Control of acute myeloid leukemia and generation of immune memory in vivo using AMV564, a bivalent bispecific CD33 x CD3 T cell engager.

Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate. When the concentration of bispecific becomes negligible, the effector: target ratio has also shifted, and these activated T cells mediate long-term tumor control. To test the efficacy of AMV564 in vivo, we generated a CD33+ MOLM13CG bioluminescent human cell line and optimized conditions needed to control these cells for 62 days in vivo in NSG mice. Of note, not only did MOLM13CG become undetectable by bioluminescence imaging in response to infusion of human T cells plus AMV564, but also NSG mice that had cleared the tumor also resisted rechallenge with MOLM13CG in spite of no additional AMV564 treatment. In these mice, we identified effector and effector memory human CD4+ and CD8+ T cells in the peripheral blood immediately prior to rechallenge that expanded significantly during the subsequent 18 days. In addition to the anti-tumor effects of AMV564 on the clearance of MOLM13CG cells in vivo, similar effects were seen when primary CD33+ human AML cells were engrafted in NSG mice even when the human T cells made up only 2% of the peripheral blood cells and AML cells made up 98%. These studies suggest that AMV564 is a novel and effective bispecific diabody for the targeting of CD33+ AML that may provide long-term survival advantages in the clinic.

Immune Adjuvant Therapy With Interleukin-7 in a Lymphopenic Patient With Aplastic Anemia and Mucormycosis.

BACKGROUND: We report the case of a patient with aplastic anemia and pancytopenia on immune-suppressive therapy who developed invasive pulmonary infection with mucormycosis and was treated with immune adjuvant therapy. CASE SUMMARY: Given the patient's profound lymphopenia and progressive invasive mucor despite dual antifungal drug therapy, interleukin (IL)-7, a cytokine that induces lymphocyte activation and proliferation, was instituted and resulted in normalization of absolute lymphocyte counts and was temporally associated with clearance of fungal pathogens and resolution of clinical symptoms. CONCLUSION: Patients with life-threatening fungal infections are frequently immune suppressed and immune adjuvant therapies should be considered in patients who are not responding to antifungal drugs and source control. Well-designed, double-blind, placebo-controlled trials are needed to advance the field. Although a number of immune adjuvants may be beneficial in fungal sepsis, IL-7 is a particularly attractive immune adjuvant because of its broad immunologic effects on key immunologic pathways that mediate enhanced antifungal immune system activity.

SOHO State of the Art Updates and Next Questions: Tailoring Upfront Therapy in Mantle Cell Lymphoma.

In this article, we will review current strategies for the front-line management of mantle cell lymphoma, an uncommon and biologically and clinically heterogeneous subtype of non-Hodgkin lymphoma that remains incurable with current therapies. Patients invariably relapse with time, and as a result, treatment strategies involve persistent therapy over the course of months to years, including induction, consolidation, and maintenance. Topics discussed include the historical development of various chemoimmunotherapy backbones with continued modifications to maintain and improve efficacy while limiting off-target, off-tumor effects. Chemotherapy-free induction regimens were developed initially for elderly or less fit patients though are now being utilized for younger, transplant-eligible patients due to deeper, more prolonged remission durations with fewer toxicities. The historic paradigm of recommending autologous hematopoietic cell transplant for fit patients in complete or partial remission is now being challenged based in part on ongoing clinical trials in which minimal residual disease directed approaches influence the consolidation strategy for any particular individual. The addition of novel agents, namely first and second generation Bruton tyrosine kinase inhibitors as well as immunomodulatory drugs, BH3 mimetics, and type II glycoengineered anti-CD20 monoclonal antibodies have been tested in various combinations with or without immunochemotherapy. We will attempt to help the reader by systematically explaining and simplifying the various approaches for treating this complicated group of disorders.

Bendamustine/Rituximab Plus Cytarabine/Rituximab, With or Without Acalabrutinib, for the Initial Treatment of Transplant-Eligible Mantle Cell Lymphoma Patients: Pooled Data From Two Pilot Studies.

