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BackgroundLittle data exists to guide the treatment of persistent COVID-19 in immunocompromised patients. We have employed a unique protocol combining tixegavimab/cilgavimab, and short-term combination antivirals including remdesivir.MethodsA retrospective single-center analysis of persistent COVID-19 in immunocompromised patients. Response was assessed by symptom resolution, declining C-reactive protein (CRP) levels and increasing SARS-CoV-2-PCR cycle-threshold (Ct) values.ResultsFourteen patients were included, including 2 kidney transplant recipients, 11 with B-cell lymphoproliferative disease, treated with anti-CD20 or ibrutinib, and 1 with rheumatoid arthritis, treated with anti-CD20. Median Ct-value was 27 (interquartile range (IQR):24-32). All patients received tixegavimab/cilgavimab and a 5-day course of remdesivir. Eleven also received nirmaltrevir/ritonavir and one received molnupiravir. Median follow-up was 45 days (IQR:12-89). Eleven patients had complete responses including symptom resolution, decrease in CRP, and increase in Ct values (all with either a negative PCR or Ct value>30 on day 4-16). Three patients had a partial response with relapses requiring re-admission. One had died, and two responded to prolonged antiviral treatments.ConclusionsA combination of monoclonal antibodies with antivirals has led to complete resolution of persistent COVID-19 in most severely-immunocompromised patients. Controlled studies will further direct the treatment of these patients, while more effective antivirals are urgently needed.Key pointsSome immunocompromised patients develop persistent symptomatic SARS-CoV-2 infection. Combination of monoclonal antibodies plus one or more antivirals cured 11/14 patients. Non-responders benefitted from prolonged combination antiviral treatment. Controlled trials are needed to find optimal treatment of persistent COVID-19.

Selinexor is a first-in-class, oral therapy that selectively inhibits nuclear export. The drug is active with an overall response rate (ORR) of approximately 30% in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL). Long-term patient follow-up has not been reported. Thirty-one NHL patients were treated between July 2012 and July 2018; 22 were evaluated for response. ORR was 32% (7/22). Two patients achieved complete remission (CR) and were alive and lymphoma-free at the end of follow-up. Fifteen patients (68%) progressed during treatment, most of them died within 3-10 months. The most common grade 3/4 adverse events were gastrointestinal and hematological. Median follow up was 50 months. Overall survival for the entire cohort was 16%. Selinexor monotherapy for r/r NHL is an active therapy with the potential for long-term disease control. It may serve as a 'bridge' to subsequent therapy. Additional studies are needed to identify predictive biomarkers and to evaluate combination approaches.

Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival (OS) in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, p = .043) and from the time of ASCT (51.8% vs. 59.3%, p = .018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, p = .445). In terms of specific-gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, p = .011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications.

Mantle cell lymphoma (MCL) is a B-cell malignancy, comprising between 3% and 10% of all adult-onset non-Hodgkin lymphomas. MCL is considered incurable with current treatment modalities and most patients require multiple lines of treatment during their lifetime. MCL is very sensitive to radiotherapy (RT), even when delivered in low doses. In limited-stage MCL, RT can enable the de-escalation of systemic therapy. RT monotherapy is a valid option for frail patients. In advanced-stage disease, RT is very potent mode of palliation, even in heavily pretreated and chemo-resistant patients. Furthermore, it can provide a respite during which systemic treatment is unnecessary. In general, RT has a favorable toxicity profile and can be repeated as necessary for local relapse or distant disease. This effective, safe, and relatively inexpensive modality of therapy has been underutilized for patients with MCL. In this review, we will outline the use of RT for limited and advanced-stage disease and its potential application in combination with novel drugs.

