LILRB3 Modulates Acute Myeloid Leukemia Progression and Acts as an Effective Target for CAR T-cell Therapy.

Identifying novel cell surface receptors that regulate leukemia cell differentiation and can be targeted to inhibit cellular proliferation is crucial to improve current treatment modalities in acute myeloid leukemia (AML), especially for relapsed or chemotherapy-refractory leukemia. Leukocyte immunoglobulin-like receptor type B (LILRB) is an immunomodulatory receptor originally found to be expressed in myeloid cells. In this study, we found that LILRB receptors can be induced under inflammatory stimuli and chemotherapy treatment conditions. Blockade of LILRB3 inhibited leukemia cell proliferation and leukemia progression. In addition, treatment with LILRB3 blocking antibodies upregulated myeloid lineage differentiation transcription factors, including PU.1, C/EBP family, and IRF, whereas phosphorylation of proliferation regulators, for example, AKT, cyclin D1, and retinoblastoma protein, was decreased. Conversely, transcriptomic analysis showed LILRB3 activation by agonist antibodies may enhance leukemia survival through upregulation of cholesterol metabolism, which has been shown to promote leukemia cell survival. Moreover, LILRB3-targeted CAR T cells exhibited potent antitumor effects both in vitro and in vivo. Taken together, our results suggest that LILRB3 is a potentially potent target for multiple treatment modalities in AML. SIGNIFICANCE: LILRB3 regulates differentiation and proliferation in acute myeloid leukemia and can be targeted with monoclonal antibodies and CAR T cells to suppress leukemia growth.

Long-term outcomes in patients with Burkitt lymphoma older than 65 years: an analysis of the Texas Cancer Registry.

Burkitt lymphoma (BL) is an extremely aggressive but curable subtype of non-Hodgkin lymphoma. While younger patients have excellent outcomes in response to aggressive chemoimmunotherapy, the rarity of this disease in older patients and limitations caused by age, comorbidities, and performance status may negate survival advantages. This analysis assessed outcomes of older adults with BL through data provided by the Texas Cancer Registry (TCR). Patients ≥65 years with BL were assessed. Patients were dichotomized into 1997-2007 and 2008-2018. Median overall survival (OS) and disease-specific survival (DSS) were assessed using Kaplan-Meier methodology, and covariates including age, race, sex, stage, primary site, and poverty index were analyzed using Pearson Chi-squared analysis. Odds ratio (OR) with 95% confidence intervals (CI) was used to assess factors contributing to patients not offered systemic therapy. P value <0.05 was considered statistically significant. Non-BL mortality events were also categorized. There were 325 adults, 167 in 1997-2007 and 158 in 2008-2018; 106 (63.5%) and 121 (76.6%) received systemic therapy, a trend that increased with time (p = 0.010). Median OS for 1997-2007 and 2008-2018 was 5 months (95% CI 2.469, 7.531) and 9 months (95% CI 0.000, 19.154) (p = 0.013), and DSS was 72 months (95% CI 56.397, 87.603) (p = 0.604) and not reached, respectively. For patients that received systemic therapy, median OS was 8 months (95% CI 1.278, 14.722) and 26 months (95% CI 5.824, 46.176) (p = 0.072), respectively, and DSS was 79 months (95% CI: 56.416, 101.584) and not reached, respectively (p = 0.607). Age ≥75 years (HR 1.39 [95% CI 1.078, 1.791], p = 0.011) and non-Hispanic whites (HR 1.407 [95% CI 1.024, 1.935], p = 0.035) had poorer outcomes, and patients at the 20-100% poverty index (OR 0.387 [95% CI 0.163, 0.921], p = 0.032) and increasing age at diagnosis (OR 0.947 [95% CI 0.913, 0.983], p = 0.004) were less likely to receive systemic therapy. Of 259 (79.7%) deaths, 62 (23.9%) were non-BL deaths, and 6 (9.6%) of these were from a second cancer. This two-decade analysis of older Texas patients with BL indicates a significant improvement in OS over time. Although patients were more likely to receive systemic therapy over time, treatment disparities existed in patients residing in poverty-stricken regions of Texas and in advancing age. These statewide findings reflect an unmet national need to find a systemic therapeutic strategy that can be tolerated by and augment outcomes in the growing elderly population.

Long term outcomes in older patients with primary central nervous system lymphoma: an analysis of the Texas Cancer Registry.

