A phase ib clinical trial of oral ciprofloxacin and etoposide in subjects with resistant acute myeloid leukemia.

A phase 1b study was conducted to evaluate the safety and feasibility of ciprofloxacin and etoposide combination treatment in subjects with relapsed and refractory acute myeloid leukemia. Eleven subjects were enrolled in the study. Utilizing the standard '3 + 3' design, escalating ciprofloxacin doses (750 mg, 1000 mg) twice daily on D1-D10 in combination with a fixed dose (200 mg) of etoposide on D2-D8 were administered. Maximum tolerated dose was determined to be 1000 mg of ciprofloxacin in combination with 200 mg of etoposide. Serious adverse events occurred in 54.5% (n = 6) subjects and 91% (n = 10) subjects reported ≥ grade 3 toxicities. Nine subjects completed treatment, one had a dose-limiting toxicity, and one withdrew. One subject achieved complete remission with a duration of 111 days and one subject achieved morphologic leukemia-free state after cycle 1. While the combination demonstrated safety and an acceptable toxicity profile, only modest hematologic and clinical benefits were observed.This trial was registered at www.clinicaltrials.gov as #NCT02773732.

CMPK2 restricts Zika virus replication by inhibiting viral translation.

Flaviviruses continue to emerge as global health threats. There are currently no Food and Drug Administration (FDA) approved antiviral treatments for flaviviral infections. Therefore, there is a pressing need to identify host and viral factors that can be targeted for effective therapeutic intervention. Type I interferon (IFN-I) production in response to microbial products is one of the host's first line of defense against invading pathogens. Cytidine/uridine monophosphate kinase 2 (CMPK2) is a type I interferon-stimulated gene (ISG) that exerts antiviral effects. However, the molecular mechanism by which CMPK2 inhibits viral replication is unclear. Here, we report that CMPK2 expression restricts Zika virus (ZIKV) replication by specifically inhibiting viral translation and that IFN-I- induced CMPK2 contributes significantly to the overall antiviral response against ZIKV. We demonstrate that expression of CMPK2 results in a significant decrease in the replication of other pathogenic flaviviruses including dengue virus (DENV-2), Kunjin virus (KUNV) and yellow fever virus (YFV). Importantly, we determine that the N-terminal domain (NTD) of CMPK2, which lacks kinase activity, is sufficient to restrict viral translation. Thus, its kinase function is not required for CMPK2's antiviral activity. Furthermore, we identify seven conserved cysteine residues within the NTD as critical for CMPK2 antiviral activity. Thus, these residues may form an unknown functional site in the NTD of CMPK2 contributing to its antiviral function. Finally, we show that mitochondrial localization of CMPK2 is required for its antiviral effects. Given its broad antiviral activity against flaviviruses, CMPK2 is a promising potential pan-flavivirus inhibitor.

Association of ABO mismatch with the outcomes of allogeneic hematopoietic cell transplantation for acute leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT, the independent impact of donor-recipient ABO mismatching remains unclear. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified patients aged ≥18 years with AML or ALL who underwent allo-HCT between 2008 and 2018. Our objectives were to analyze the outcomes of allo-HCT based on the donor-recipient ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Among 4946 eligible patients, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had a minor ABO mismatch, 899 patients (18.1%) had a major ABO mismatch, and 276 patients (5.6%) had a bidirectional ABO mismatch. In multivariable analyses, compared to ABO matched allo-HCT, the presence of a major ABO mismatch was associated with worse overall survival (HR 1.16, 95% CI 1.05-1.29; p = 0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p < 0.001), and higher primary graft failure (HR 1.60, 95% CI 1.12-2.30, p = 0.01). Relapse, acute graft versus host disease (GVHD) grades III-IV and chronic GVHD were not significantly associated with ABO status. While donor age was not significantly associated with outcomes, older recipient age was associated with worse survival and non-relapse mortality. Our study demonstrates that donor-recipient ABO status is independently associated with survival and other post-transplantation outcomes in acute leukemia. This underscores the importance of considering the ABO status in donor selection algorithms and its impact in acute leukemia.

SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to down-regulate MHC-I surface expression.

Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small-protein ß2-microglobulin (ß2m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells, these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8+ T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that down-regulate MHC-I expression to avoid CD8+ T cell recognition. Here, we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, down-regulate MHC-I expression using distinct mechanisms. First, ORF3a, a viroporin, reduces the global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of ß2m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a specific mechanism that allows immune evasion by SARS-CoV-2.

Protocol for assessing translational regulation in mammalian cell lines by OP-Puro labeling.

Translational regulation is a fundamental step in gene expression with critical roles in biological processes within a cell. Here, we describe a protocol to assess translation activity in mammalian cells by incorporation of O-propargyl-puromycin (OP-Puro). OP-Puro is a puromycin analog that is incorporated into newly synthesized proteins and is detected by click chemistry reaction. We use OP-Puro labeling to assess translation activity between different cell types or cells under different growth conditions by confocal microscopy and flow cytometry. For complete details on the use and execution of this protocol, please refer to Hsu et al. (2021) and Hsu et al. (2022).

The Impact of Pre-Apheresis Health Related Quality of Life on Peripheral Blood Progenitor Cell Yield and Donor's Health and Outcome: Secondary Analysis of Patient-Reported Outcome Data from the RDSafe and BMT CTN 0201 Clinical Trials.

There is a lack of evidence about how health-related quality of life (HRQoL), including psychosocial factors, might affect donation-related experiences and clinical markers in the context of hematopoietic stem cell donation. The broader literature suggests that psychological factors, including anxiety and depression, are associated with higher levels of inflammatory burden leading to poorer postprocedural outcomes including longer hospital stays and increased pain perception. In this study, we aimed to evaluate whether predonation HRQoL markers predict toxicity profile and stem cell yield after peripheral blood stem cell (PBSC) donation in healthy donors. The study population comprised adult granulocyte colony-stimulating factor mobilized PBSC-related donors (RD) (n = 157) and unrelated donors (URD) (n = 179) enrolled in the related donor safety study (RDSafe) and Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0201 clinical trials. Pre-donation HRQoL was assessed using the Short-Form-12 (SF-12) in RDSafe and SF-8 questionnaire in BMT CTN 0201 (higher score is better). The aims of this study were to (a) determine the impact of pre-donation HRQoL on peri-collection pain and acute toxicities experienced and (b) to investigate the pre-procedural HRQoL indicators on stem cells yield. URDs were younger than RDs (median age 35 versus 63). A higher proportion of RDs were female (50% versus 40%) and obese (41% versus 35%). A higher proportion of RD PBSC donations required 2 days or more of apheresis (44% versus 21%). More RD collections were lower volume procedures (<18L, 16% versus 28%), and required a central line (28% versus 11%). RDs were more likely to report pre-donation grade 1-2 pain (27% versus 8%) and other toxicities (16% versus 6%). Among RDs, a lower pre-donation physical component summary (PCS) score was associated with significantly more grade 2-4 pain at 1 month (P = .004) and at 1-year after donation (P = .0099) in univariable analyses. In multivariable analysis, pre-donation PCS remained significantly associated with grade 2-4 pain 1 month after donation (P = .0098). More specifically, RDs with predonation PCS scores in the highest quartile were less likely to report pain compared with donors with PCS scores in the lowest quartile (odds ratio 0.1; 95% confidence interval 0.01-0.83; P = .005). There was also a trend toward higher grade 2-4 pain at 1-year post-donation among RDs with lower predonation PCS score (P = .018). Among URDs, neither PCS nor mental component summary (MCS) scores were associated with pain or toxicities at any time point after donation based on the univariable analysis. Because of low rates of postdonation grade 2-4 pain and toxicities, multivariable analysis was not performed in the URD setting. Moreover, there was no correlation between preapheresis HRQoL score (PCS or MCS) and PBSC collection yield in either the RD or URD setting. Our study demonstrates that pre-donation HRQoL scores are significantly associated with the toxicity profile after PBSC donation in the RD setting, with adult RDs with lower predonation physical HRQoL experiencing higher levels of pain at 1 month and persisting up to 12 months after a PBSC collection procedure. There were no such associations found in URD. Our findings can help clinicians identify donors at higher risk of pain with donation, and lead to personalized information and interventions for specific donors. Lack of correlation between predonation HRQoL and stem cell yield may be due to a small sample size and warrants further evaluation.

