and the Department of Medicine, Weill Cornell Medical College (J.U.P., Y.T., K.A.M., M.D.D., R.J.L., G.L.S., C.C., M.S., I.P., B.G., D.M.P., J.N.B., M.-A.P., S.A.G., M.R.M.B.) - both in New York; Duchossois Family Institute of the University of Chicago, Chicago (E.R.L., E.G.P.); the Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center (A.D.S., M.V.L., A.B., L.B., N.J.C.), the Division of Infectious Diseases, Department of Medicine, Duke University (J.A.M.), and the Duke Office of Clinical Research, Duke University School of Medicine (K.R.) - all in Durham, NC; the Department of Hematology and Oncology, Internal Medicine III, University Medical Center (D.W., E.H.), the Collaborative Research Center Transregio 221 (D.W., A.G., E.H.), and Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg (A.G.) - all in Regensburg, Germany; the Department of Hematology, Hokkaido University Faculty of Medicine (D.H., Y.H., T.T.), and the Division of Laboratory and Transfusion Medicine, Hokkaido University Hospital (K.H., T.T.) - both in Sapporo, Japan; Research Institute Marqués de Valdecilla-IDIVAL (M.S.-E.) and the Department of Hematology, Hospital Universitario Marqués de Valdecilla-IDIVAL, University of Cantabria (L.Y.S.S.), Santander, and Hospital Universitario Puerta de Hierro, Madrid (A.A.T.) - all in Spain; and the Departments of Genomic Medicine and Stem Cell Transplantation Cellular Therapy, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (R.R.J.).

Background: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable.

Methods: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death.

Results: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival.

Conclusions: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).
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http://dx.doi.org/10.1056/NEJMoa1900623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534690PMC
February 2020

Robust CD4+ T-cell recovery in adults transplanted with cord blood and no antithymocyte globulin.

Blood Adv 2020 01;4(1):191-202

Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Quality of immune reconstitution after cord blood transplantation (CBT) without antithymocyte globulin (ATG) in adults is not established. We analyzed immune recovery in 106 engrafted adult CBT recipients (median age 50 years [range 22-70]) transplanted for hematologic malignancies with cyclosporine/mycophenolate mofetil immunoprophylaxis and no ATG. Patients were treated predominantly for acute leukemia (66%), and almost all (96%) underwent myeloablation. Recovery of CD4+ T cells was faster than CD8+ T cells with median CD4+ T-cell counts exceeding 200/mm3 at 4 months. Early post-CBT, effector memory (EM), and central memory cells were the most common CD4+ subsets, whereas effector and EM were the most common CD8+ T-cell subsets. Naive T-cell subsets increased gradually after 6 to 9 months post-CBT. A higher engrafting CB unit infused viable CD3+ cell dose was associated with improved CD4+ and CD4+CD45RA+ T-cell recovery. Cytomegalovirus reactivation by day 60 was associated with an expansion of total, EM, and effector CD8+ T cells, but lower CD4+ T-cell counts. Acute graft-versus-host disease (aGVHD) did not significantly compromise T-cell reconstitution. In serial landmark analyses, higher CD4+ T-cell counts and phytohemagglutinin responses were associated with reduced overall mortality. In contrast, CD8+ T-cell counts were not significant. Recovery of natural killer and B cells was prompt, reaching medians of 252/mm3 and 150/mm3 by 4 months, respectively, although B-cell recovery was delayed by aGVHD. Neither subset was significantly associated with mortality. ATG-free adult CBT is associated with robust thymus-independent CD4+ T-cell recovery, and CD4+ recovery reduced mortality risk.
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http://dx.doi.org/10.1182/bloodadvances.2019000836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960461PMC
January 2020

F-18 FDG PET brain imaging in symptomatic arthroprosthetic cobaltism.

Eur J Nucl Med Mol Imaging 2020 07 20;47(8):1961-1970. Epub 2019 Dec 20.

Aegis Imaging Consultants, LLC, P.O. Box 751, 170 Cervin Circle, Girdwood, AK, 99587, USA.

