Search

Invariant natural killer T (iNKT) cells, a unique T cell population, lend themselves for use as adoptive therapy due to diverse roles in orchestrating immune responses. Originally developed for use in cancer, agenT-797 is a donor-unrestricted allogeneic ex vivo expanded iNKT cell therapy. We conducted an open-label study in virally induced acute respiratory distress syndrome (ARDS) caused by the severe acute respiratory syndrome-2 virus (trial registration NCT04582201). Here we show that agenT-797 rescues exhausted T cells and rapidly activates both innate and adaptive immunity. In 21 ventilated patients including 5 individuals receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO), there are no dose-limiting toxicities. We observe an anti-inflammatory systemic cytokine response and infused iNKT cells are persistent during follow-up, inducing only transient donor-specific antibodies. Clinical signals of associated survival and prevention of secondary infections are evident. Cellular therapy using off-the-shelf iNKT cells is safe, can be rapidly scaled and is associated with an anti-inflammatory response. The safety and therapeutic potential of iNKT cells across diseases including infections and cancer, warrants randomized-controlled trials., (© 2024. The Author(s).)

Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors., Significance: XPO1 regulates the dynamic ribonucleoprotein nuclear export in response to genotoxic stress to support tolerance and can be targeted to enhance the sensitivity of cancer cells to endogenous and exogenous DNA damage. See related commentary by Knittel and Reinhardt, p. 3., (©2023 The Authors; Published by the American Association for Cancer Research.)

Aims: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality., Methods and Results: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden., Conclusion: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin., Competing Interests: Conflict of interest S.S.M. has received consulting fees from Nektar Therapeutics, Health & Wellness Partners, Medicure. P.A.R. has received consulting fees from AbbVie, BMS, Janssen, Novartis, BeiGene, Kite/Gilead, Intellia Therapeutics, Sana Biotechnology, CVS Caremark, Genmab, Pharmacyclics, Takeda, Karyopharm, Nektar Therapeutics, Nurix Therapeutics, and ADC Therapeutics. M.A.P. reports consulting fees from Adicet, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma, is participating in DSMB of Cidara Therapeutics, Medigene, and Sellas Life Sciences, and is on the scientific advisory board of NexImmune and Omeros. M.B.G. has received institutional grant funding from Sanofi, Amgen, and Actinium and consulting fees from Sanofi, Novartis, and Allogene. M.L.P. has received royalties from Juno and Sers and consulting fees from Novartis, Cellectar, Synthekine, Kite, Seres, Magenta, WindMIL, Rheos, Nektar, Notch, Priothera, Ceramedix, Lygenesis, and Pluto. R.S. has received consulting fees from Mudexus and MyBiotics. G.S. has received research funding from Janssen, Amgen, Beyond Spring, and BMS and is on DSMB of ArcellX. E.H.Y. has received institutional grand funding from CSL Behring, Boehringer Ingelheim, BMS and Eli and Lilly and consulting fees from Pfizer. J.P.L. has received institutional grants from Genentech, Janssen, and Epizyme and consulting fees from Abbvie, Astellas, AstraZeneca, Bayer, Beigene, BMS, Calithera, Constellation, Caribou Biosciences, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Jansssen, MEI Pharma, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro, ADC Therapeutics, Miltenyi, and Karyopharm. T.G.N. has received consulting fees from BMS, Genentech, Abbvie, Roche, CRO Oncology, and Sanofi and participates in DSMB of Genentech and received research grant funding from AstraZeneca and BMS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Autologous T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19 are approved for the treatment of various CD19 + hematological malignancies. While CAR T cells induce objective responses in a majority of patients, relapse frequently occurs upon loss of CD19 expression by neoplastic cells. Radiation therapy (RT) has been successfully employed to circumvent the loss of CAR targets in preclinical models of pancreatic cancer. At least in part, this reflects the ability of RT to elicit death receptor (DR) expression by malignant cells, enabling at least some degree of CAR-independent tumor killing. In a human model of CD19 + acute lymphoblastic leukemia (ALL), we also observed DR upregulation by RT, both in vitro and in vivo. Moreover, low-dose total body irradiation (LD-TBI) delivered to ALL-bearing mice prior to CAR T cell infusion considerably extended the overall survival benefit afforded by CAR T cells alone. Such an improved therapeutic activity was accompanied by a superior expansion of CAR T cells in vivo. These data encourage the initiation of clinical trials combining LD-TBI with CAR T cells in patients with hematological malignancies., (© 2023. The Author(s).)

Peripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6. The primary end point was end-of-treatment complete response (CR). Secondary end points included safety and survival. Correlative studies assessed mutations, gene expression, and methylation in tumor samples. Grade 3 to 4 hematologic toxicities were mostly neutropenia (71%), with febrile neutropenia uncommon (14%). Nonhematologic toxicities included fatigue (14%) and gastrointestinal symptoms (5%). In 20 evaluable patients, CR was 75%, including 88.2% for PTCL-TFH (n = 17). The 2-year progression-free survival (PFS) was 65.8% for all and 69.2% for PTCL-TFH, whereas 2-year overall survival (OS) was 68.4% for all and 76.1% for PTCL-TFH. The frequencies of the TET2, RHOA, DNMT3A, and IDH2 mutations were 76.5%, 41.1%, 23.5%, and 23.5%, respectively, with TET2 mutations significantly associated with CR (P = .007), favorable PFS (P = .004) and OS (P = .015), and DNMT3A mutations associated with adverse PFS (P = .016). CC-486 priming contributed to the reprograming of the tumor microenvironment by upregulation of genes related to apoptosis (P < .01) and inflammation (P < .01). DNA methylation did not show significant shift. This safe and active regimen is being further evaluated in the ALLIANCE randomized study A051902 in CD30-negative PTCL. This trial was registered at www.clinicaltrials.gov as #NCT03542266., (© 2023 by The American Society of Hematology.)

Pulmonary complications constitute a major cause of morbidity and mortality in the post-allogenic hematopoietic stem cell transplantation (alloHSCT) period. Although chest X-ray (CXR) is customarily used for screening, we have used chest computed tomography (CT) scans. To characterize the prevalence of abnormalities and explore their impact on alloHSCT eligibility and outcomes post-transplantation, we conducted a retrospective analysis using real-world data collected at our center for adult patients who were evaluated for alloHSCT between January 2013 and December 2020 and identified 511 eligible patients. The most common primary disease was acute myeloid leukemia, in 49% of patients, followed by myelodysplastic syndrome (23%), lymphoma (11%), and acute lymphocytic leukemia (10%). Abnormal screening chest CT results were found in 199 patients (39%). The most frequent detected abnormality was pulmonary nodule, in 78 patients (35%), followed by consolidation in 42 (19%), ground-glass opacification in 33 (15%), bronchitis and bronchiolitis in 25 (11%), pleural effusions in 14 (6%), and new primary cancer in 7 (2%). CXR detected abnormalities in only approximately one-half of the patients (48%) with an abnormal chest CT scan. Among the 199 patients with an abnormal chest CT scan, 98 (49%) underwent further assessment and/or intervention before transplantation. The most common workup was pulmonary consultation in 32%, followed by infectious diseases consultation in 24%. Lung biopsy was obtained in 20%, and antimicrobial therapy was initiated after confirming an infection diagnosis in 20%. Patients with an abnormal chest CT scan demonstrated worse overall survival (P = .032), nonrelapse mortality (P = .015), and pulmonary-related mortality (P < .001) compared to those with a normal chest CT scan. Our study suggests that pretransplantation screening chest CT is beneficial in uncovering invasive infections and underlying malignancies and allows for appropriate interventions before alloHSCT to prevent potentially serious post-transplantation complications without causing a delay in alloHSCT. Nevertheless, abnormal CT findings prior to transplantation may be associated with overall worse prognosis., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Covid-19 vaccination is recommended in allogeneic transplant recipients, but many questions remain regarding its efficacy. Here we studied serologic responses in 145 patients who had undergone allogeneic transplantation using in vivo T-cell depletion. Median age was 57 (range 21-79) at transplantation and 61 (range 24-80) at vaccination. Sixty-nine percent were Caucasian. One third each received transplants from HLA-identical related (MRD), adult unrelated (MUD), or haploidentical-cord blood donors. Graft-versus-host disease (GVHD) prophylaxis involved in-vivo T-cell depletion using alemtuzumab for MRD or MUD transplants and anti-thymocyte globulin for haplo-cord transplants. Patients were vaccinated between January 2021 and January 2022, an average of 31 months (range 3-111 months) after transplantation. Sixty-one percent received the BNT162b2 (bioNtech/Pfizer) vaccine, 34% received mRNA-1273 (Moderna), and 5% received JNJ-78436735 (Johnson & Johnson). After the initial vaccinations (2 doses for BNT162b2 and mRNA-1273, 1 dose for JNJ-7843673), 124 of the 145 (85%) patients had a detectable SARS-CoV-2 spike protein (S) antibody, and 21 (15%) did not respond. Ninety-nine (68%) had high-level responses (≥100 binding antibody units [BAU]/mL)m and 25 (17%) had a low-level response (<100 BAU/mL). In multivariable analysis, lymphocyte count less than 1 × 10 9 / mL, having chronic GVHD, and being vaccinated in the first year after transplantation emerged as independent predictors for poor response. Neither donor source nor prior exposure to rituximab was predictive of antibody response. SARS-CoV-2 vaccination induced generally high response rates in recipients of allogeneic transplants including recipients of umbilical cord blood transplants and after in-vivo T cell depletion. Responses are less robust in those vaccinated in the first year after transplantation, those with low lymphocyte counts, and those with chronic GVHD., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The incidence of adenovirus viremia and the role of screening in preventing adenovirus disease in adult transplant recipients are not well defined. Between January 2017 and May 2020, 262 allogeneic transplants were performed using in vivo T-cell depletion. Adenovirus viremia was found in 59 patients for a cumulative incidence of 10% by one hundred days and 23% (95% CI 20-26%) by one year. There was a higher incidence of viremia associated with cord blood transplant ( p  = .04). No other patient, donor or transplant characteristics were identified that predicted for viremia. In 47 patients (80%), viremia remained well below 200,000 copies/mL and resolved. Twelve patients developed high level viremia. Treatment with antivirals and in some cases adoptive cell therapy, was often ineffective and only two survived. Low lymphocyte count at initial detection of adenovirus viremia was the best predictor of uncontrolled disease.