This national Israeli multicenter retrospective study aimed to characterize the clinical course of COVID-19 infection among patients with hematological malignancies, with special emphasis on treatment efficacy and outcome. Clinical and laboratory data from haemato-oncological patients diagnosed with COVID-19 from 16 medical centers were centrally reported. Multivariate regression analyses were used to determine variables associated with severe disease, hospitalization, and mortality. In total, 313 patients were included: 103 (35.7%) developed severe/critical respiratory infection, 178 (61.4%) were hospitalized, and 60 (20.0%) died. Age > 70 years was associated with severe/critical disease (p = 0.036) and mortality (p = 0.023), hypertension with severe/critical disease (p = 0.046) and hospitalization (p = 0.001), active haemato-oncological treatment with hospitalization (p = 0.009), and remdesivir treatment was associated with decreased mortality (p = 0.021). Convalescent plasma, enoxaparin, and corticosteroids resulted in no clinical benefit. In conclusion, COVID-19 infection seems particularly severe in patients with hematological malignancies, and of all examined therapies, remdesivir appears to be the most effective.

The incidence of systemic diffuse large B cell lymphoma (DLBCL) concurrently involving the central nervous system (CNS) at diagnosis, is very low and data regarding the clinical course of these patients are scarce. We investigated characteristics, efficacy of treatment regimens including consolidative autologous stem cell transplantation and outcome of patients presenting with concomitant systemic and CNS DLBCL. The records of 44 patients, diagnosed between 2004 and 2017, who fulfilled the inclusion criteria, were retrospectively reviewed. CNS involvement was diagnosed as solely parenchymal in 41%, solely leptomeningeal in 43%, and paranchymal with leptomeningeal in 11% of the patients. Induction regimens were anthracycline-based combined with high-dose methotrexate (HD-MTX) in 80% (n = 35) of patients, anthracycline-based combined with intrathecal MTX in 3, cytarabine-based (without antracyclines) in 2, HD-MTX in 1 and palliative in three. Five of 41 patients treated with chemotherapy died of treatment-related toxicity, all due to infections. Nineteen patients had consolidative autologous transplantation. Overall response rate following induction was 80% (complete responses 66% and partial responses 15%). All relapses (n = 11) occurred within less than 2 years. Within a median follow-up of 26.8 months, 3-years projected overall survival (OS) and progression free survival rates for the entire cohort were 56% ± 8.3 and 42% ± 8.9, respectively. In multivariate analysis, RCHOP-HD MTX-based induction [HR = 0.228, (0.054-0.964)], administration of 3.5 g/m2 MTX [HR = 0.735 (0.620-0.871)], and attaining CR following induction [HR = 0.185, (0.051-0.667)] predicted longer OS. RCHOP-HD MTX can provide prolonged remissions in DLBCL patients presenting with concomitant systemic and CNS involvement whereas role of autograft remains uncertain.

Objective: Graft-versus-host disease (GVHD) is an immune phenomenon that occurs in 30 to 70% of patients after allogeneic hematopoietic stem cell transplantation (HST). Chronic GVHD is a state of immune dysregulation wherein, depending on the severity and organ involved, patients may require prolonged treatment with additional or higher corticosteroids and other immunosuppressive agents. The objective of this study was to review the endocrine manifestations following HST that can arise as a consequence of the primary disease or its treatment, including chemotherapeutic agents, corticosteroids, radiation, or GVHD. Methods: We performed a narrative review of GVHD after HST. An English-language search for relevant studies was conducted on PubMed from inception to August 1, 2018, using the following search terms: "endocrine complications," "bone marrow transplantation," "graft-versus-host disease," and "GVHD." The reference lists of relevant studies were also reviewed. Results: Chronic GVHD may be associated with considerable pediatric growth impairment and may also contribute to thyroid gland dysfunction and thyroid cancer. These patients may also be at increased risk for low bone mineral density, reduced fertility, metabolic syndrome, and suppression of the pituitary-adrenal axis with adrenal insufficiency. Conclusion: This review indicates the importance of monitoring, diagnosing, and properly treating the endocrine complications in this population. More studies are needed to investigate the independent impact of GVHD on the endocrine system and treatment for complications. Abbreviations: BMD = bone mineral density; GH = growth hormone; GVHD = graft-versus-host disease; HST = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1.