Primary central nervous system lymphoma (PCNSL) is an aggressive subtype of non-Hodgkin lymphoma that carries a poor prognosis in the elderly. The aim of this study is to investigate treatment patterns and survival trends in patients ≥ 65 years with PCNSL through data provided by the Texas Cancer Registry. Adults ≥ 65 years diagnosed with PCNSL and followed between 1995-2017 were identified and separated into three eras: 1995-2003, 2004-2012, and 2013-2017. Baseline covariates compared included patient demographics and treatments administered. Pearson's chi-squared test and Cox proportional hazard models compared covariates; overall survival (OS) and disease-specific survival (DSS) were assessed via Kaplan-Meier methodology. There were 375 patients; 104 (27.7%) in 1995-2003, 146 (38.9%) in 2004-2012, and 125 (33.3%) in 2013-2017. There were 50 (48.1%), 55 (37.7%), and 31 (24.8%) in 1995-2003, 2004-2012, and 2013-2017, respectively, that did not receive treatment. At last follow up, 101 (97.1%), 130 (89.0%), and 94 (75.2%) in each era died, of which 89 (85.6%), 112 (76.7%), and 70 (56.0%) were attributed to PCNSL. Median OS per era was eight (95% confidence interval [CI] 5.06-10.93), six (95% CI, 2.30-9.69), and five months (95% CI, 2.26-7.73) (p = 0.638). DSS per era was nine (95% CI: 0.00, 26.53), 10 (95% CI: 5.14, 14.86), and 19 (95% CI, 0.00-45.49) (p = 0.931) months. Spinal cord as primary disease site (HR: 0.668 [95% CI, 0.45-0.99], p = 0.049), and chemotherapy (HR 0.532 [95% CI, 0.42-0.673], p = < 0.001) or chemotherapy + radiation (HR, 0.233 [95% CI, 0.11-0.48] p < 0.001) had better outcomes compared to no therapy or radiation therapy alone. Survival in older patients ≥ 65 with PCNSL has not improved per our analysis of the TCR from 1995-2017 despite increasing trends of treatment utilization. Strategies to augment recruitment of older individuals in trials are needed in order to determine who would derive treatment benefit and minimize treatment toxicities.

Prognostic Effect of Systemic Therapy and Radiation Therapy in Stage I Nodal Marginal Zone Lymphoma.

PURPOSE: Nodal marginal zone lymphoma (NMZL) localized to a single lymphatic region (ie, stage I) is a relatively rare diagnosis. Current guidelines permit these patients to be either observed or treated with systemic therapy (ST), radiation therapy (RT), or both modalities. The prognostic effect of ST or RT compared with observation has not been established. The purpose of this study was to assess the prognostic effect of therapy in stage I NMZL. METHODS AND MATERIALS: The National Cancer Database was queried (2004-2018) for all patients with stage I NMZL. Patients were stratified based on treatment received. Propensity score matching (PSM) was performed overall and for each disease site to create 1:1 matched cohorts of patients who received RT and those who did not. Kaplan-Meier analysis evaluated overall survival (OS). Univariable (UVA) and multivariable Cox proportional hazard analyses identified clinical and treatment factors prognostic for OS. Subset analysis excluded patients deceased within 1 month of diagnosis to account for immortal time bias. RESULTS: A total of 3201 patients (median age 67) met inclusion criteria. A total of 1042 patients (33%) were head/neck/face, 208 (7%) intrathoracic, 613 (19%) intra-abdominal, 382 (12%) axilla/upper extremity, 292 (9%) inguinal/lower extremity, 86 (3%) pelvic, and 578 (18%) unspecified. A total of 1562 patients (49%) received no treatment, 721 (23%) received ST alone, 799 (25%) received RT alone, and 119 (4%) received both ST and RT. After PSM, ST was not prognostic on UVA while RT was prognostic on both UVA and multivariable analysis. After PSM, the 5-year OS was 84% for those who received RT and 79% for those who did not (P = .026). On subset analysis, these findings remained statistically significant for the head/neck/face cohort and the axilla/upper extremity cohort. After accounting for immortal time bias and performing PSM on this subset, the 5-year OS was 82% for those who received RT and 77% for those who did not (P = .047). CONCLUSIONS: In the overall cohort, RT improved OS compared with no RT, and ST was not a factor associated with OS. A radiation oncologist should be consulted for all patients with stage I NMZL for multidisciplinary decision making.

Loss of AID exacerbates the malignant progression of CLL.

