Hematology and oncology clinical care during the coronavirus disease 2019 pandemic.

New York City has been at the epicenter of the coronavirus disease 2019 (COVID-19) pandemic that has already infected over a million people and resulted in more than 70,000 deaths as of early May 2020 in the United States alone. This rapid and enormous influx of patients into the health care system has had profound effects on all aspects of health care, including the care of patients with cancer. In this report, the authors highlight the transformation they underwent within the Division of Hematology and Medical Oncology as they prepared for the COVID-19 crisis in New York City. Under stressful and uncertain conditions, some of the many changes they enacted within their division included developing a regular line of communication among division leaders to ensure the development and implementation of a restructuring strategy, completely reconfiguring the inpatient and outpatient units, rapidly developing the ability to perform telemedicine video visits, and creating new COVID-rule-out and COVID-positive clinics for their patients. These changes allowed them to manage the storm while minimizing the disruption of important continuity of care to their patients with cancer. The authors hope that their experiences will be helpful to other oncology practices about to experience their own individual COVID-19 crises.

Cardiac Arrest during Cesarean Section - A Case Report and Review of the Differential Diagnosis.

AIM: According to the World Health Organization, approximately 810 pregnant women die every day as a consequence of peripartum complications. A large proportion of deaths happen in developing countries. Peripartum cardiac arrest is a rare event that must be treated immediately. It is important to consider the differential diagnoses in order to save lives. METHODS: In this review, we discuss a differential diagnosis of cardiac arrest according to the BEAU-CHOPS scheme of the American Heart Association in the relation to the case report of our 40-year-old G5/P3 patient who went into cardiac arrest during cesarean delivery. RESULTS: Typical differentials for cardiac arrest during labor are bleeding, embolism, anesthetic complications, cardiovascular diseases, eclampsia, and sepsis. All of them were considered and ruled out in this patient. In the end, we suspect that physiological cardio-inhibitory reflexes triggered by sudden profound hypovolemia after placental separation along with the patient's risk factors, especially obesity and maternal age, and the administration of spinal anesthesia all potentially contributed to the cardiac arrest. CONCLUSIONS: This review highlights that the cardiac arrest during labor can be triggered by the multifactorial etiology, but firstly the typical differential diagnosis needs to be excluded.

Colonization With Fluoroquinolone-Resistant Enterobacterales Decreases the Effectiveness of Fluoroquinolone Prophylaxis in Hematopoietic Cell Transplant Recipients.

BACKGROUND: Levofloxacin prophylaxis is recommended to prevent gram-negative bloodstream infections (BSIs) in patients with prolonged chemotherapy-induced neutropenia. However, increasing fluoroquinolone resistance may decrease the effectiveness of this approach. METHODS: We assessed the prevalence of colonization with fluoroquinolone-resistant Enterobacterales (FQRE) among patients admitted for hematopoietic cell transplantation (HCT) from November 2016 to August 2019 and compared the risk of gram-negative BSI between FQRE-colonized and noncolonized patients. All patients received levofloxacin prophylaxis during neutropenia. Stool samples were collected upon admission for HCT and weekly thereafter until recovery from neutropenia, and underwent selective culture for FQRE. All isolates were identified and underwent antimicrobial susceptibility testing by broth microdilution. FQRE isolates also underwent whole-genome sequencing. RESULTS: Fifty-four of 234 (23%) patients were colonized with FQRE prior to HCT, including 30 of 119 (25%) allogeneic and 24 of 115 (21%) autologous HCT recipients. Recent antibacterial use was associated with FQRE colonization (P = .048). Ninety-one percent of colonizing FQRE isolates were Escherichia coli and 29% produced extended-spectrum ß-lactamases. Seventeen (31%) FQRE-colonized patients developed gram-negative BSI despite levofloxacin prophylaxis, compared to only 2 of 180 (1.1%) patients who were not colonized with FQRE on admission (P < .001). Of the 17 gram-negative BSIs in FQRE-colonized patients, 15 (88%) were caused by FQRE isolates that were genetically identical to the colonizing strain. CONCLUSIONS: Nearly one-third of HCT recipients with pretransplant FQRE colonization developed gram-negative BSI while receiving levofloxacin prophylaxis, and infections were typically caused by their colonizing strains. In contrast, levofloxacin prophylaxis was highly effective in patients not initially colonized with FQRE.