The in vivo depletion of recipient and donor T lymphocytes using antithymocyte globulin (ATG; Thymoglobulin) is widely adopted in allogeneic hematopoietic stem cell transplantation (HCT) to reduce the incidence of both graft failure and graft-versus-host disease (GVHD). However, excess toxicity to donor lymphocytes may hamper immune reconstitution, compromising antitumor effects and increasing infection. Granulocyte-colony stimulating factor (G-CSF) administered early after HCT may increase ATG-mediated lymphotoxicity. This study aimed to investigate the effect of an interaction between ATG and post-transplantation granulocyte colony-stimulating factor (G-CSF) on allogeneic HCT outcomes, using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. We studied patients age ≥18 years with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) who received Thymoglobulin-containing preparative regimens for HLA-matched sibling/unrelated or mismatched unrelated donor HCT between 2010 and 2018. The effect of planned G-CSF that was started between pretransplantation day 3 and post-transplantation day 12 was studied in comparison with transplantations that did not include G-CSF. Cox regression models were built to identify risk factors associated with outcomes at 1 year after transplantation. A total of 874 patients met the study eligibility criteria, of whom 459 (53%) received planned G-CSF. HCT with planned G-CSF was associated with a significantly increased risk for nonrelapse mortality (NRM) (hazard ratio [HR] 2.03; P <.0001; 21% versus 12%) compared to HCT without G-CSF. The 6-month incidence of viral infection was higher with G-CSF (56% versus 47%; P = .007), with a particular increase in Epstein-Barr virus infections (19% versus 11%; P = .002). The observed higher NRM with planned G-CSF led to lower overall survival (HR, 1.52; P = .0005; 61% versus 72%). There was no difference in GVHD risk between the treatment groups. We performed 2 subgroup analyses showing that our findings held true in patients age ≥50 years and in centers where G-CSF was used in some, but not all, patients. In allogeneic peripheral blood HCT performed with Thymoglobulin for AML and MDS, G-CSF administered early post-transplantation resulted in a 2-fold increase in NRM and a 10% absolute decrement in survival. The use of planned G-CSF in the early post-transplantation period should be carefully considered on an individual patient basis, weighing any perceived benefits against these risks., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