Activation-induced cytidine deaminase (AID) has been implicated as both a positive and a negative factor in the progression of B cell chronic lymphocytic leukemia (CLL), but the role that it plays in the development and progression of this disease is still unclear. We generated an AID knockout CLL mouse model, AID-/-/Eµ-TCL1, and found that these mice die significantly earlier than their AID-proficient counterparts. AID-deficient CLL cells exhibit a higher ER stress response compared to Eµ-TCL1 controls, particularly through activation of the IRE1/XBP1s pathway. The increased production of secretory IgM in AID-deficient CLL cells contributes to their elevated expression levels of XBP1s, while secretory IgM-deficient CLL cells express less XBP1s. This increase in XBP1s in turn leads AID-deficient CLL cells to exhibit higher levels of B cell receptor signaling, supporting leukemic growth and survival. Further, AID-/-/Eµ-TCL1 CLL cells downregulate the tumor suppressive SMAD1/S1PR2 pathway and have altered homing to non-lymphoid organs. Notably, CLL cells from patients with IgHV-unmutated disease express higher levels of XBP1s mRNA compared to those from patients with IgHV-mutated CLL. Our studies thus reveal novel mechanisms by which the loss of AID leads to worsened CLL and may explain why unmutated CLL is more aggressive than mutated CLL.

A novel role of lysophosphatidic acid (LPA) in human myeloma resistance to proteasome inhibitors.

Lysophosphatidic acid (LPA) is a naturally occurring phospholipid that regulates cell proliferation, survival, and migration. However, its role on human multiple myeloma (MM) cells is largely unknown. In this study, we show that LPA, which is highly elevated in MM patients, plays an important role in protecting human MM cells against proteasome inhibitor (PI)-induced apoptosis. LPA bound to its receptor LPAR2 activated its downstream MEK1/2-ERK1/2 signaling pathway and enhanced oxidative phosphorylation (OXPHOS) in mitochondria in MM cells. Increased OXPHOS activity produced more NAD+ and ATP, reduced proteasome activity, and enhanced protein folding and refolding in endoplasmic reticulum (ER), leading to induction of MM resistance to PIs. Importantly, inhibiting LPAR2 activity or knocking out LPAR2 in MM cells significantly enhanced MM sensitivity to PI-induced apoptosis in vitro and in vivo. Interestingly, primary MM cells from LPA-high patients were more resistant to PI-induced apoptosis than MM cells from LPA-low patients. Thus, our study indicates that LPA-LPAR2-mediated signaling pathways play an important role in MM sensitivity to PIs and targeting LPA or LPAR2 may potentially be used to (re)sensitize patients to PI-based therapy.

Use of ifosfamide, carboplatin and etoposide in combination with brentuximab vedotin or romidepsin based on CD30 positivity in relapsed/refractory peripheral T-cell lymphoma.

BACKGROUND: Relapsed/refractory peripheral T-cell lymphoma (R/R PTCL) has a poor prognosis. Romidepsin (Ro) and brentuximab vedotin (Bv), combined with ifosfamide, carboplatin, and etoposide (ICE) has not been significantly studied in PTCL. AIM: We report outcomes of Bv-ICE in CD30 (+) and Ro-ICE in CD30 (-) R/R PTCL treated in "Blinded for peer review" Cancer Center. METHODS AND RESULTS: We retrospectively identified R/R PTCL patients treated with BV-ICE or romidepsin-ICE from May 2016 to September 2019. Out of 13 R/R PTCL patients, 6 were treated with Bv-ICE and 7 with Ro-ICE. Bv-ICE had an overall response rate (ORR) of 66.7%, with all the patients achieving a complete response. ORR was 71.4% for Ro-ICE with 57.1% of patients achieving a complete response. Two patients treated with Bv-ICE and three treated with Ro-ICE received transplantation. CONCLUSION: In our experience, treatment with Bv-ICE and Ro-ICE based on CD30 positivity is feasible and effective to treat patients with R/R PTCL.

RARγ activation sensitizes human myeloma cells to carfilzomib treatment through the OAS-RNase L innate immune pathway.