Purpose: Imaging studies of cobalt toxicity from cobalt-chromium alloy arthroprosthetics have focused on the local intra-articular and peri-articular presentation from failing joint replacements. Most studies investigating neurological findings have been small case series focused on the clinical findings of memory loss, diminished executive function, tremor, hearing and vision loss, depression, and emotional lability. This study utilizes software-based quantitative analysis of brain metabolism to assess the degree of hypometabolism and areas of susceptibility, determine if a pattern of involvement exists, and measure reversibility of findings after prosthetic revision to cobalt-free appliances.

Methods: Over 48 months, 247 consecutive patients presenting to an orthopedic clinic with an arthroprosthetic joint containing any cobalt-chromium part were screened with whole blood and urine cobalt levels. A clinically validated inventory of 10 symptoms was obtained. Symptomatic patients with a blood cobalt level above 0.4 mcg/L or urine cobalt greater than 1 mcg/L underwent F-18 FDG PET brain imaging. Analysis was performed with FDA-approved quantitative brain analysis software with the pons as the reference region. Control group was the normal brain atlas within the software.

Results: Of the 247 consecutively screened patients, 123 had blood and urine cobalt levels above the threshold. The 69 scanned patients had statistically significant regional hypometabolism and higher symptoms inventory. Fifty-seven patients were retained in the study. Distribution of hypometabolism was in descending order: temporal, frontal, Broca's areas, anterior cingulate, parietal, posterior cingulate, visual, sensorimotor, thalamic, and lastly caudate. Metal-on-metal (MoM) and metal-on-plastic (MoP) joint replacements produced similar patterns of hypometabolism. Of 15 patients with necessary revision surgery, 8 demonstrated improved metabolism when later re-scanned.

Conclusion: All scanned patients had regions of significant hypometabolism. Neurological toxicity from elevated systemic cobalt levels following arthroprosthetic joint replacement has a pattern of regional susceptibility similar to heavy metals and solvents, differing from classical dementias and may occur at blood and urine cobalt levels as low as 0.4 mcg/L and 1 mcg/L, respectively. Presently accepted thresholds for cobalt exposure and monitoring may need revision. Quantitative F-18 FDG PET brain imaging may aid in the decision process for treatment options and timing of possible medical versus surgical intervention.
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http://dx.doi.org/10.1007/s00259-019-04648-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299907PMC
July 2020

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34 Selected Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 08 1;25(8):1526-1535. Epub 2019 Mar 1.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.
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http://dx.doi.org/10.1016/j.bbmt.2019.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302932PMC
August 2019

Understanding technology adoption by orthodontists: A qualitative study.

Am J Orthod Dentofacial Orthop 2019 Mar;155(3):432-442

Orthodontics Department, University of North Carolina School of Dentistry, Chapel Hill, NC. Electronic address:

Introduction: Orthodontics is evolving with advances in 3D imaging, additive fabrication, digital scanning, and treatment planning. With digital tools, orthodontic treatment may become more predictable, efficient, and effective while reducing side-effects. These technologies are affecting patient care, but knowledge of their adoption patterns and influence is incomplete. We aimed to identify adoption decision makers, information sources, perspectives, incentives, and barriers.

Methods: Twenty-four privately practicing orthodontists were interviewed in a semistructured format following a topic guide. Interview transcripts were analyzed to identify factors in technology adoption and its perceived influence on practice. Thematic patterns were established through iterative systematic analysis, and qualitative validity was ensured with researcher triangulation.

Results: Qualitative interviews revealed that orthodontists make purchasing decisions independently from staff, after consulting other dentists and company representatives. Meetings, residency training, and continuing education courses are influential information sources, whereas research literature is not. Early and middle adopters are integrating digital imaging, planning, and fabrication technologies into practice and view enhanced ease of use, capabilities, performance, and procedural efficiency as primary incentives to adoption. Improving outcomes and patient comfort are not frequently cited as incentives, and all interviewees view cost as the largest barrier. Orthodontists positively perceive the influence of technology on their practices, but are concerned that further innovation and direct-to-consumer products will cause loss of market share.

Conclusions: CAD/CAM appliances, 3D imaging, and digital treatment planning are viewed as future standards of care and are increasingly being incorporated into the orthodontic office. Understanding the technology adoption process can guide innovation to improve treatment and ease the transition into a digital workflow.
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http://dx.doi.org/10.1016/j.ajodo.2018.08.018DOI Listing
March 2019

An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles.