INTRODUCTION: Mantle cell lymphoma (MCL) is a moderately aggressive lymphoma subtype, generally viewed as incurable. For younger, fit patients, the standard of care remains various high-dose cytarabine-based induction regimens followed by autologous hematopoietic cell transplant and 3 years of rituximab maintenance. Despite reasonably good outcomes, with median progression-free survival in the range of 7 to 9 years, most patients eventually relapse, indicating a need to improve the safety and tolerability of remission induction strategies. METHODS: Given the impressive activity of bendamustine/rituximab (BR) in older patients with MCL, we developed an induction regimen modeled after the Nordic Regimen but substituted BR in place of R-CHOP. In a second pilot study, we incorporated the second-generation Bruton tyrosine kinase inhibitor (BTKi), acalabrutinib, into the regimen. The primary endpoint of both studies was stem cell mobilization success rate. RESULTS: All patients successfully underwent stem cell harvest in both studies. CONCLUSION: The experience from our single institution pilot study suggested that sequential rather than alternating BR and cytarabine/rituximab (CR) was easier to administer from the standpoint of toxicities and subsequent dose modifications. Safety and efficacy data from the 2 pilot studies, FitMCL 1.0 and 2.0, were similar. The pilot studies provided preliminary safety data supporting the development of the NCTN trial EA4181, assessing three different induction regimens with or without acalabrutinib.

Acute Graft-versus-Host Disease: An Update on New Treatment Options.

Acute graft-versus-host disease (GVHD) occurs in approximately 50% of patients and remains a primary driver of non-relapse and transplant-related mortality. The best treatment remains prevention with either in vivo or ex vivo T-cell depletion, with multiple strategies used worldwide based on factors such as institution preference, ability to perform graft manipulation, and ongoing clinical trials. Predicting patients at high risk for developing severe acute GVHD based on clinical and biomarker-based criteria allows for escalation or potential de-escalation of therapy. Modern therapies for treatment of the disease include JAK/STAT pathway inhibitors, which are standard of care in the second-line setting and are being investigated for upfront management of non-severe risk based on biomarkers. Salvage therapies beyond the second-line remain suboptimal. In this review, we will focus on the most clinically used GVHD prevention and treatment strategies, including the accumulating data on JAK inhibitors in both settings.

Top advances in lymphoma for 2021.

Chimeric antigen receptor (CAR) T-cell therapy, antibody-drug conjugates, bispecific T-cell redirectors, and agents targeting tonic B-cell receptor signaling have altered the paradigm for three of the most common lymphomas in the year 2021. For diffuse large B-cell lymphoma, the POLARIX study has shown improvement on the standard backbone of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in the frontline setting, a feat that had not been achieved despite great efforts over the past 20 years. In the relapsed and refractory setting, two unique CAR T-cell products have displaced autologous transplantation to the third line, and they allow patients with chemotherapy-resistant disease to receive approved therapy earlier. CAR T-cell products, once used exclusively in the aggressive lymphoma arena, are now showing high response rates and durable activity against indolent lymphomas. The investigation of mosunetuzumab in indolent lymphomas offers another option for patients who have received multiple lines of cytotoxic drugs. On the basis of these trends, PI3K inhibitors are being displaced in favor of safer and more durable constructs. In addition, within the past year, the approval and implementation of zanubrutinib for marginal zone lymphoma have filled a need for later line therapy, especially for less fit and elderly patients.

Mouse models of graft-versus-host disease.

Transplantation of allogeneic hematopoietic stem and progenitor cells (allo-HCT) allows for cure of life-limiting malignant and non-malignant hematologic diseases. Crossing the human leukocyte antigen (HLA) barrier, however, comes at the cost of graft-versus-host disease (GVHD), a life-threatening syndrome mediated in part by the same donor T-lymphocytes that eliminate malignant cells. Acute GVHD occurs in the skin, gut, and/or liver in 25-55% of patients with a mortality rate of 15-40%, while chronic GVHD develops in 30-65% of patients who survive at least 3 months following allo-HCT and is highly debilitating in its extensive form, with a 30-50% 5year mortality rate stemming in part from immune dysregulation and opportunistic infections. Knowledge gaps remain in understanding the pathogenesis and in developing novel and effective treatments for the acute and chronic GVHD, which have distinct biology and yet are both treated with front line systemic corticosteroids. Novel and informative mouse models remain the primary means by which these diseases are studied and drugs initially developed prior to testing in humans. In this chapter, we describe allo-HCT mouse models and protocols using these mouse models by which to study acute and chronic GVHD with the goal of improving prevention and therapy.

Current practice for primary headache disorders and perspectives on peripheral nerve blocks among emergency physicians in Canada: A national survey.