Proteasome inhibitors (PIs) such as bortezomib (Btz) and carfilzomib (Cfz) are highly efficacious for patients with multiple myeloma (MM). However, relapses are frequent, and acquired resistance to PI treatment emerges in most patients. Here, we performed a high-throughput screen of 1855 Food and Drug Administration (FDA)-approved drugs and identified all-trans retinoic acid (ATRA), which alone has no antimyeloma effect, as a potent drug that enhanced MM sensitivity to Cfz-induced cytotoxicity and resensitized Cfz-resistant MM cells to Cfz in vitro. ATRA activated retinoic acid receptor (RAR)γ and interferon-ß response pathway, leading to upregulated expression of IRF1. IRF1 in turn initiated the transcription of OAS1, which synthesized 2-5A upon binding to double-stranded RNA (dsRNA) induced by Cfz and resulted in cellular RNA degradation by RNase L and cell death. Similar to ATRA, BMS961, a selective RARγ agonist, could also (re)sensitize MM cells to Cfz in vitro, and both ATRA and BMS961 significantly enhanced the therapeutic effects of Cfz in established MM in vivo. In support of these findings, analyses of large datasets of patients' gene profiling showed a strong and positive correlation between RARγ and OAS1 expression and patient's response to PI treatment. Thus, this study highlights the potential for RARγ agonists to sensitize and overcome MM resistance to Cfz treatment in patients.

Post-Marketing Analysis of Peripheral Neuropathy Burden with New-Generation Proteasome Inhibitors Using the FDA Adverse Event Reporting System

Proteasome inhibitors (PIs) are an integral component of multiple myeloma therapies. Peripheral neuropathy (PN) is a well-knownconsequence of PIs, most frequently reported with earlier generations such as bortezomib (BTZ). There is a paucity of data highlighting the risk of developing PN with the new-generation PIs carfilzomib (CFZ) and ixazomib (IZB). This study evaluated reports of PN encountered with all three PIs using the Food and Drug Administration Adverse Event (AE) Reporting System (FAERS). Signal disproportionality analysis was reported using the reporting odds ratio (ROR) with 95% confidence interval (CI). PN was reported in a total of 2.1%, 5.0%, and 10.9% of AEs with CFZ, IZB, and BTZ, respectively. The ROR (95% CI) for PN secondary to BTZ, CFZ, and IZB was 34.10 (32.76-35.49), 6.37 (5.50-7.37), and 14.97 (13.63-16.44), respectively. Compared to BTZ, CFZ and IZB have lower rates of reported PN, with RORs of 0.19 (0.16-0.22) and 0.48 (0.43-0.54), respectively.

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management.

Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac events that occur with CRS that may result in prolonged length of hospital stay, admission to the intensive care unit for pressor support, or cardiac death. This review focuses on the various manifestations of cardiotoxicity, potential risk factors, real world and clinical trial data on prevalence of reported cardiotoxicity events, and treatment recommendations.

G6PD deficiency and severity of COVID19 pneumonia and acute respiratory distress syndrome: tip of the iceberg?

The severe pneumonia caused by the human coronavirus (hCoV)-SARS-CoV-2 has inflicted heavy casualties, especially among the elderly and those with co-morbid illnesses irrespective of their age. The high mortality in African-Americans and males, in general, raises the concern for a possible X-linked mediated process that could affect the viral pathogenesis and the immune system. We hypothesized that G6PD, the most common X-linked enzyme deficiency, associated with redox status, may have a role in severity of pneumonia. Retrospective chart review was performed in hospitalized patients with COVID19 pneumonia needing supplemental oxygen. A total of 17 patients were evaluated: six with G6PD deficiency (G6PDd) and 11 with normal levels. The two groups (normal and G6PDd) were comparable in terms of age, sex, co-morbidities, and laboratory parameters-LDH, IL-6, CRP, and ferritin, respectively. Thirteen patients needed ventilatory support ; 8 in the normal group and 5 in the G6PDd group (72% vs.83%). The main differences indicating increasing severity in normal vs. G6PDd groups included G6PD levels (12.2 vs. 5.6, P = 0.0002), PaO2/FiO2 ratio (159 vs. 108, P = 0.05), days on mechanical ventilation (10.25 vs. 21 days P = 0.04), hemoglobin level (10 vs. 8.1 P = 0.03), and hematocrit (32 vs. 26 P = 0.015). Only one patient with G6PDd died; 16 were discharged home. Our clinical series ascribes a possible biological role for G6PDd in SARS-CoV2 viral proliferation. It is imperative that further studies are performed to understand the interplay between the viral and host factors in G6PDd that may lead to disparity in outcomes. KEY POINTS: • COVID19 studies show higher mortality in men, due to severe pneumonia and ARDS, indicating possible X-linked mediated differences • G6PD, the most common X-linked enzymopathy, highly prevalent in African Americans and Italians, maintains redox homeostasis. • Preclinical studies using G6PD deficient (G6PDd) cells infected with human coronavirus (hCoV), show impaired cellular responses, viral proliferation and worsening oxidative damage. • Retrospective chart review in hospitalized patients with COVID19 pneumonia needing supplemental oxygen shows differences between the two groups (Normal and G6PDd) in hematological indices; the G6PDdgroup demonstrated prolonged PaO2/FiO2 ratio, and longer days on mechanical ventilation indicating the severity of the pneumonia.