Cancer Cell 2019 01;35(1):33-45.e6

Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Tumor-derived extracellular vesicles (TEV) "educate" healthy cells to promote metastases. We found that melanoma TEV downregulated type I interferon (IFN) receptor and expression of IFN-inducible cholesterol 25-hydroxylase (CH25H). CH25H produces 25-hydroxycholesterol, which inhibited TEV uptake. Low CH25H levels in leukocytes from melanoma patients correlated with poor prognosis. Mice incapable of downregulating the IFN receptor and Ch25h were resistant to TEV uptake, TEV-induced pre-metastatic niche, and melanoma lung metastases; however, ablation of Ch25h reversed these phenotypes. An anti-hypertensive drug, reserpine, suppressed TEV uptake and disrupted TEV-induced formation of the pre-metastatic niche and melanoma lung metastases. These results suggest the importance of CH25H in defense against education of normal cells by TEV and argue for the use of reserpine in adjuvant melanoma therapy.
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http://dx.doi.org/10.1016/j.ccell.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336114PMC
January 2019

Immune Cytopenias after Ex Vivo CD34+-Selected Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2019 06 6;25(6):1136-1141. Epub 2019 Jan 6.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

Immune-mediated cytopenias (ICs), such as immune thrombocytopenia and immune hemolytic anemia, are among the adverse events after allogeneic hematopoietic cell transplantation (allo-HCT). Previous reports suggest that in vivo T cell depletion may increase the incidence of IC after allo-HCT. We evaluated whether a strategy that reduces functional donor T cells via ex vivo CD34-selection associates with the development of IC in a cohort of 408 patients who underwent allo-HCT for hematologic malignancy. The cumulative incidence of IC at 6, 12, and 36 months after the 30-day landmark post-HCT was 3.4%, 4.9%, and 5.8%, respectively. Among 23 patients who developed IC, 7 died of relapse-related mortality and 4 of nonrelapse mortality. A median 2 types of treatment (range, 1 to 5) was required to resolve IC, and there was considerable heterogeneity in the therapies used. In univariable analyses, a hematologic malignancy Disease Risk Index (DRI) score of 3 was significantly associated with an increased risk of IC compared with a DRI of 1 or 2 (hazard ratio [HR], 4.12; P = .003), and IC (HR, 2.4; P = .03) was associated with increased risk of relapse. In a multivariable analysis that included DRI, IC remained significantly associated with increased risk of relapse (HR, 2.4; P = .03). Our findings show that IC events occur with relatively similar frequency in patients after ex vivo CD34-selected allo-HCT compared with unmodified allo-HCT, suggesting that reduced donor T cell immunity is not causative of IC. Moreover, we noted a possible link between its development and/or treatment and increased risk of relapse.
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http://dx.doi.org/10.1016/j.bbmt.2018.12.842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559823PMC
June 2019

Expanding Therapeutic Opportunities for Hematopoietic Stem Cell Transplantation: T Cell Depletion as a Model for the Targeted Allograft.

Annu Rev Med 2019 01 25;70:381-393. Epub 2018 Oct 25.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; email: ,

Allogeneic hematopoietic cell transplantation is a fundamental part of the treatment of hematologic malignancies and marrow failure syndromes, but complications including graft-versus-host disease, prolonged immune deficiency and infection, and organ toxicities, as well as relapse, remain obstacles to improved overall survival. As the cellular characteristics of the allograft can exert significant impact on outcomes, the development of more strategically designed grafts represents a rich area for therapeutic intervention. We describe the use of ex vivo T cell-depleted grafts as a model for the targeted graft and review evolving knowledge and approaches for further refinement of allografts to improve patient outcomes.
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http://dx.doi.org/10.1146/annurev-med-120617-041210DOI Listing
January 2019

Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC.

J Hematol Oncol 2018 10 20;11(1):127. Epub 2018 Oct 20.

Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Graft-versus-host disease (GVHD) is one of the leading causes of non-relapse mortality and morbidity after allogeneic hematopoietic stem cell transplantation (allo-HCT).