SARS-CoV-2 accessory proteins ORF7a and ORF3a use distinct mechanisms to downregulate MHC-I surface expression.

Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small protein ß 2 -microglobulin (ß 2 m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8 + T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that downregulate MHC-I expression to avoid CD8 + T cell recognition. Here we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, downregulate MHC-I expression using distinct mechanisms. One, ORF3a, a viroporin, reduces global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of ß 2 m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a novel and specific mechanism that allows immune evasion by SARS-CoV-2. Significance Statement: Viruses may down-regulate MHC class I expression on infected cells to avoid elimination by cytotoxic T cells. We report that the accessory proteins ORF7a and ORF3a of SARS-CoV-2 mediate this function and delineate the two distinct mechanisms involved. While ORF3a inhibits global protein trafficking to the cell surface, ORF7a acts specifically on MHC-I by competing with ß 2 m for binding to the MHC-I heavy chain. This is the first account of molecular mimicry of ß 2 m as a viral mechanism of MHC-I down-regulation to facilitate immune evasion.

Viperin triggers ribosome collision-dependent translation inhibition to restrict viral replication.

Innate immune responses induce hundreds of interferon-stimulated genes (ISGs). Viperin, a member of the radical S-adenosyl methionine (SAM) superfamily of enzymes, is the product of one such ISG that restricts the replication of a broad spectrum of viruses. Here, we report a previously unknown antiviral mechanism in which viperin activates a ribosome collision-dependent pathway that inhibits both cellular and viral RNA translation. We found that the radical SAM activity of viperin is required for translation inhibition and that this is mediated by viperin's enzymatic product, 3'-deoxy-3',4'-didehydro-CTP (ddhCTP). Viperin triggers ribosome collisions and activates the MAPKKK ZAK pathway that in turn activates the GCN2 arm of the integrated stress response pathway to inhibit translation. The study illustrates the importance of translational repression in the antiviral response and identifies viperin as a translation regulator in innate immunity.

Immune Recovery Following Autologous Hematopoietic Stem Cell Transplantation in HIV-Related Lymphoma Patients on the BMT CTN 0803/AMC 071 Trial.

We report a first in-depth comparison of immune reconstitution in patients with HIV-related lymphoma following autologous hematopoietic cell transplant (AHCT) recipients (n=37, lymphoma, BEAM conditioning), HIV(-) AHCT recipients (n=30, myeloma, melphalan conditioning) at 56, 180, and 365 days post-AHCT, and 71 healthy control subjects. Principal component analysis showed that immune cell composition in HIV(+) and HIV(-) AHCT recipients clustered away from healthy controls and from each other at each time point, but approached healthy controls over time. Unsupervised feature importance score analysis identified activated T cells, cytotoxic memory and effector T cells [higher in HIV(+)], and naïve and memory T helper cells [lower HIV(+)] as a having a significant impact on differences between HIV(+) AHCT recipient and healthy control lymphocyte composition (p<0.0033). HIV(+) AHCT recipients also demonstrated lower median absolute numbers of activated B cells and lower NK cell sub-populations, compared to healthy controls (p<0.0033) and HIV(-) AHCT recipients (p<0.006). HIV(+) patient T cells showed robust IFNγ production in response to HIV and EBV recall antigens. Overall, HIV(+) AHCT recipients, but not HIV(-) AHCT recipients, exhibited reconstitution of pro-inflammatory immune profiling that was consistent with that seen in patients with chronic HIV infection treated with antiretroviral regimens. Our results further support the use of AHCT in HIV(+) individuals with relapsed/refractory lymphoma.

Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia.

PURPOSE: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS: One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS: Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION: Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein.