Outcomes of Allogeneic Stem Cell Transplant for Elderly Patients with Hematologic Malignancies.

Reduced-intensity conditioning (RIC) regimens, improved HLA matching, and better supportive care allow allogeneic stem cell transplant (alloSCT) to be offered to older patients. Only a small percentage of eligible patients between ages 65 and 74 years actually undergo alloSCT, and comprehensive outcome data from the aging population are still lacking. We examined the outcome of older patients who underwent alloSCT using melphalan-based RIC for hematologic malignancies at our institution. We identified 125 patients older than 65 years (median, 69; range, 66 to 77) who underwent matched related donor, matched unrelated donor, or combined haploidentical/umbilical cord alloSCT between 2012 through November, 2017. Among them, 52 (41.6%) and 70 (56%) had, respectively, intermediate and high/very high Center for International Blood and Marrow Transplant Research (CIBMTR) disease risk index (DRI). One hundred six patients (85%) received fludarabine/melphalan-based RIC regimen with either antithymocyte globulin (ATG) or alemtuzumab. The median time to neutrophil engraftment was 13 days (range, 8 to 37) and platelet engraftment 17 days (range, 9 to 169). The cumulative incidence of nonrelapse mortality was 11.5% at 100 days and 30.1% and 34.8% at 1 and 2 years, respectively. The cumulative incidence of relapse was 35% and 40% at 1 and 2 years. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) at day 100 and 6 months was 29.5% and 34.5%, and chronic GVHD at 6, 12, and 24 months was 2.5%, 5.2%, and 6.3%, respectively. With a median follow-up of 32 months, the 1-, 2-, and 3-year progression-free survival (PFS) was 34.6%, 24.4%, and 16.5%, respectively. The graft GVHD-free survival was 24.6%, 16.1%, and 9.3%, respectively. The 1-, 2-, and 3-year overall survival (OS) was 44.5%, 30.7%, and 26.5%, respectively. In multivariable analysis, low albumin was predictive of poor PFS and OS and high hematopoietic cell transplantation-specific comorbidity index, and CIBMTR DRI was predictive of worse graft GVHD-free survival. Among long-term survivors the median Karnofsky performance status was 80. Older patients, even when referred with advanced disease, can benefit from melphalan-based alloSCT with HLA-matched or alternative donor sources without discernible impact of donor source on outcome. Using alemtuzumab- or ATG-based in vivo T cell depletion, the incidence of chronic GVHD is extremely low. Performance status in survivors is excellent. Better predictors for outcome in this patient population need to be identified.

Bortezomib and Immune Globulin Have Limited Effects on Donor-Specific HLA Antibodies in Haploidentical Cord Blood Stem Cell Transplantation: Detrimental Effect of Persistent Haploidentical Donor-Specific HLA Antibodies.

Donor-specific HLA antibodies (DSAs) have been associated with an increased risk of graft failure. To decrease DSA levels and reduce the risk of graft failure in haploidentical cord blood transplantation recipients, we studied the effect of bortezomib (BTZ) and i.v. immune globulin (IVIG) pretransplantation. Between 2012 and 2016, 14 patients with a DSA level >2000 mean fluorescence intensity (MFI) to 1 or more mismatched HLA alleles of haploidentical donors, cord blood donors, or both were treated with BTZ and IVIG. Fourteen patients received a median of 4 doses (range, 2 to 8 doses) of BTZ 1.3 mg/m2 and a median total IVIG of 2 g/kg before transplantation. Only 2 of 14 patients attained a reduction in MFI to <2000 with this combination. After additional IVIG (n = 8), rituximab (n = 4), and/or plasmapheresis (n = 11), 12 of 14 patients were desensitized to a DSA level <2000 MFI at the time of engraftment. All obtained initial hematopoietic reconstitution, and no DSA rebound phenomenon was observed. Responders with DSA MFI <2000 to the haploidentical donor by transplantation engrafted at a rate comparable to that of historical controls, whereas engraftment in nonresponders took 3 times as long. BTZ and IVIG alone do not appear sufficient to rapidly induce DSA desensitization, and persistent DSAs to a haploidentical donor lead to delayed count recovery. Our data suggest that additional pretreatment with BTZ and IVIG in combination with the conditioning regimen may help abrogate the rebound phenomenon observed with plasmapheresis.