Methods: We evaluated the outcomes of two well-established strategies used for GVHD prevention: in vivo T cell depletion using antithymocyte globulin (ATG) and ex vivo T cell depletion using a CD34-selected (CD34+) graft. A total of 525 adult patients (363 ATG, 162 CD34+) with intermediate or high-risk cytogenetics acute myeloid leukemia (AML) in first complete remission (CR1) were included. Patients underwent myeloablative allo-HCT using matched related or unrelated donors.

Results: Two-year overall survival estimate was 69.9% (95% CI, 58.5-69.4) in the ATG group and 67.6% (95% CI, 60.3-74.9) in the CD34+ group (p = 0.31). The cumulative incidence of grade II-IV acute GVHD and chronic GVHD was higher in the ATG cohort [HR 2.0 (95% CI 1.1-3.7), p = 0.02; HR 15.1 (95% CI 5.3-42.2), p < 0.0001]. Parameters associated with a lower GVHD-free relapse-free survival (GRFS) were ATG [HR 1.6 (95% CI 1.1-2.2), p = 0.006], adverse cytogenetic [HR 1.7 (95% CI 1.3-2.2), p = 0.0004], and the use of an unrelated donor [HR 1.4 (95% CI 1.0-1.9), p = 0.02]. There were no statistical differences between ATG and CD34+ in terms of relapse [HR 1.52 (95% CI 0.96-2.42), p = 0.07], non-relapse mortality [HR 0.96 (95% CI 0.54-1.74), p = 0.90], overall survival [HR 1.43 (95% CI 0.97-2.11), p = 0.07], and leukemia-free survival [HR 1.25 (95% CI 0.88-1.78), p = 0.21]. Significantly, more deaths related to infection occurred in the CD34+ group (16/52 vs. 19/112, p = 0.04).

Conclusions: These data suggest that both ex vivo CD34-selected and in vivo ATG T cell depletion are associated with a rather high OS and should be compared in a prospective randomized trial.
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http://dx.doi.org/10.1186/s13045-018-0668-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195954PMC
October 2018

Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit).

Cancer Med 2018 09 16;7(9):4447-4455. Epub 2018 Aug 16.

Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background: Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.

Methods: Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).

Results: Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P < 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P < 0.0001).

Conclusions: I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).
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http://dx.doi.org/10.1002/cam4.1733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144246PMC
September 2018

Early Fluid Overload Is Associated with an Increased Risk of Nonrelapse Mortality after Ex Vivo CD34-Selected Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2018 12 26;24(12):2517-2522. Epub 2018 Jul 26.

Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.

In a recently published and validated definition of fluid overload (FO), grade ≥ 2 FO was significantly associated with an increased risk of nonrelapse mortality (NRM) after unmodified and haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using calcineurin inhibitor (CNI)-based graft-versus-host disease (GVHD) prophylaxis. We evaluated the effect of FO on outcomes in 169 patients undergoing myeloablative-conditioned ex vivo CD34 selected allo-HCT using the same grading scale. Thirty patients (17.8%) had grade ≥ 2 FO within the 30 days after ex vivo CD34 selected allo-HCT with a median onset at day 11 (range, -8 to 28). Age ≥ 55 years (odds ratio, 3.43; P = .005) and chemotherapy-based conditioning (odds ratio, 3.89; P = .007) were associated with an increased risk of grade ≥ 2 FO. Patients with early grade ≥ 2 FO had a significantly higher NRM when compared with patients with grade < 2 FO (24.1% versus 3.6% at day 100, P = .01). The HCT-specific comorbidity index (HCT-CI) ≥ 3, FEV < 80, adjusted DL < 80, and HLA mismatch were associated with an increased risk of NRM, whereas total body irradiation-based conditioning was associated with a reduced risk of NRM. In a multivariate analysis grade ≥ 2 FO was associated with increased NRM after adjusting for HCT-CI and HLA match (hazard ratio, 2.3; P = .014). There was a trend toward inferior relapse-free survival in patients with grade ≥ 2 FO compared with patients with grade < 2 FO, 62% versus 72% at 1 year (P = .07), and a trend toward inferior overall survival, 69% versus 79% at 1 year (P = 0.06), respectively. Our findings show that FO should be routinely assessed to identify patients at risk for NRM. Despite a CNI-free allo-HCT platform, regimen-related tissue and endothelial injury leads to FO in susceptible patients. FO is a highly relevant post-HCT toxicity that requires further inquiry.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286243PMC
December 2018

Sequential systematic anti-mold prophylaxis with micafungin and voriconazole results in very low incidence of invasive mold infections in patients undergoing allogeneic hematopoietic stem cell transplantation.