The ongoing COVID-19 pandemic has caused an unprecedented global health crisis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Subversion of host protein synthesis is a common strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to shut down host protein synthesis and that SARS-CoV-2 nonstructural protein NSP14 exerts this activity. We show that the translation inhibition activity of NSP14 is conserved in human coronaviruses. NSP14 is required for virus replication through contribution of its exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) activities. Mutations in the ExoN or N7-MTase active sites of SARS-CoV-2 NSP14 abolish its translation inhibition activity. In addition, we show that the formation of NSP14-NSP10 complex enhances translation inhibition executed by NSP14. Consequently, the translational shutdown by NSP14 abolishes the type I interferon (IFN-I)-dependent induction of interferon-stimulated genes (ISGs). Together, we find that SARS-CoV-2 shuts down host innate immune responses via a translation inhibitor, providing insights into the pathogenesis of SARS-CoV-2.

SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2.

Despite mounting evidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engagement with immune cells, most express little, if any, of the canonical receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2). Here, using a myeloid cell receptor-focused ectopic expression screen, we identified several C-type lectins (DC-SIGN, L-SIGN, LSECtin, ASGR1, and CLEC10A) and Tweety family member 2 (TTYH2) as glycan-dependent binding partners of the SARS-CoV-2 spike. Except for TTYH2, these molecules primarily interacted with spike via regions outside of the receptor-binding domain. Single-cell RNA sequencing analysis of pulmonary cells from individuals with coronavirus disease 2019 (COVID-19) indicated predominant expression of these molecules on myeloid cells. Although these receptors do not support active replication of SARS-CoV-2, their engagement with the virus induced robust proinflammatory responses in myeloid cells that correlated with COVID-19 severity. We also generated a bispecific anti-spike nanobody that not only blocked ACE2-mediated infection but also the myeloid receptor-mediated proinflammatory responses. Our findings suggest that SARS-CoV-2-myeloid receptor interactions promote immune hyperactivation, which represents potential targets for COVID-19 therapy.

The Effect of Donor Graft Cryopreservation on Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center for International Blood and Marrow Transplant Research Analysis. Implications during the COVID-19 Pandemic.

The COVID-19 pandemic has resulted in the increased use of cryopreserved grafts for allogeneic hematopoietic cell transplantation (HCT). However, information about the effect of cryopreservation on outcomes for patients receiving allogeneic donor grafts is limited. We evaluated outcomes of HCT recipients who received either fresh or cryopreserved allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) grafts reported to the Center for International Blood and Marrow Transplant Research. A total of 7397 patients were included in the analysis. Recipients of cryopreserved graft were divided into 3 cohorts based on graft source: HLA-matched related PBSC donors (n = 1051), matched unrelated PBSC donors (n = 678), and matched related or unrelated BM donors (n = 154). These patients were propensity score matched with 5514 patients who received fresh allografts. The primary endpoint was engraftment. Multivariate analyses showed no significant increased risk of delayed engraftment, relapse, nonrelapse mortality (NRM), or survival with cryopreservation of BM grafts. In contrast, cryopreservation of related donor PBSC grafts was associated with decreased platelet recovery (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.68 to 0.78; P < .001) and an increased risk of grade II-IV (HR, 1.27; 95% CI, 1.09 to 1.48; P = .002) and grade III-IV (HR, 1.48; 95% CI, 1.19 to 1.84; P < .001) acute graft-versus-host disease. Cryopreservation of unrelated PBSC grafts was associated with delayed engraftment of neutrophils (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001) and platelets (HR, 0.61; 95% CI, 0.56 to 0.66; P < .001) as well as an increased risk of NRM (HR, 1.4; 95% CI, 1.18 to 1.66; P < .001) and relapse (HR, 1.32; 95% CI, 1.11 to 1.58; P = .002) and decreased progression-free survival (HR, 1.36; 95% CI, 1.20 to 1.55; P < .001) and overall survival (OS) (HR, 1.38; 95% CI, 1.22 to 1.58; P < .001). Reasons for cryopreservation were not routinely collected; however, in a subset of unrelated donor HCT recipients, the reason was typically a change in patient condition. Products cryopreserved for patient reasons were significantly associated with inferior OS in multivariate analysis (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). We conclude that cryopreservation is associated with slower engraftment of PBSC grafts, which may be associated with inferior transplantation outcomes in some patient populations. However, the small numbers in the cryopreserved BM cohort and the lack of information on the reason for cryopreservation in all patients suggests that these data should be interpreted with caution, particularly in the context of the risks associated with unexpected loss of a graft during the pandemic. Future analyses addressing outcomes when cryopreservation is universally applied are urgently required.