Adoptive Immunotherapy with Cord Blood for the Treatment of Refractory Acute Myelogenous Leukemia: Feasibility, Safety, and Preliminary Outcomes.

Adoptive immunotherapy has shown efficacy in patients with relapsed/refractory acute myelogenous leukemia (AML). We conducted a prospective evaluation of cord blood (CB)-based adoptive cell therapy following salvage chemotherapy in patients with AML or myelodysplastic syndrome (MDS) and describe the safety and early outcomes of this approach. To enhance the antileukemic effect, we selected CB units (CBUs) with a shared inherited paternal antigen (IPA) and/or noninherited maternal antigen (NIMA) match with the recipients. Furthermore, the CBUs had total nucleated cell (TNC) dose <2.5 × 107/kg and were at least 4/6 HLA-matched with the patients; a higher allele-level match was preferred. Heavily pretreated adult patients with AML/MDS were enrolled. CBU searches were performed for 50 patients. CBUs with shared IPA targets were identified for all, and CBUs with NIMA matches were found for 80%. Twenty-one patients underwent treatment (AML, primary induction failure, n = 8; refractory relapse, n = 10, including 7 recipients of previous allogeneic HSCT; blast crisis chronic myelogenous leukemia, n = 1; MDS, n = 2). Most received combination chemotherapy; those not fit for intensive treatment received a hypomethylating agent. Response was defined as <10% residual blasts in hypocellular bone marrow at approximately 2 weeks after treatment. Ten of the 19 evaluable patients responded, including 5 of the 7 recipients of previous transplant. Response was seen in 4 of 4 patients with full CBU-derived chimerism, 2 of 2 of those with partial, low-level chimerism and 4 of 12 of the recipients with no detectable CBU chimerism. The most common adverse events were infections (bacterial, n = 5; viral, n = 2; fungal, n = 5). Grade IV acute graft-versus-host disease (GVHD) developed in 2 patients with full CBU chimerism; 2 other patients had grade 1 skin GVHD. A total of 11 patients died, 7 from disease recurrence and 4 from infections (1 early death; the other 3 in remission at the time of death). Overall, 12 patients proceeded to allogeneic HSCT; of those, 7 had responded to treatment, 3 had not (and had received additional therapy), and 2 had persistent minimal residual disease. In conclusion, the use of CB as adoptive immunotherapy in combination with salvage chemotherapy for patients with refractory AML/MDS is feasible, can induce disease control, can serve as a bridge to allogeneic HSCT, and has an acceptable incidence of adverse events. Alloreactivity was enhanced through the selection of CBUs targeting a shared IPA and/or NIMA match with the patients. CBUs with lower cell doses, already available in the CB bank and unlikely to be adequate grafts for adult transplants, can be used for cell therapy within a short time frame.

Sexual activity and quality of life in patients after treatment for breast and ovarian cancer.

OBJECTIVE: Sexual activity (SA) and functioning (SF) are important factors influencing quality of life (QoL). Anticancer treatment can cause or promote sexual dysfunctions. In this study we analyzed the SA, SF and QoL in patients after completion of treatment for breast cancer (BC) and ovarian cancer (OC). METHODS: In this retrospective multicenter study 396 BC patients and 93 OC patients aged between 18 and 70 years were surveyed at least 24 months after cancer diagnosis and compared to 60 healthy women. Data were collected through validated questionnaires (Sexual Activity Questionnaire, Female Sexual Function Index-d, EORTC Quality of Life Questionnaire-C30). RESULTS: 45.9% of BC patients and 56.5% of OC patients reported SA. SF and well-being of sexually active BC patients were not influenced by the type and radicality of surgery or the administration of chemotherapy. Patients who received antihormonal therapy at the time of evaluation showed a lower frequency of SA (p = 0.007), less satisfaction (p = 0.003) and more discomfort during SA (p = < 0.001) compared to healthy controls but no differences in experiencing orgasms, health status, QoL and global health status. In contrast, BC patients without antihormonal therapy showed only a higher discomfort score (p = 0.028) than healthy controls and estimated their health status and QoL significantly better than patients who received antihormonal therapy (p = 0006). In general, SA was associated with a better health status (p = 0.007), a better QoL (p = 0.004) and a better global health status (p = 0.004) in BC patients. Sexually active OC patients showed no significant differences in SF, QoL and health status compared to healthy controls. CONCLUSIONS: Compared to healthy controls BC patients showed limitations in SF with a lower SA rate and more discomfort. Antihormonal therapy was an important factor influencing SF and well-being. Breast and OC survivors reported good physical and psychical health without differences in QoL and health status compared to controls. This might be explained by a change of perspective on life difficulties and altered priorities through a life threatening disease.

Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia.

Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results.

Granulocyte Colony-Stimulating Factor Use after Autologous Peripheral Blood Stem Cell Transplantation: Comparison of Two Practices.

Administration of granulocyte colony-stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (PBSCT) is generally recommended to reduce the duration of severe neutropenia; however, data regarding the optimal timing of G-CSFs post-transplantation are limited and conflicting. This retrospective study was performed at NewYork-Presbyterian/Weill Cornell Medical Center between November 5, 2013, and August 9, 2016, of adult inpatient autologous PBSCT recipients who received G-CSF empirically starting on day +5 (early) versus on those who received G-CSF on day +12 only if absolute neutrophil count (ANC) was <0.5 × 109/L (ANC-driven). G-CSF was dosed at 300 µg in patients weighing <75 kg and 480 µg in those weighing ≥75 kg. One hundred consecutive patients underwent autologous PBSCT using either the early (n = 50) or ANC-driven (n = 50) G-CSF regimen. Patient and transplantation characteristics were comparable in the 2 groups. In the ANC-driven group, 24% (n = 12) received G-CSF on day +12 and 60% (n = 30) started G-CSF earlier due to febrile neutropenia or at the physician's discretion, 6% (n = 3) started after day +12 at the physician's discretion, and 10% (n = 5) did not receive any G-CSF. The median start day of G-CSF therapy was day +10 in the ANC-driven group versus day +5 in the early group (P < .0001). For the primary outcome, the median time to neutrophil engraftment was 12 days (interquartile range [IQR] 11-13 days) in the early group versus 13 days (IQR, 12-14 days) in the ANC-driven group (P = .07). There were no significant between-group differences in time to platelet engraftment, 1-year relapse rate, or 1-year overall survival. The incidence of febrile neutropenia was 74% in the early group versus 90% in the ANC-driven group (P = .04); however, there was no significant between-group difference in the incidence of positive bacterial cultures or transfer to the intensive care unit. The duration of G-CSF administration until neutrophil engraftment was 6 days in the early group versus 3 days in the ANC-driven group (P < .0001). The median duration of post-transplantation hospitalization was 15 days (IQR, 14-19 days) in the early group versus 16 days (IQR, 15-22 days) in the ANC-driven group (P = .28). Our data show that early initiation of G-CSF (on day +5) and ANC-driven initiation of G-CSF following autologous PBSCT were associated with a similar time to neutrophil engraftment, length of stay post-transplantation, and 1-year overall survival.

Reduced-Intensity Allogeneic Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome Using Combined CD34-Selected Haploidentical Graft and a Single Umbilical Cord Unit Compared with Matched Unrelated Donor Stem Cells in Older Adults.

Haplo/cord transplantation combines an umbilical cord blood (UCB) graft with CD34-selected haploidentical cells and results in rapid hematopoietic recovery followed by durable UCB engraftment. We compared outcomes of transplants in older patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) who received either HLA-matched unrelated donor (MUD) cells or haplo/cord grafts. Between 2007 and 2013, 109 adults ages 50 and older underwent similar reduced-intensity conditioning with fludarabine and melphalan and antibody-mediated T cell depletion for AML (n = 83) or high-risk MDS (n = 26) followed by either a MUD (n = 68) or haplo/cord (n = 41) graft. Patient characteristics were similar for each graft source except for more minority patients receiving a haplo/cord transplant (P = .01). One half of the AML patients were not in remission. Two-year progression-free survival (PFS), overall survival (OS), and graft-versus-host disease-free relapse-free survival were 38%, 48%, and 32.1% for MUD and 33%, 48%, and 33.8% for haplo/cord transplants (P = .62 for PFS; P = .97 for OS; P= .84), respectively. Acute grades II to IV and chronic graft-versus-host-disease rates did not differ at 19.5% and 4.9% in haplo/cord compared with 25% and 7.4% after MUD (P = .53 and P = .62, respectively). Multivariate analysis confirmed no significant differences in transplant outcomes by donor type. Haplo/cord reduced-intensity transplantation achieves similar outcomes relative to MUD in older AML and MDS patients, making this a promising option for those without matched donors.

Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors.

Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.

A Phase I Trial of High-Dose Lenalidomide and Melphalan as Conditioning for Autologous Stem Cell Transplantation in Relapsed or Refractory Multiple Myeloma.

Autologous stem cell transplantation (ASCT) conditioned with high-dose chemotherapy has long been established as the standard of care for eligible patients with newly diagnosed multiple myeloma. Despite recent therapeutic advances, high-dose melphalan (HDM) remains the chemotherapy regimen of choice in this setting. Lenalidomide (LEN) in combination with low-dose dexamethasone is recognized as a standard of care for patients with relapsed or refractory multiple myeloma (RRMM), and there is growing support for the administration of LEN as maintenance therapy post-ASCT. In view of the above, the present phase I clinical trial was designed to evaluate the safety and tolerability of high-dose LEN (HDLEN) in patients with RRMM, and to determine the maximum tolerated dose of HDLEN when added to HDM before ASCT. Despite administering HDLEN at doses of up to 350 mg/day, the maximum tolerated dose could not be determined, owing to an insufficient number of dose-limiting toxicities in the 21 patients enrolled in the trial. Conditioning with HDLEN plus HDM was associated with a favorable tolerability profile. Adverse events following ASCT were as expected with HDM. Median progression-free and overall survival were 10 months and 22 months, respectively, in this population of heavily pretreated patients. Our findings suggest that HDLEN in combination with HDM may offer significant potential as a conditioning regimen before ASCT in patients with RRMM. These preliminary findings are now being evaluated further in an ongoing phase II clinical trial.

Comparison of Subcutaneous versus Intravenous Alemtuzumab for Graft-versus-Host Disease Prophylaxis with Fludarabine/Melphalan-Based Conditioning in Matched Unrelated Donor Allogeneic Stem Cell Transplantation.

The objective of this study was to compare infusion-related reactions and outcomes of using subcutaneous (subQ) alemtuzumab versus intravenous (i.v.) alemtuzumab as graft-versus-host disease (GVHD) prophylaxis for matched unrelated donor stem cell transplantations. Outcomes include incidence of cytomegalovirus (CMV)/Epstein-Barr (EBV) viremia, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, time to engraftment, relapse rate, and survival. We conducted a retrospective study of all adult matched unrelated donor stem cell transplantations patients who received fludarabine/melphalan with subQ or i.v. alemtuzumab in combination with tacrolimus as part of their conditioning for unrelated donor transplantation at New York-Presbyterian/Weill Cornell Medical Center from January 1, 2012 to March 21, 2014. Alemtuzumab was administered at a total cumulative dose of 100 mg (divided over days -7 to -3). Forty-six patients received an unrelated donor stem cell transplantation with fludarabine/melphalan and either subQ (n = 26) or i.v. (n = 20) alemtuzumab in combination with tacrolimus. Within the evaluable population, 130 subQ and 100 i.v. alemtuzumab doses were administered. For the primary outcome, ≥grade 2 infusion-related reactions occurred in 11 (8%) versus 25 (25%) infusions in the subQ and i.v. cohorts, respectively (P = .001). Overall, 12 injections (9%) in the subQ arm versus 26 infusions (26%) in the i.v. arm experienced an infusion-related reaction of any grade (P = .001). There were no significant differences between the subQ and i.v. arms in rates of reactivation of CMV/EBV, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, acute and chronic GVHD, relapse, or survival. Subcutaneous administration of alemtuzumab for GVHD prophylaxis was associated with fewer infusion-related reactions compared with i.v. administration in the SCT setting. Incidences of acute and chronic GVHD were similar between both arms. There was also no difference in reactivation of CMV/EBV viremia, development of CMV disease or post-transplantation lymphoproliferative disorder, fatal infections, relapse, or survival.

Frequency and Risk Factors Associated with Cord Graft Failure after Transplant with Single-Unit Umbilical Cord Cells Supplemented by Haploidentical Cells with Reduced-Intensity Conditioning.