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 β-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., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We evaluate the safety of bendamustine as a bridge to stem cell transplantation (SCT) in patients with relapsed/refractory lymphoma and residual disease after salvage therapy. Thirty-four subjects without complete responses (CR) received bendamustine 200 mg/m 2 /day for 2 days followed 14 days later by SCT. Sixteen subjects in partial remission (PR) with maximal FDG-PET SUVs ≤8 prior to bendamustine received autologous SCT, while 13 with suboptimal responses were allografted. Five subjects did not proceed to transplant. No bendamustine toxicities precluded transplantation and no detrimental effect on engraftment or early treatment-related mortality (TRM) was attributable to bendamustine. At 1 year, 75% of auto-recipients and 31% of allo-recipients were alive with CR. Two subjects in the autologous arm developed therapy-related myeloid neoplasia (t-MN). In conclusion, a bendamustine bridge to SCT can be administered without early toxicity to patients with suboptimal responses to salvage chemotherapy. However this approach may increase the risk of t-MN. (NCT02059239).Supplemental data for this article is available online at here.

The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.

The emergence of the Coronavirus Disease -19 (COVID-19) pandemic, has had a tremendous global impact, resulting in substantial morbidity and mortality worldwide and especially in the United States, where nearly one third of the cases are located. Although involvement of the lower respiratory track accounts for most of the morbidity and mortality seen, the virus involves several organ systems and the syndrome exhibits clinical diversity with a wide range of symptoms and manifestations. The involvement of elements of the hematopoietic system is prominent in severe cases and associated with poor outcomes and mortality. Lymphopenia, leukopenia, thrombocytopenia, disseminated intravascular coagulation, and a prothrombotic state are common manifestations of COVID-19 and have important treatment and prognostic implications. Better understanding of the mechanisms of the pathophysiology of COVID-19-induced hematological abnormalities may ultimately result in better ways to treat them and decrease the associated morbidity and mortality.

Alternative donor transplantation with the haplo-cord platform allows the use of a lower-dose single umbilical cord blood unit (CBU) by co-infusion of third-party CD34 + -selected cells from a haploidentical relative, which provides early transient engraftment while awaiting durable CBU engraftment. In our experience, ~15% of patients lack a suitable haploidentical donor. Here we report 26 patients who underwent haplo-cord transplant using CD34 + -selected partially matched unrelated donor grafts. Twenty-four were conditioned with fludarabine/melphalan +/- low-dose TBI (n = 16). Twenty-five received ATG and all received posttransplant tacrolimus and mycophenolate mofetil. Median time to neutrophil and platelet recovery was 11 and 18 days. CBU engraftment, with CD33 and CD3 >5% cord chimerism in the myeloid/lymphoid compartment by day +60, occurred in 20 of 24 patients (83%). Incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 27% at day +100, and chronic GVHD was 4% at 1 year. Overall survival at 1 year was 54%. For patients in need of an alternative transplant who lack a haploidentical donor, haplo-cord transplantation using CD34 + -selected partially matched unrelated donor grafts results in rapid engraftment with no increased rate of cord graft failure or GVHD.