Introduction: Selinexor is a first-in-class, oral therapeutic that selectively inhibits nuclear export. It has received fast track designation from the FDA for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) recently, and continues to be evaluated as a potential treatment for DLBCL.Area covered: This article reviews the available data from clinical trials regarding the efficacy of selinexor in DLBCL and highlights the key toxicity issues and how they may best be managed. Ongoing and future studies in DLBCL are also discussed.Expert opinion: More translational studies are necessary to leverage the unique mechanism action and rationally inform the use of selinexor in combination strategies. There are several different genetic subtypes of DLBCL, but it is not clear if these classifications will identify patients that may benefit from targeted therapies. The broad potential mechanism of action of selinexor will require careful analysis to inform predictive or prognostic biomarkers. Further evaluation of selinexor in combination with standard lymphoma regimens could identify deliverable promising regimens. Future randomized trials are key for registration and to determine the optimal role for this first-in-class agent.

Introduction : Peripheral blood samples of healthy individuals may harbour detectable mutations in genes recurrently mutated in myeloid malignancies, a situation referred to as clonal hematopoiesis (CH). Risk factors for CH include increasing age as well as previous exposure to cytotoxic therapy. CH has been associated with an increased risk of overall mortality, including in the setting of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (Gibson et al, JCO, 2017). The excess mortality is largely driven by cardio-vascular disease, but may also be additionally attributable to an increased risk of myeloid malignancies that arise through the selection of CH subclones. Herein, we aimed to investigate the prognostic implications of CH after ASCT in an independent and diversified, large cohort of lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. Methods : DNA was obtained from 420 residual apheresis products obtained from patients who had undergone autologous stem cell transplantation for lymphoma at the Princess Margaret Cancer Center between 2002 and 2018. Target DNA sequences corresponding to regions recurrently mutated in myeloid neoplasms (affecting n = 36 genes) were captured using single molecule molecular inversion probes (smMIPs) that incorporate molecular tagging. Single nucleotide variants and short insertions and deletions were identified using SmMIP-tools (Medeiros et al, bioRxiv, 2021), which implements a series of steps including probabilistic modeling of allele-specific error rates and generation of consensus sequences to suppress next-generation sequencing-associated errors. Given the high sensitivity and precision of our method, we did not prespecify a variant allele fraction cut-off. Results : All patients had relapsed/refractory lymphoma, except for 98 (23.3%) mantle cell lymphoma patients and one patient with extranodal NK/T-cell lymphoma where ASCT was part of frontline management. The most common conditioning regimens were high-dose melphalan and etoposide (77.5%) and high-dose melphalan and Ara-C (16.4%). We identified 275 high-confidence mutations in 181 out of 420 patients (43.1%), with 64 of these 181 patient samples (35.4%) having more than one mutation. The median age was higher in patients with CH than in patients without (55 years vs. 51, P = 0.002). The most frequently mutated gene were PPM1D (11.9%), followed by TET2 (11.4%), DNMT3A (8.8%), ASXL1 (5.2%) and TP53 (4.5%). The lymphoma subtype with the highest prevalence of CH was T-cell lymphoma (CH found in 72.2% of cases), followed by transformed indolent lymphoma (51.4%), mantle cell lymphoma (47.5%), diffuse large B-cell lymphoma (40.4%) and Hodgkin lymphoma (33.3%). While there was no difference in the number of CD34+ cells infused for patients with and without CH, the median time to neutrophil engraftment and the median time to platelet engraftment were significantly longer in patients with CH (11 days vs. 10 days, P = 0.025; and 14 days vs. 13 days, P < 0.001, respectively). The median follow-up of living patients was 4.2 years. Patients with CH had inferior 5-year OS from the time of first relapse (38.9% vs. 45.5%, P = 0.037) and from the time of ASCT (51.2% vs. 59.1%, P = 0.017, see figure). Five-year OS from ASCT was 47.5% vs. 53.7% in patients with 1 mutation and > 1 mutation, respectively, compared to 59.1% in patients without CH (P = 0.005). The presence of CH did not have an impact on the risk of post-ASCT relapse. In multivariate Cox regression analysis in which CH and age (as a continuous variable) were included, CH remained significantly associated with adverse OS post-ASCT (HR 1.39, 95% 1.02-1.91, P = 0.038). Only seven patients out of 420 (1.7%) developed a therapy-related myeloid neoplasm (TMN). The cumulative incidence of TMN was not significantly increased in patients with CH (10-year cumulative incidence 3.3% vs. 3.0% in those without CH, P = 0.433). Conclusions : Our results show that CH was associated with delayed neutrophil and platelet engraftment. Moreover, CH conferred an increased risk of death after ASCT that was not explained by lymphoma relapse. The risk of TMN was low in our cohort and CH was not a risk factor for TMN, an observation that is distinct from prior observations (e.g. Gibson et al, JCO, 2017 and Husby et al, Leukemia, 2020). Our results raise the possibility that the risk of TMN may be modulated by factors other than CH. Figure 1 Figure 1. Disclosures Minden: Astellas: Consultancy. Kuruvilla: Janssen: Honoraria, Research Funding; Antengene: Honoraria; AstraZeneca: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Pfizer: Honoraria; AbbVie: Honoraria; TG Therapeutics: Honoraria; Medison Ventures: Honoraria; Merck: Honoraria; Gilead: Honoraria; BMS: Honoraria; Roche: Honoraria, Research Funding; Seattle Genetics: Honoraria. Crump: Roche: Research Funding; Epizyme: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Prica: Kite Gilead: Honoraria; Astra-Zeneca: Honoraria. Chen: Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Kridel: Gilead Sciences: Research Funding.