Delayed engraftment and cord graft failure (CGF) are serious complications after unrelated cord blood (UCB) hematopoietic stem cell transplantation (HSCT), particularly when using low-cell-dose UCB units. The haplo-cord HSCT approach allows the use of a lower dose single UCB unit by co-infusion of a CD34(+) selected haploidentical graft, which provides early transient engraftment while awaiting durable UCB engraftment. We describe the frequency, complications, and risk factors of CGF after reduced-intensity conditioning haplo-cord HSCT. Among 107 patients who underwent haplo-cord HSCT, 94 were assessable for CGF, defined as <5% cord blood chimerism at day 60 in the myeloid and CD3 compartments, irrespective of neutrophil and platelet counts. CGF occurred in 14 of 94 assessable patients (15%). Median survival after CGF was 12.7 months with haploidentical or mixed haploidentical-autologous hematopoiesis persisting in the 7 surviving. Median progression-free survival after CGF was 7.7 months and was not statistically different from those without CGF (10.47 months; P = .18). In univariate analyses, no UCB factors were associated with CGF, including cell dose, cell viability, recipient major ABO mismatch against the UCB unit, or degree of HLA match. We also found no association of CGF with recipient cytomegalovirus serostatus, haploidentical donor age, or day 30 haploidentical chimerism. However, higher haploidentical total nucleated and CD34(+) cell doses and day 30 UCB chimerism < 5% in either the myeloid or CD3 compartments were associated with greater risk of CGF. We conclude that assessing chimerism at day 30 may foretell impending CGF, and avoidance of high haploidentical cell doses may reduce risk of CGF after haplo-cord HSCT. However, long-term survival is possible after CGF because of predominant haploidentical or mixed chimerism and hematopoietic function.

Late Acute and Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.

Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the National Institutes of Health Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate 4 GVHD syndromes: late acute GVHD (aGVHD), chronic GVHD (cGVHD), bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. The majority of patients received a peripheral blood stem cell transplant (81%) following nonmyeloablative or reduced-intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood grafts were underrepresented in our cohort (≤11%). The cumulative incidence of late aGVHD (late onset and recurrent) was 10% at a median of 5.5 months post-HCT, that of cGVHD was 47% at a median of 7.4 months, that of bronchiolitis obliterans was 3% at a median of 12.2 months, and that of cutaneous sclerosis was 8% at a median onset of 14.0 months. Late aGVHD and bronchiolitis obliterans had particularly high nonrelapse mortality of 23% and 32%, respectively, by 2 years after diagnosis. The probability of late aGVHD- and cGVHD-free, relapse-free survival was 38% at 1 year post-HCT and 26% at 2 years post-HCT. This multicenter prospective study confirms the high rate of late aGVHD and cGVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success.

Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation.

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n = 27). Patient-reported outcomes at 3 months were statistically significantly improved for Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n = 24). At 6 months, 36% had treatment failure (95% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.

Reduced intensity haplo plus single cord transplant compared to double cord transplant: improved engraftment and graft-versus-host disease-free, relapse-free survival.

Umbilical cord blood stem cell transplants are commonly used in adults lacking HLA-identical donors. Delays in hematopoietic recovery contribute to mortality and morbidity. To hasten recovery, we used co-infusion of progenitor cells from a partially matched related donor and from an umbilical cord blood graft (haplo-cord transplant). Here we compared the outcomes of haplo-cord and double-cord transplants. A total of 97 adults underwent reduced intensity conditioning followed by haplo-cord transplant and 193 patients received reduced intensity conditioning followed by double umbilical cord blood transplantation. Patients in the haplo-cord group were more often from minority groups and had more advanced malignancy. Haplo-cord recipients received fludarabine-melphalan-anti-thymocyte globulin. Double umbilical cord blood recipients received fludarabine-cyclophosphamide and low-dose total body irradiation. In a multivariate analysis, haplo-cord had faster neutrophil (HR=1.42, P=0.007) and platelet (HR=2.54, P<0.0001) recovery, lower risk of grade II-IV acute graft-versus-host disease (HR=0.26, P<0.0001) and chronic graft-versus-host disease (HR=0.06, P<0.0001). Haplo-cord was associated with decreased risk of relapse (HR 0.48, P=0.001). Graft-versus-host disease-free, relapse-free survival was superior with haplo-cord (HR 0.63, P=0.002) but not overall survival (HR=0.97, P=0.85). Haplo-cord transplantation using fludarabine-melphalan-thymoglobulin conditioning hastens hematopoietic recovery with a lower risk of relapse relative to double umbilical cord blood transplantation using the commonly used fludarabine-cyclophosphamide-low-dose total body irradiation conditioning. Graft-versus-host disease-free and relapse-free survival is significantly improved. Haplo-cord is a readily available graft source that improves outcomes and access to transplant for those lacking HLA-matched donors. Trials registered at clinicaltrials.gov identifiers 00943800 and 01810588.