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma to develop a clinical practice guideline for the education of healthcare professionals on various aspects of immunotherapeutic treatment. The panel discussed subjects including treatment scheduling, immune-related adverse events (irAEs), and the integration of immunotherapy and stem cell transplant to form recommendations to guide healthcare professionals treating patients with lymphoma., Competing Interests: Competing interests: SMA–Research funding to institution: Bristol Myers Squibb, Seattle Genetics, Affimed, Trillium, AI Therapeutics, ADC Therapeutics, Regeneron. MSC–Advisory board: Bayer, Celgene, and Nektar; Speaker honoraria: Jazz Pharmaceuticals. JWF–NSMC activity: Astellas Pharma, Bayer; Research support: Seattle Genetics. JPK–Consulting fees: Merck, Verastem; Research support: iTeos Therapeutics, Merck, Verastem; Speaker’s bureau: Kite. RL–Consulting: BeiGene, Corvus, Five Prime, Innate Pharma, Immune Design, Kite Pharma; Grant/research support: Bristol-Myers, Squibb, Dynavax, Pfizer, and Pharmacyclics; Stockholder: Merck. SSN–Advisory board/consultant: Allogene, Bristol-Myers Squibb, Celgene, Cell Medica/Kuur, Gilead, Incyte, Kite Pharma, Merck, Novartis, Pfizer, Precision BioSciences, Unum Therapeutics; Research support: Acerta, Allogene, Bristol-Myers Squibb, Gilead, Karus, Kite Pharma, Merck, Precision BioSciences, and Unum Therapeutics; Royalties: Takeda Pharmaceuticals (patents related to immune cell therapy). DLP–Honorarium/advisory board: Incyte, Kite Pharma, Novartis, Janssen, Glenmark; Research funding: Novartis; Patent: CD19 CAR T cells; Royalty: Novartis; Employment and stock/options: Genentech/Roche (spouse employment). KVB– Advisory board: Cellectis; Financial interest: Hemogenyx; Research support: Novartis. SA, JB, MRB, and MW–Nothing to disclose. SITC staff members: PI, AK, BL, RL, LL, and SMW–Nothing to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We conducted a prospective evaluation of cord blood (CB)-derived adoptive cell therapy, after salvage chemotherapy, for patients with advanced myeloid malignancies and poor prognosis. Previously, we reported safety, feasibility, and preliminary efficacy of this approach. We present updated results in 31 patients who received intensive chemotherapy followed by CB infusion and identify predictors of response. To enhance the antileukemic effect, we selected CB units (CBU) with shared inherited paternal antigens and/or noninherited maternal antigens with the recipients. Twenty-eight patients with acute myeloid leukemia (AML), 2 with myelodysplastic syndrome, and 1 in chronic myeloid leukemia myeloid blast crisis were enrolled; 9 had relapsed after allogeneic transplant. Response was defined as <5% blasts in hypocellular bone marrow at 2 weeks after treatment. Thirteen patients (42%) responded; a rate higher than historical data with chemotherapy only. Twelve had CBU-derived chimerism detected; chimerism was a powerful predictor of response (P < .001). CBU lymphocyte content and a prior transplant were associated with chimerism (P < .01). Safety was acceptable: 3 patients developed mild cytokine release syndrome, 2 had grade 1 and 2 had grade 4 graft-versus-host disease. Seven responders and 6 nonresponders (after additional therapy) received subsequent transplant; 5 are alive (follow-up, 5-47 months). The most common cause of death for nonresponders was disease progression, whereas for responders it was infection. CB-derived adoptive cell therapy is feasible and efficacious for refractory AML. Banked CBU are readily available for treatment. Response depends on chimerism, highlighting the graft-versus-leukemia effect of CB cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02508324., (© 2020 by The American Society of Hematology.)

Background: Diarrhea is common and associated with substantial morbidity among hematopoietic cell transplant (HCT) recipients, but the etiology is often not identified. Multiplexed polymerase chain reaction (PCR) assays increase the detection of diarrheal pathogens, but the impact of this technology in this population has not been evaluated., Methods: Our center replaced stool cultures and other conventional microbiologic methods with the FilmArray Gastrointestinal Panel (GI PCR) in June 2016. We reviewed all adult patients who received an HCT from June 2014-May 2015 (pre-GI PCR, n = 163) and from June 2016-May 2017 (post-GI PCR, n = 182) and followed them for 1 year after transplantation. Clostridioides difficile infection was diagnosed by an independent PCR test in both cohorts., Results: The proportion of patients with ≥1 identified infectious diarrheal pathogen increased from 25% to 37% after implementation of GI PCR (P = .01). Eight patients (5%) in the pre-GI PCR cohort tested positive for a pathogen other than C. difficile versus 49 patients (27%) in the post-GI PCR cohort (P < .001). The most common non-C. difficile diarrheal pathogens in the post-GI PCR cohort were enteropathogenic Escherichia coli (n = 14, 8%), norovirus (n = 14, 8%), and Yersinia enterocolitica (n = 7, 4%). The percentage of diarrheal episodes with an identified infectious etiology increased from 14% to 23% (P = .001). Median total costs of stool testing per patient did not increase (pre: $473; post: $425; P = .25)., Conclusions: Infectious etiologies of diarrhea were identified in a higher proportion of HCT recipients after replacing conventional stool testing with a multiplexed PCR assay, without an increase in testing costs., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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., (© 2020 American Cancer Society.)

With the emerging application of novel targeted agents in the induction, maintenance and salvage strategies, management of aggressive mantle cell lymphoma is being transformed from high-intensity chemo-immunotherapy applicable to only selected patients, to more personalized treatment incorporating novel agents that are effective and accessible for the majority of the patients. This review summarizes risk-stratified management paradigm for aggressive mantle cell lymphoma, providing context for clinical applications of novel agents and cellular therapy including stem cell transplant and CAR-T.