Transpl Infect Dis 2018 Aug 7;20(4):e12897. Epub 2018 May 7.

Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at high risk for invasive mold infections (IMI). The goal of the study is to describe the incidence and outcome of IMI in patients after allo-HSCT in a large cohort of patients receiving anti-mold prophylaxis. We conducted a retrospective review of 988 consecutive adults who underwent allo-HSCT in our center from 2008 through 2014. Standard prophylaxis consisted of micafungin 150 mg IV daily from admission to day +7 ± 3 followed by voriconazole until day +75 to +100. Cases meeting criteria for proven or probable IMI according to EORTC-MSG criteria were included. Median age at HSCT was 54 years. The most common diagnoses were acute myeloid leukemia (n = 351, 36%) and lymphoid malignancies (n = 248, 25%). Matched related or unrelated donors (URD) were used in 686 (69%) patients, mismatched URD in 142 (14%) and cord blood units in 154 (16%). Twenty-one patients were diagnosed with IMI after allo-HSCT, 19 probable and 2 proven, and one patient was diagnosed postmortem. Microbiological diagnosis was established in 9 cases, 5 of them being Aspergillus. One-year cumulative incidence (CI) of IMI was 1.6% (95% CI 0.9-2.5) while 12-week overall survival after IMI was 39% (95% CI 24-65) Analyzed by disease, there was a trend for a higher 1-year CI of IMI in patients with ALL (5% [95% CI 1.6-11.4]) when compared with AML (1.4%), MDS (1.5%) and lymphoma (1.2%), P = .06. The 1-year CI of IMI after transplantation is low in patients receiving anti-mold prophylaxis with micafungin bridged to voriconazole, although these infections are associated with a higher risk of mortality.
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http://dx.doi.org/10.1111/tid.12897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913888PMC
August 2018

CD34 Cell Selection versus Reduced-Intensity Conditioning and Unmodified Grafts for Allogeneic Hematopoietic Cell Transplantation in Patients Age >50 Years with Acute Myelogenous Leukemia and Myelodysplastic Syndrome .

Biol Blood Marrow Transplant 2018 05 2;24(5):964-972. Epub 2018 Jan 2.

Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College; New York, New York. Electronic address:

Reduced-intensity conditioning (RIC) and T cell depletion (TCD) through CD34 cell selection without the use of post-transplantation immunosuppression are 2 strategies used to reduce nonrelapse mortality (NRM) in older patients after allogeneic hematopoietic cell transplantation (allo-HCT). To compare the efficacy of the RIC and TCD approaches, we evaluated the outcomes of patients age >50 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allo-HCT from an HLA-matched donor with one of these strategies. Baseline characteristics were comparable in the patients receiving TCD (n = 204) and those receiving RIC (n = 151), except for a higher proportion of unrelated donors (68% versus 40%; P < .001) and a higher comorbidity burden (Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI] ≥3: 51% versus 38%; P < .001) in the TCD cohort. Analysis of outcomes at 3 years showed a higher chronic graft-versus-host disease (GVHD)/relapse-free survival (CRFS) (51% versus 7%; P < .001), lower incidences of grade II-IV acute GVHD (18% versus 46% at day +180) and chronic GVHD (6% versus 55% at 3 years; P < .001), and a lower incidence of relapse (19% versus 33% at 3 years; P = .001) in the TCD group compared with the RIC group. Relapse-free survival (RFS), overall survival (OS), and NRM were similar in the 2 groups. Combining transplantation approach (RIC versus TCD) and comorbidity burden (HCT-CI 0-2 versus ≥3), patients with an HCT-CI score of 0-2 seemed to benefit from the TCD approach. In conclusion, in this retrospective study, the use of a CD34 cell-selected graft and a myeloablative conditioning regimen was associated with higher CRFS and similar RFS and OS compared with unmodified allo-RIC in patients age >50 years with AML and MDS.
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http://dx.doi.org/10.1016/j.bbmt.2017.12.804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800017PMC
May 2018