OBJECTIVE: This national postal survey aimed to examine Canadian emergency physicians' practice patterns with respect to drug treatment and perspectives on peripheral nerve blocks. BACKGROUND: The treatment of primary headache disorders in the emergency department is variable. METHODS: We surveyed 500 emergency physicians listed in the Canadian Medical Directory according to a modified Dillman's method: an initial invitation was followed by up to four reminders to nonresponders. Physicians were asked questions regarding their frequency of medication administration and perspectives toward peripheral nerve blocks. RESULTS: Of 500 mailed surveys, 468 were delivered and 179 physicians responded (response rate = 38.2%). The majority of physicians were men (92/144, 63.9%); 80.6% (116/144) had been in practice for greater than or equal to 10 years with 50.7% (75/148) in a community or district general teaching hospital. Commonly used pharmacotherapies for primary headaches were intravenous dopamine receptor antagonists (69%), co-administration of ketorolac and a dopamine receptor antagonist (54.2%), intravenous fluid boluses (54%), nonsteroidal anti-inflammatory drugs (NSAIDs) alone (53.5%), and acetaminophen (51.4%). Only 80 of 144 physicians (55.6%) reported previous experience with peripheral nerve blocks (95% confidence interval [CI] = 48%-65%). The majority (68/80, 85.0%) agreed peripheral nerve blocks are safe and 55.1% (43/78) agreed they are effective. The vast majority (118/140, 84.3%) would consider peripheral nerve blocks as a first-line treatment option given sufficient evidence from a future trial (95% CI = 78%-90%). CONCLUSION: NSAIDs alone, as well as dopamine receptor antagonists with or without ketorolac are commonly used for primary headache in Canadian emergency departments. A large proportion of physicians have never used a peripheral nerve block in their practice; among those who have experience with peripheral nerve blocks, the majority find them safe and effective. The majority of respondents would consider peripheral nerve blocks as a first-line treatment option given sufficient evidence from a future trial.

Association between mortality and frailty in emergency general surgery: a systematic review and meta-analysis.

PURPOSE: The purpose of this review was to determine the association between frailty and mortality among adults ≥ 65 years old undergoing emergency general surgery (EGS). METHODS: This systematic review followed the PRISMA guidelines (CRD42020172482 on PROSPERO). A search in MEDLINE, PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Database of Systematic Reviews was conducted from inception to March 5, 2020. Studies with patients ≥ 65 years undergoing EGS were included. The primary exposure was frailty, measured using the Clinical Frailty Scale or the Modified Frailty Index. The primary outcome was 30-day mortality. Secondary outcomes were 90-day and 1-year mortality, length of stay, complications, change in level of care at discharge, and loss of independence. Two independent reviewers screened articles and extracted data. Risk of bias was assessed according to the Newcastle-Ottawa Scale and quality of evidence was assessed using the GRADE approach. A meta-analysis was performed for 30-day mortality using a random-effects model. RESULTS: Our search yielded 847 articles and six cohort studies were included in the systematic review. There were 1289 patients, 283 being frail. The pooled OR from meta-analysis for frail compared to non-frail patients was 2.91 (95% CI 2.00, 4.23) for 30-day mortality. Frailty was associated with increased odds of all secondary outcomes. CONCLUSION: Frailty is significantly associated with worse outcomes after emergency general surgery in adults ≥ 65 years of age. The Clinical Frailty Scale could be used to improve preoperative risk assessment for patients and shared decision-making between patients and healthcare providers. REGISTRATION NUMBER: CRD42020172482 (PROSPERO).

Sodium Valproate Versus Dopamine Antagonists for Acute Migraine in the Emergency Department: A Systematic Review.

BACKGROUND: Migraine is a common primary headache disorder diagnosed in the emergency department (ED). This systematic review sought to compare the efficacy of sodium valproate (SV) to dopamine antagonists (DA) in relieving pain due to acute migraine. METHODS: Two research librarians helped create a search strategy including Embase, Ovid Medline, and the Cochrane Database of Clinical Trials from inception to June 1, 2020, updated May 19, 2021. Two investigators identified randomized control trials (RCTs) including adult patients with acute migraine presenting to the ED or acute clinical setting comparing SV to a DA with the aim of relieving pain. Primary outcome was headache relief at 1 hour from treatment. Secondary outcomes included pain relief at 24 hours, relief of associated symptoms (e.g. nausea, photo-/phonophobia, etc.), and need for rescue analgesia. Meta-analysis was performed and presented as odds ratios. RESULTS: Four RCTs with 470 patients were identified from an initial pool of 454 titles. Two studies compared SV to a DA alone and two compared SV to a DA plus one other agent (sumatriptan or dihydroergotamine). Three studies were included for meta-analysis. Pain relief had a pooled odds ratio of 1.14 at 1 hour and 0.42 at 24 hours. Three articles reporting the need for rescue analgesia had pooled odds ratio of 2.76. CONCLUSIONS: Sodium valproate is not more effective than DA at reducing migraine headache pain at 1 hour and less effective at 24 hours. Dopamine antagonists should be used over SV for the management of patients with acute migraine.