Background: Seasonal influenza causes significant morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. In this population, influenza virus can replicate for prolonged periods, despite neuraminidase inhibitor treatment, leading to resistance and treatment failure. Baloxavir targets the influenza polymerase and may be an effective treatment option in these patients., Methods: We used baloxavir to treat five allogeneic SCT recipients that were still symptomatic and shedding influenza virus after completing one or more treatment courses of oseltamivir and characterized the viral isolates before and during treatment., Results: Two patients were infected with influenza A/H1pdm09 carrying a neuraminidase variant (H275Y) linked to oseltamivir resistance. Both these two patients were successfully treated with baloxavir. Of the three patients infected with wild-type influenza virus, two cleared the virus after baloxavir treatment, while the third patient developed the polymerase I38T variant linked to baloxavir resistance., Conclusions: Our data suggest that baloxavir treatment can be effective in treating neuraminidase inhibitor-resistant influenza in profoundly immunocompromised patients. Randomized clinical trials are needed to define the role of baloxavir alone and combined with oseltamivir for the treatment of influenza in SCT recipients and other immunocompromised populations., (© 2020 Wiley Periodicals LLC.)

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., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Natural killer (NK) cell recognition and killing of target cells are enhanced when inhibitory killer immunoglobulin-like receptors (KIR) are unable to engage their cognate HLA class I ligands. The genes of the KIR locus are organized into either KIR B haplotypes, containing 1 or more activating KIR genes or KIR A haplotypes, which lack those genes. Analysis of unrelated donor (URD) hematopoietic cell transplants (HCT), given to acute myeloid leukemia (AML) patients between 1988 and 2009, showed that KIR B haplotype donors were associated with better outcomes, primarily from relapse protection. Most of these transplants involved marrow grafts, fully myeloablative (MAC) preparative regimens, and significant HLA mismatch. Because the practice of HCT continues to evolve, with increasing use of reduced intensity conditioning (RIC), peripheral blood stem cell grafts, and better HLA match, we evaluated the impact of URD KIR genotype on HCT outcome for AML in the modern era (2010-2016). This analysis combined data from a prospective trial testing URD selection based on KIR genotypes (n = 243) with that from a larger contemporaneous cohort of transplants (n = 2419). We found that KIR B haplotype donors conferred a significantly reduced risk of leukemia relapse and improved disease-free survival after RIC, but not MAC HCT. All genes defining KIR B haplotypes were associated with relapse protection, which was significant only in transplant recipients expressing the C1 epitope of HLA-C. In the context of current HCT practice using RIC, selection of KIR B donors could reduce relapse and improve overall outcome for AML patients receiving an allogeneic HCT., (© 2020 by The American Society of Hematology.)

The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints. This trial was registered at www.clinicaltrials.gov as #NCT02445248., (© 2020 by The American Society of Hematology.)

Background: Candida tropicalis is a virulent fungal pathogen for which echinocandins are the primary therapy. Emergence of resistance to echinocandins of C. tropicalis carries potentially ominous therapeutic implications., Methods: We describe herein two patients with breakthrough C. tropicalis fungemia during echinocandin therapy, characterize their molecular mechanism of resistance, and systematically review 13 previously reported cases of echinocandin-resistant C. tropicalis bloodstream infections (BSIs) and other diseases., Results: Among these 15 patients with echinocandin-resistant C. tropicalis infections, the median age was 61 years (ages 28-84 years) and 13 (86%) were immunocompromised. Thirteen (86%) of all patients had a history of pervious or concurrent exposure to echinocandins. Isolates of C. tropicalis from 11 cases, including the two index cases, underwent DNA sequencing of the FKS1 gene for mutations known to confer echinocandin resistance. The amino acid substitution Ser654Pro was shown in four cases, while other FKS1 mutations encoded Ser80S/Pro, Phe641Leu, Phe641Ser, Ser80S/Pro substitutions. These mutational events were not associated with collateral increases in minimum inhibitory concentrations to antifungal triazoles and amphotericin B. Overall mortality in patients with echinocandin-resistant C. tropicalis infections was 40%. Among those six patients who died, two received monotherapy with voriconazole, one was treated with fluconazole, one remained on caspofungin, and two were switched to liposomal amphotericin B. Nine patients (60%) survived after being treated with an antifungal agent other than an echinocandin., Conclusions: Emergence of resistance to echinocandins by C. tropicalis, occurs during antifungal therapy, is associated with high mortality, is mediated by a diverse range of FKS1 mutations, retains in vitro susceptibility to triazoles and amphotericin B, and constitutes an emerging threat to patients with hematological malignancies.