Clinical Outcomes Following Tocilizumab Administration in Mechanically Ventilated Coronavirus Disease 2019 Patients.

Effective treatments for the critically ill patient with novel coronavirus disease 2019 are desperately needed. Given the role of cytokine release syndrome in the pathogenesis of coronavirus disease 2019-associated respiratory distress, therapies aimed at mitigating cytokine release, such as the interleukin-6 receptor-inhibiting monoclonal antibody tocilizumab, represent potential treatment strategies. Therefore, we examined the outcomes of critically ill coronavirus disease 2019 patients treated with tocilizumab and factors associated with clinical improvement. DESIGN: A retrospective cohort analysis of 21-day outcomes for consecutive mechanically ventilated patients treated with tocilizumab from March 24, 2020, to May 4, 2020. SETTING: Nine ICUs at six hospitals within a hospital system in Houston, Texas, United States. PATIENTS: The first 62 coronavirus disease 2019 patients on invasive mechanical ventilation who were treated with tocilizumab, which was considered for all patients with severe disease. INTERVENTIONS: Tocilizumab was administered either at a weight-based dose of 4-8 mg/kg or at a flat dose of 400 mg, with repeat administration in some patients at the physician's discretion. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were mortality and clinical improvement, defined as extubation. By day 21 post-tocilizumab, clinical improvement occurred in 36 patients (58%) and 13 patients (21%) died. In both univariable and multivariable analyses, age less than 60 years was associated with clinical improvement. Transient transaminitis was the most common adverse reaction, occurring in 25 patients (40%). CONCLUSIONS: Based on clinical outcomes and mortality rates seen in previous reports of mechanically ventilated patients, tocilizumab, as part of the management strategy for severe coronavirus disease 2019, represents a promising option. These findings support the need for evaluation of tocilizumab in a randomized controlled trial.

Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors that block programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved outcomes for many cancer subtypes but do exhibit toxicity, in the form of immune-related adverse events. OBJECTIVE: The aim of this study was to investigate the emerging toxicities of PD-1 and PD-L1 inhibitors including acute or reactivation of tuberculosis (TB) and atypical mycobacterial infection (AMI). METHODS: This study was completed as a retrospective review using the US Food and Drug Administration Adverse Events Reporting System (FAERS) for incidence of TB and AMI due to PD-1 and PD-L1 inhibitors compared with other FDA (Food and Drug Administration) approved drugs. The statistical methods included disproportionality signal analysis using the reporting OR (ROR) to compare cases. The 95% Wald CI was reported to assess the precision of the ROR. RESULTS: Out of the 10 146 481 adverse events (AEs) reported to FAERS for all drugs between 1 January 2015 and 31 March 2020, 73 886 AEs were due to the five FDA approved PD-1/PD-L1 inhibitors. Seventy-two cases of TB were due to PD-1/PD-L1 inhibitors. Specifically, 45 cases (62.5%) due to nivolumab, 18 (25%) due to pembrolizumab, 5 (7%) due to atezolizumab and 4 (5.5%) due to durvalumab. There were 13 cases of AMI: 9 (69.3%) due to nivolumab, 2 (15.3%) due to pembrolizumab and 1 (7.7%) each due to durvalumab and atezolizumab. Avelumab was not attributed to any AE of TB or AMI. From analysis of the FAERS database, the calculated ROR for TB due to PD-1/PD-L1 inhibitors was 1.79 (95% CI, 1.42 to 2.26) (p<0.0001) and for AMI was 5.49 (95% CI, 3.15 to 9.55) (p<0.0001). CONCLUSION: PD-1/PD-L1 inhibitors used in the treatment of cancer subtypes is associated with increased TB and AMI risk. Although this complication is rare, clinicians using PD-1/PD-L1 inhibitors should be aware of the risks.

Recurrent small bowel obstruction caused by Burkitt lymphoma in an elderly man: a case report and review of the literature.