Effectiveness of Peripheral Nerve Blocks for the Treatment of Primary Headache Disorders: A Systematic Review and Meta-Analysis.

STUDY OBJECTIVE: Primary headache disorders are prevalent and account for 2% of all emergency department visits. Current treatment options are effective; however, time to pain relief is suboptimal. Alternatives such as peripheral nerve blocks have shown promising results. The objective of this systematic review is to examine the effectiveness of peripheral nerve blocks for timely pain relief. METHODS: We searched Ovid MEDLINE, EMBASE, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials and included randomized controlled trials comparing peripheral nerve blocks to placebo or active therapy. The primary outcome was pain within 120 minutes. Secondary outcomes were pain after 120 minutes, adverse events, need for rescue medications, and relapse of headache. Two reviewers screened and extracted data independently; mean differences (MDs) were calculated, and results were pooled using a random-effects model. RESULTS: Eleven studies met our eligibility criteria (n=860), of which 9 were included in the meta-analysis. Pain scores were significantly lower in patients treated with peripheral nerve blocks than with placebo at 15 minutes (MD: -1.17; 95% confidence interval: -1.82 to -0.51) and 30 minutes (MD: -0.99; 95% confidence interval: -1.66 to -0.32), and no serious adverse events were reported. Pain scores for peripheral nerve blocks versus active therapy and secondary outcomes were not pooled due to clinical heterogeneity. CONCLUSION: Our review shows peripheral nerve blocks are effective as a rapid treatment option when compared to placebo; however, we were unable to assess effectiveness against standard treatment. Emergency physicians should consider peripheral nerve blocks as an adjunct therapy for patients with primary headache disorders.

Integrating sex and gender in studies of cardiac resynchronization therapy: a systematic review.

AIMS: To examine the prevalence, temporal changes, and impact of the National Institute of Health (NIH) Sex as a Biological Variable (SABV) policy on sex and gender reporting and analysis in cardiac resynchronization therapy (CRT) cohort studies. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and Web of Science for cohort studies reporting the effectiveness and safety of CRT in heart failure patients from January 2000 to June 2020, with no language restrictions. Segmented regression analysis was used for policy analysis. We included 253 studies. Fourteen per cent considered sex in the study design. Outcome data disaggregated by sex were only reported in 17% of the studies. Of the studies with statistical models (n = 173), 57% were adjusted for sex. Sixty-eight per cent of those reported an effect size for sex on the outcome. Sex-stratified analyses were conducted in 13% of the studies. Temporal analysis shows an increase in sex reporting in background, statistical models, study design, and discussion. Besides statistical models, NIH SABV policy analysis showed no significant change in the reporting of sex in study sections. Gender was not reported or analysed in any study. CONCLUSIONS: There is a need to improve the study design, analysis, and completeness of reporting of sex in CRT cohort studies. Inadequate sex integration in study design and analysis may potentially hinder progress in understanding sex disparities in CRT. Deficiencies in the integration of sex in studies could be overcome by implementing guidance that already exists.

Dural Marginal Zone Lymphoma in a Patient With a Hepatitis C Virus Infection.

Primary dural marginal zone lymphomas (MZLs) are exceptionally rare, with fewer than 100 cases reported to date. While the association between hepatitis C virus (HCV) infection and lymphoma is well established, it is unclear if this association extends to all anatomic sites. Here we report a case of dural MZL in a 61-year-old woman with an HCV infection. To our knowledge, this is the first report of a dural MZL associated with an HCV infection in an immunocompetent patient and was successfully treated with radiotherapy and rituximab. As such, future cases of primary MZL found in the dura should prompt consideration of co-infection with microbials such as HCV and upfront treatment with anti-virals should be considered.

Haploidentical bone marrow transplant with posttransplant cyclophosphamide for sickle cell disease: An update.