High-dose melphalan (MEL200) followed by autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma (MM). Bendamustine induces responses in MM resistant to other alkylators. Our prior Phase I trial adding bendamustine to MEL200 transplant conditioning resulted in no additional toxicity. We now report a single-arm, phase II study that evaluated the efficacy of bendamustine 225 mg/m 2 with MEL200 conditioning for ASCT in 18 patients with newly diagnosed MM (NDMM) and 17 with relapsed or refractory MM (RRMM). The primary end point was the complete response (CR/sCR) rate at day+ 100. Sample size was determined according to Simon's two-stage design. At stage 1, sixteen patients entered the study. As there were eight patients with CR/sCR, enrollment increased to 28 patients. Sixteen out of the first 28 evaluable patients achieved CR/sCR, meeting the design criteria. Enrollment was then expanded to a total of 35 patients. 51% achieved a CR/sCR. After a median follow-up of 65 months, 21 patients progressed, including 7 deaths. The median PFS for NDMM and RRMM was 48 and 45 months, respectively. Bendamustine/MEL200 conditioning resulted in excellent overall and depth of response as well as PFS, particularly in the RRMM patients, and is worthy of further investigation (NCT00916058).

Antiviral-resistant influenza viruses in the clinical environment, especially type B, are reported rarely. A stem cell transplant recipient remained influenza B positive for 2 months, despite repeated antiviral treatments. Laboratory tests demonstrated the evolution and persistence of neuraminidase inhibitor-resistant influenza B virus with a substitution at codon 119., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Acute graft versus host disease (aGVHD) was first described by Barnes et al. in 1962, who reported a 'secondary disease' in mice after irradiation and infusion of allogeneic spleen cells. The disease manifested as fatal diarrhea and skin abnormalities. They postulated that aGVHD resulted from introducing immunologically competent cells into an immunocompetent host. Treatments were developed to address this problem, and most centers use calcineurin inhibitors (tacrolimus or cyclosporine) combined with mycophenolate mofetil or methotrexate to prevents aGVHD. This classic GVHD prophylaxis is associated with an incidence of acute GVHD of approximately sixty percent. Other methods of GVHD prevention, including T-cell depletion and more recently post-trasnplant cyclophosphamid, have been tested, but all have their own limitations. The most effective methods tend to be more immunosuppressive and are not clearly superior in regards to long-term survival. Acute GVHD then remains a major problem in hematopoietic stem cell allogeneic transplantation (HCT). Its initial treatment consists of high-dose glucocorticosteroids (1-2 mg/kg daily). However, only one-third of patients are cured, leaving the majority of patients requiring more therapy. Patients with glucocorticosteroid refractory acute GVHD (SR aGVHD) have a very high mortality and to date, there is no effective treatment.

While the majority of thyroid cancer patients are easily treatable, those with anaplastic or poorly differentiated recurrent thyroid carcinomas have a very poor prognosis with a median survival of less than a year. Previously, we have shown a significant correlation between ICAM-1 overexpression and malignancy in thyroid cancer, and have pioneered the use of ICAM-1 targeted CAR T cells as a novel treatment modality. For clinical translation of this novel modality, we designed CAR T cells possessing micromolar rather than nanomolar affinity to ICAM-1 to avoid cytotoxicity in normal cells with basal levels of ICAM-1 expression. Herein, we report the automated process of CAR T cell manufacturing with CliniMACS Prodigy (Miltenyi Biotec) using cryopreserved peripheral blood leukocytes from apheresis collections. Using Prodigy, thawed leukopak cells were enriched for CD4 + and CD8 + T cells, subjected to double transduction using lentiviral vector, and expanded in culture for a total of 10 days with a final yield of 2-4 × 10 9 cells. The resulting CAR T cells were formulated for cryopreservation to be used directly for infusion into patients after thawing with no further processing. We examined cross-reactivity of CAR T cells toward both human and murine ICAM-1 and ICAM-1 expression in human and mouse tissues to demonstrate that both efficacy and on-target, off-tumor toxicity can be studied in our preclinical model. Selective anti-tumor activity in the absence of toxicity provides proof-of-concept that micromolar affinity tuned CAR T cells can be used to target tumors expressing high levels of antigen while avoiding normal tissues expressing basal levels of the same antigen. These studies support the initiation of a phase I study to evaluate the safety and potential efficacy of micromolar affinity tuned CAR T cells against newly diagnosed anaplastic and refractory or recurrent thyroid cancers.