Shorter Interdonation Interval Contributes to Lower Cell Counts in Subsequent Stem Cell Donations.

Approximately 7% of unrelated hematopoietic stem cell donors are asked to donate stem cells a subsequent time to the same or a different recipient. Recent studies have shown that donation-related symptoms for second donations are similar to those for the first donation. Little is known about differences in stem cell mobilization and yields for subsequent peripheral blood stem cell (PBSC) and bone marrow (BM) collections. We hypothesized that CD34+ cell yields and total nucleated cell (TNC) concentrations for subsequent PBSC or BM donations are lower than those at the first donation. We also evaluated the factors influencing stem cell yields in healthy unrelated second-time donors. Data were gathered from the Center for International Blood and Marrow Transplant Research database on 513 PBSC and 43 BM donors who donated a second time between 2006 and 2017 through the National Marrow Donor Program. Among the second-time PBSC donors, we found significantly lower preapheresis peripheral blood CD34+ cell counts (68.6 × 106/L versus 73.9 × 106/L; P = .03), and collection yields (556 × 106 versus 608 × 106; P = .02) at the second donation compared to the first. This decrease at the subsequent donation was associated with a shorter interdonation interval, lower body mass index (BMI), and a lower total G-CSF dose. In most instances, suboptimal mobilizers at their first donation donated suboptimal numbers of stem cells at their subsequent donations. Among repeat BM donors, the TNC concentration was lower at the second donation. The small size of this group precluded additional analysis. Overall, when considering repeat donations, increasing the interdonation intervals and evaluating for BMI changes should be considered to optimize stem cell yields. Some of these parameters may be improved by increasing G-CSF dose in PBSC donors within permissible limits.

Prolonged incubation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a patient on rituximab therapy.

The incubation period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rarely >14 days. We report a patient with hypogammaglobulinemia who developed coronavirus disease 2019 (COVID-19) with a confirmed incubation period of at least 21 days. These findings raise concern for a prolonged presymptomatic transmission phase, necessitating a longer quarantine duration in this patient population.

Timing of allogeneic hematopoietic cell transplantation (alloHCT) for chronic myeloid leukemia (CML) patients.

While TKI are the preferred first-line treatment for chronic phase (CP) CML, alloHCT remains an important consideration. The aim is to estimate residual life expectancy (RLE) for patients initially diagnosed with CP CML based on timing of alloHCT or continuation of TKI in various settings: CP1 CML, CP2 + [after transformation to accelerated phase (AP) or blast phase (BP)], AP, or BP. Non-transplant cohort included single-institution patients initiating TKI and switched TKI due to failure. CIBMTR transplant cohort included CML patients who underwent HLA sibling matched (MRD) or unrelated donor (MUD) alloHCT. AlloHCT appeared to shorten survival in CP1 CML with overall mortality hazard ratio (HR) for alloHCT of 2.4 (95% CI 1.2-4.9; p = .02). In BP CML, there was a trend toward higher survival with alloHCT; HR = 0.7 (0.5-1.1; p = .099). AlloHCT in CP2 + [HR = 2.0 (0.8-4.9), p = .13] and AP [HR = 1.1 (0.6-2.1); p = .80] is less clear and should be determined on a case-by-case basis.

Weighty choices: selecting optimal G-CSF doses for stem cell mobilization to optimize yield.