Hyperthermia-driven aberrations of secreted microRNAs in breast cancer in vitro.

PURPOSE: Expression profile alterations of nine breast cancer (BC)-associated secreted microRNAs (miRs) were determined under microenvironmental alterations occurring in tumour progression, metastasis or specific oncological treatment modalities. Thereto, the potential influence of the exogenic stimuli hypoxia, acidosis and hyperthermia was investigated in vitro. MATERIAL AND METHODS: Four established BC cell lines were applied as in vitro BC model systems. Quantitative analyses of secreted microRNA specimens were performed by RNA isolation from cell culture supernatant and subsequent real-time PCR in cells under physiological versus hypoxic, acidic or hyperthermia conditions. RESULTS: The in vitro application of exogenic stimuli hypoxia, extracellular acidosis and hyperthermia caused heterogeneous expression alterations for the investigated secreted miRNA phenotypes. The majority of relevant exogenic stimuli-dependent microRNA expression alterations were restricted to single events displaying distinct cell type and stimulus dependent correlations only. Most remarkably, hyperthermia triggered a uniform significant down-regulatory effect on the expression levels of the three secreted microRNAs miR-10b, miR-15b and miR-139, respectively. The marked decrease in miR-10b and miR-15b levels was detectable in all four, while miR-139 was found significantly reduced in three out of four BC cell lines. CONCLUSION: Hyperthermia-dependent down-regulatory influence on three distinct BC-related microRNAs in vitro generates translational aspects for clinical BC treatment, since the identified microRNAs miR-10b, miR-15b and miR-139 are known to have oncogenic as well as tumour suppressor functions in BC. However, an evaluation regarding the potential impact of microRNA-related hyperthermia-dependent alterations for innovative BC treatment approaches demands further analysis including in vivo data.

Feasibility of urinary microRNA detection in breast cancer patients and its potential as an innovative non-invasive biomarker.

BACKGROUND: Since recent studies revealed the feasibility to detect blood-based microRNAs (miRNAs, miRs) in breast cancer (BC) patients a new field has been opened for circulating miRNAs as potential biomarkers in BC. In this pilot study, we evaluated to our knowledge for the first time whether distinct pattern of urinary miRNAs might be also applicable as innovative biomarkers for BC detection. METHODS: Urinary miRNA expression levels of nine BC-related miRNAs (miR-21, miR-34a, miR-125b, miR-155, miR-195, miR-200b, miR-200c, miR-375, miR-451) from 24 untreated, primary BC patients and 24 healthy controls were quantified by realtime-PCR. The receiver operating characteristic analyses (ROC) and logistic regression were calculated to assess discriminatory accuracy. RESULTS: Significant differences were found in the expression of four BC-associated miRNAs quantified as median miRNA expression levels. Urinary miR-155 levels were significantly higher in BC patients compared to healthy controls (1.49vs.0.25; p < 0.001). In contrast, compared to healthy controls, BC patients exhibited significantly lower urinary expression levels of miR-21 (2.27vs.5.07; p < 0.001), miR-125b (0.71vs.1.62; p < 0.001), and miR-451 (0.02vs.0.59 p = 0.004), respectively. The ROC including all miRNAs as well as the group of the four significant deregulated miRNAs separated BC patients from healthy controls with a very high (area under the receiver operating characteristic curve [AUC] = 0.932) and high accuracy (AUC = 0.887), respectively. CONCLUSIONS: We were able to demonstrate for the first time the feasibility to detect distinct BC-dependent urinary miRNA profiles. The expression levels of four urinary miRNAs were specifically altered in our cohort of BC patients compared to healthy controls. This distinct pattern offers the possibility for a specific discrimination between healthy women and primary BC patients. This sustains the potential role of urinary miRNAs as non-invasive innovative urine-based biomarkers for BC detection.