Hematopoietic stem cell transplant (HSCT) recipients are at increased risk of respiratory viral infections and their associated complications. Unlike other respiratory viruses, little is known about the clinical significance of human coronavirus infection (HCoV) in this population. We retrospectively identified all HSCT recipients who were transplanted between May 2013 and June 2017 at our institution and characterized the cumulative incidence of post-transplant HCoV infection. Of 678 patients who underwent HSCT during the study period, 112 (17%) developed HCoV infection, making HCoV the fourth most common respiratory viral infection. Thirty-four (30%) HCoV-infected patients progressed to proven or probable lower respiratory tract infection (LRTI). Age ≥50, graft-versus-host disease, corticosteroids, hypoalbuminemia, and inpatient status at the time of infection were independently associated with progression to LRTI. Twenty-seven (59%) patients who underwent repeat NP swab had persistent viral shedding for ≥21 days, with a median duration of 4 weeks of viral shedding. We conclude that HCoV is common and clinically significant in HSCT recipients, with nearly one-third of patients progressing to proven or probable LRTI. Evaluating for LRTI risk factors found in this study may identify patients who require closer surveillance and aggressive supportive care when infected with HCoV.

Epstein-Barr virus (EBV) reactivation and post-transplant lymphoproliferative disorders (PTLD) are common and potentially fatal complications after allogeneic transplantation with mismatched donors and T-cell depletion. Haplo-cord transplantation combines a mismatched UCB graft with third-party cells. Conditioning involves thymoglobulin. EBV reactivation and PTLD were common in initial patients. As of March 2017, we administered a prophylactic dose of rituximab 375 mg/m 2 pre-transplant. Among 147 patients who did not receive rituximab, the cumulative incidence of post-transplant EBV reactivation and of EBV PTLD was 13% and 8%, respectively. Among 51 who received pre-transplant rituximab, the incidences were 2% ( p  = .0017) and 0% ( p  = .04), respectively. There was no difference in time to hematopoietic recovery, in the incidence of CMV reactivation, of invasive blood stream infections or of proven or probable invasive fungal infections. Pre-transplant administration of rituximab is an effective and nontoxic intervention that drastically reduces EBV reactivation and PTLD in high-risk patients.

Haplo-identical transplant with posttransplant cyclophosphamide (haplo) and umbilical cord blood transplant supported by third-party CD34 cells (haplo-cord) are competing approaches to alternative donor transplant. We compared, in adults younger than age 60 years, the outcomes of 170 haplo at 1 institution with that of 137 haplo-cord at 2 other institutions. All received reduced intensity conditioning with fludarabine and melphalan ± total body irradiation. GVHD prophylaxis for haplo consisted of cyclophosphamide, tacrolimus, and mycophenolate, whereas haplo-cord received antithymocyte globulin, tacrolimus, and mycophenolate. Haplo transplant used mostly bone marrow, and peripheral blood stem cells were used in haplo-cord transplants. Haplo-cord were older and had more advanced disease. Haplo-cord hastened median time to neutrophil (11 vs 18 days, P = .001) and platelet recovery (22 vs 25 days, P = .03). At 4 years, overall survival (OS) was 50% for haplo-cord vs 49% for haplo. Progression-free survival (PFS) was 40% for haplo-cord vs 45% for haplo. In multivariate analysis, the disease risk index was significant for OS (hazard ratio, 1.8; 95% confidence interval, 1.48-2.17; P = .00) and PFS. Total body irradiation was associated with decreased recurrence and improved PFS, age >40 with increased nonrelapse mortality. The type of transplant had no effect on OS, PFS, relapse, or nonrelapse mortality. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) by day 100 was 16% after haplo-cord vs 33% after haplo ( P < .0001), but grade 3-4 GVHD was similar. Chronic GVHD at 1 year was 4% after haplo-cord vs 16% after haplo ( P < .0001). Haplo or haplo-cord results in similar and encouraging outcomes. Haplo-cord is associated with more rapid neutrophil and platelet recovery and lower acute and chronic GVHD. Institutional review board authorization for this retrospective study was obtained at each institution. Some patients participated in trials registered at www.clinicaltrials.gov as #NCT01810588 and NCT01050946., (© 2019 by The American Society of Hematology.)