Background: Both busulfan-cyclophosphamide (BuCy) and the reduced toxicity regimen busulfan-fludarabine (BuFlu) are considered myeloablative preparative regimens given prior to allogeneic hematopoietic cell transplantation (HCT). A comprehensive literature evaluation of BuFlu vs. BuCy is lacking and the question of the preferable regimen is still debatable. Objectives: We aimed to compare the efficacy and safety of BuFlu (intervention arm) vs. BuCy (comparable arm) as preparative regimens in patients given allografts. Methods: Systematic review and meta-analysis of all randomized controlled trials (RCTs) and non-randomized comparative trials of patients given BuFlu vs. BuCy as preparative regimens prior to allografts. Electronic search in the Cochrane Library, MEDLINE and conference proceedings was conducted up-to July 2014. Primary outcomes were all-cause mortality at 100 days and at the end of study. Secondary outcomes were time to neutrophil engraftment, primary & secondary rejection, risk for grade 3-4 mucositis, sinusoidal obstruction syndrome (SOS), microbiology documented infection, overall and grade 3-4 acute graft vs. host disease (GVHD), overall and extensive chronic GVHD, non-relapse mortality at 100 day and at the end of study, and relapse risk. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous variables we calculated weighted mean difference (WMD). Results: Our search yielded 14 trials recruiting 1578 patients. Three trials were RCTs and 11 were either one arm intervention trials compared to historical controls or retrospective studies. There were no differences in all-cause mortality at 100 days and end of study ( RR 0.85; 95% CI 0.56-1.30, 9 trials and RR 0.77; 95% CI 0.59-1.02, 12 trials, respectively), Figure, with similar results in sensitivity analyses including only RCTs and only studies in which patients' age and status of disease at HCT were well matched. Both primary and secondary rejections were comparable between the two regimens. Time to neutrophil engraftment was 1-day longer in patients given the BuCy regimen (WMD 0.84; 95% CI 0.37-1.31, 6 trials). Both the risks for SOS and microbiology documented infections were lower in the BuFlu patients (RR 0.34; 95% CI 0.19-0.62, 8 trials and RR 0.79; 95% CI 0.64-0.97, 2 trials, respectively). Grade 3-4 mucositis was comparable between the two groups. There was a lower incidence of grade 2-4 acute GVHD in patients given FluBu (RR 0.67; 95% CI 0.46-0.99, 10 trials), however this was no longer true in sensitivity analysis including only RCTs. There were no differences between the two arms in grade 3-4 acute GVHD, overall and extensive chronic GVHD, non-relapse mortality at 100 days and at the end of study and relapse risk. Conclusions: While toxicity profile of BuFlu regimen is safer than the classic BuCy regimen, this does not translate into composite transplantation outcomes. Patients at higher risk for SOS may benefit from the BuFlu regimen; however additional RCTs are required to identify other subgroups of patients who will benefit from a tailored-preparative regimen approach. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.