There are limited data on the effect of donor body mass index (BMI) on peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF), especially in unrelated donors. Obesity has been associated with persistent leukocytosis, elevated circulating progenitor cells, and enhanced stem cell mobilization. Therefore, we hypothesized that adequate collection of CD34+ cells may be achieved with lower doses (per kilogram of body weight) of G-CSF in donors with higher BMI compared with donors with lower BMI. Using the Center for International Blood and Marrow Transplant Research database, we evaluated the impact of donor BMI on G-CSF-mobilized PBSC yield in healthy unrelated donors. We examined 20 884 PBSC donations collected at National Marrow Donor Program centers between 2006 and 2016. We found significantly higher collection yields in obese and severely obese donors compared with normal and overweight donors. An increase in average daily G-CSF dose was associated with an increase in stem cell yield in donors with normal or overweight BMI. In contrast, an increase in average daily G-CSF dose beyond 780 µg per day in obese and 900 µg per day in severely obese donors did not increase cell yield. Pain and toxicities were assessed at baseline, during G-CSF administration, and postcollection. Obesity was associated with higher levels of self-reported donation-related pain and toxicities in the pericollection and early postdonation recovery periods. This study suggests a maximum effective G-CSF dose for PBSC mobilization in obese and severely obese donors, beyond which higher doses of G-CSF add no increased yield.

Dietary Intake and Diet Quality of Hematopoietic Stem Cell Transplantation Survivors.

Hematopoietic stem cell transplantation (HCT) survivors are burdened by a high prevalence and early onset of chronic diseases. Healthy dietary patterns have been associated with lower risks of chronic health conditions in the general population. HCT survivors are susceptible to multiple complications that may result in chronic illness. Unfortunately, no study to date has comprehensively documented the adherence of HCT survivors to the Dietary Guidelines for Americans (DGA), which are designed specifically to provide guidance for making healthy food choices. The primary aim of this study was to evaluate diet quality and nutrient intake adequacy of HCT survivors. A secondary aim was to assess these survivors' willingness to take part in a future dietary intervention. The dietary intake of adults who had undergone autologous or allogeneic HCT for a hematologic disease and were at least 1 year post-transplantation was assessed using the Block 2014 food frequency questionnaire, and diet quality was estimated using the Healthy Eating Index 2015. Nutrient intake adequacies of the group were estimated by the estimated average requirement cutpoint method. Survivors' (n = 90) HEI-2015 scores averaged 61.6 ± 1.1. Adherence to a good-quality diet was reported by only 10% of survivors. Intakes of vitamins A, C, and D, as well as magnesium and calcium, suggested inadequacy. Fiber intake at 8.9 g per 1000 kcal/day fell below the recommended adequate intake. "Change in taste" was associated with lower quality of diet (P = .02). HCT survivors within 2 years post-transplantation were more receptive than survivors beyond 2 years to participating in a dietary intervention (95% versus 65%; P = .0013). Adult HCT survivors reported less-than-optimal adherence to the 2015-2020 DGA and had numerous shortfall nutrient intakes; however, their willingness to participate in a dietary intervention was relatively high. These findings reinforce the need to incorporate nutrition into HCT survivor care.

The Role of Donor Lymphocyte Infusion (DLI) in Post-Hematopoietic Cell Transplant (HCT) Relapse for Chronic Myeloid Leukemia (CML) in the Tyrosine Kinase Inhibitor (TKI) Era.

Treatment for relapse of chronic myeloid leukemia (CML) following hematopoietic cell transplantation (HCT) includes tyrosine kinase inhibitors (TKIs) with or without donor lymphocyte infusions (DLIs), but the most effective treatment strategy is unknown. This study was performed through the Center for International Blood and Marrow Transplant Research (CIBMTR) database. We retrospectively reviewed all patients reported to the CIBMTR registry from 2002 to 2014 who underwent HCT for CML and were alive 30 days postrelapse. A total of 215 HCT recipients relapsed and were analyzed in the following groups: (1) TKI alone (n = 128), (2) TKI with DLI (n = 48), and (3) DLI without TKI (n = 39). In multivariate analysis, disease status prior to HCT had a significant effect on overall survival (OS). Patients who received a DLI alone compared with a TKI with a DLI had inferior survival (hazard ratio, 2.28; 95% confidence interval, 1.23 to 4.24; P= .009). Those who received a TKI alone had similar survival compared with those who received a TKI with a DLI (P = .81). These data support that despite use of TKIs pretransplantation, TKI salvage therapy continues to provide significant survival following relapse in patients with CML following HCT. These data do not suggest that adding a DLI to a TKI adds an improvement in OS.