Hematopoietic cell transplant (HCT) can cure both children and adults with sickle cell disease. Outcomes have historically been poor for the vast majority of patients who lack a matched sibling donor. However, the development of haploidentical HCT (haplo-HCT) with high doses of posttransplant cyclophosphamide (PTCy) has allowed for curative long-term potential with favorable transplant-related outcomes, though this has not obviated the potential for graft rejection from human leukocyte antigen mismatch and repeated red blood cell transfusions. Accordingly, multiple strategies have been developed to improve outcomes, the majority of which are based on the Johns Hopkins platform from 2012. Presently, we aim to discuss results from pertinent studies and compare outcomes with the two most recent approaches involving either thiotepa plus 200-cGy total body irradiation or 400-cGy total body irradiation. Direct comparisons are required to determine the optimized curative potential. Transplant-eligible patients must be referred to tertiary medical centers for consideration of haplo-HCT.

Overcoming Proteasome Inhibitor-Refractory Multiple Myeloma With Elotuzumab, Bortezomib, Nelfinavir, and Dexamethasone.

Multiple myeloma is a common plasma cell malignancy with a median overall survival of fewer than 10 years. Proteasome inhibitors comprise an important part of the treatment regimen for this disease. The present study reports the case of a 57-year-old man who experienced a second relapse of multiple myeloma 6 years after initial treatment with bortezomib, lenalidomide, dexamethasone (VRD) followed by autologous hematopoietic cell transplant. The first relapse had been successfully treated with VRD, but this approach failed to control his second relapse. Given the lack of response to VRD therapy and relapse while on bortezomib maintenance, the patient was deemed proteasome inhibitor-refractory and received a new treatment of elotuzumab, lenalidomide, and dexamethasone. Four and a half cycles were completed before the treatment was stopped due to grade 4 cytopenias. The patient received a novel combination of elotuzumab, bortezomib, nelfinavir, and dexamethasone. After six cycles, the serum M-protein level was improved to 0.6 g/dL and the kappa light chains dropped from 3.49 to 1.04 mg/dL. A bone marrow biopsy conducted after five treatment cycles demonstrated < 1% plasma cells by immunohistochemistry and achievement of minimal residual disease status. Overall, this case study suggests that proteasome inhibitor-refractory multiple myeloma may be successfully re-treated with proteasome inhibitors when co-administered with nelfinavir.

Minimal residual disease negativity and lenalidomide maintenance therapy are associated with superior survival outcomes in multiple myeloma.

Modern combinations of therapies for multiple myeloma have led to improvement in survival outcomes with near 100% overall response rate and 25% complete response rates, particularly with autologous hematopoietic cell transplant (AHCT). Minimal residual disease (MRD) assessment with multiparameter flow cytometry is a valid prognostic biomarker for progression-free survival (PFS) and overall survival (OS). However, few data exist regarding whether MRD positivity or negativity will meaningfully influence treatment decisions. We evaluated 433 patients who received induction therapy, followed by AHCT. Participants had MRD assessment by multiparameter flow cytometry before and at days +100 and +365 following AHCT. They also received either lenalidomide, bortezomib, or no maintenance therapy following AHCT. Maintenance treatment with lenalidomide improved MRD negativity at day +365 compared to bortezomib (92.9% vs 41.6%, p = 0.01), or no maintenance therapy (92.9% vs 24.4%, p = 0.012). The median PFS for patients who were MRD negative at day + 365 was 42 vs 17.5 months (p < 0.001) and median OS was 80.6 vs 59 months (p = 0.02). Maintenance therapy following AHCT for multiple myeloma improves the depth of response as assessed by MRD.

New-onset post-transplant diabetes mellitus after haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.

Haploidentical hematopoietic cell transplant (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is utilized for patients with hematological disorders but without conventional donors. The effects of new-onset post-transplant diabetes mellitus (PTDM) following haplo-HCT are unknown. We examined PTDM incidence and outcomes after haplo-HCT with PTCY. Patients without diabetes receiving haplo-HCT (n=64) were analyzed for PTDM diagnosis (defined as blood glucose≥ 200 mg/dL). By day 100, 14 (22%) patients developed PTDM (median, 18 days). Hyperglycemia (blood glucose ≥ 200 mg/dL) preceded corticosteroids in 11 (79%) individuals. PTDM patients had increased death/relapse (p=0.029). PTDM occurs frequently, precedes corticosteroids, and leads to inferior outcomes following haplo-HCT. PTDM prophylaxis/treatment may improve HCT survival.