BACKGROUND: Acute small bowel obstruction is a common surgical emergency usually caused by abdominal adhesions, followed by intraluminal tumors from metastatic disease. Although lymphomas have been known to cause bowel obstruction, Burkitt lymphoma is seldom reported to induce an obstruction in the adult population. CASE PRESENTATION: A 78-year-old Hispanic man with a history of abdominal interventions presented to our hospital with abdominal pain. Computed tomography revealed a partial small bowel obstruction attributed to local inflammation or adhesions. Medical management with bowel rest and nasogastric decompression resulted in resolution of symptoms and quick discharge. He returned 2 days later with worsening abdominal pain. Repeat imaging showed progression of the partial small bowel obstruction, but with an additional 1.6-cm nodular density abutting the anterior aspect of the gastric antrum and lobulated anterior gastric antral wall thickening. He was taken to the operating room, where several masses were found. Intraoperative frozen sections were consistent with lymphoma, and pathology later revealed Burkitt lymphoma. Disease was found on both sides of the diaphragm by positron emission tomography. After the initial resection and adjuvant chemotherapy, the patient is alive and well about 14 months after resection. CONCLUSIONS: Small bowel obstruction is uncommonly due to Burkitt lymphoma in the geriatric population and is more frequently seen in the pediatric and young adult populations. Burkitt lymphoma is very aggressive with rapid cell turnover leading to significant morbidity. The rapid recurrence of an acute abdominal process should prompt an investigation for a more sinister cause such as malignancy.

Radiation therapy in primary mediastinal large B-cell lymphoma treated with DA-R-EPOCH.

DA-R-EPOCH is used in PMBCL due to its good outcomes without radiation. We present three cases that required consolidation with radiation despite using this regimen. More studies are needed before considering DA-R-EPOCH standard of care.

MIF as a biomarker and therapeutic target for overcoming resistance to proteasome inhibitors in human myeloma.

Multiple myeloma (MM) remains largely incurable despite significant advances in biotherapy and chemotherapy. The development of drug resistance is a major problem in MM management. Macrophage migration inhibitory factor (MIF) expression was significantly higher in purified MM cells from relapsed patients than those with sustained response, and MM patients with high MIF had significantly shorter progression-free survival (PFS) and overall survival (OS). MM cell lines also express high levels of MIF, and knocking out MIF made them more sensitive to proteasome inhibitor (PI)-induced apoptosis not observed with other chemotherapy drugs. Mechanistic studies showed that MIF protects MM cells from PI-induced apoptosis by maintaining mitochondrial function via suppression of superoxide production in response to PIs. Specifically, MIF, in the form of a homotrimer, acts as a chaperone for superoxide dismutase 1 (SOD1) to suppress PI-induced SOD1 misfolding and to maintain SOD1 activity. MIF inhibitor 4-iodo-6-phenylpyrimidine and homotrimer disrupter ebselen, which do not kill MM cells, enhanced PI-induced SOD1 misfolding and loss of function, resulting in significantly more cell death in both cell lines and primary MM cells. More importantly, inhibiting MIF activity in vivo displayed synergistic antitumor activity with PIs and resensitized PI-resistant MM cells to treatment. In support of these findings, gene-profiling data showed a significantly negative correlation between MIF and SOD1 expression and response to PI treatment in patients with MM. This study shows that MIF plays a crucial role in MM sensitivity to PIs and suggests that targeting MIF may be a promising strategy to (re)sensitize MM to the treatment.

The development of T-cell malignancies in patients with pre-existing myeloproliferative neoplasms: a report of three cases.

Secondary acute myeloid leukaemia complicating the natural disease course of pre-existing Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) is well documented and associated with treatment challenges and significant morbidity. The incidence of a T-cell malignancy developing in patients with pre-existing PN-MPN is uncommon, with one case documented in the literature. We present two cases of angioimmunoblastic T-cell lymphoma (AITL) and one case of T-cell acute lymphoblastic leukaemia (T-ALL) that developed in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), respectively. All malignancies were advanced at diagnosis and exhibited disease progression, regardless of the mutational status of the underlying ET/PMF, presence of cytogenetic abnormalities, type of T-cell neoplasm or systemic chemotherapy utilised. The median time to diagnosis of AITL or T-ALL from the onset of MPN was 4.5 years (range: 6 months-10 years). This single institutional case series demonstrates the possibility of an association between T-cell neoplasms and PN-MPNs.

T-cell lymphoma secondary to checkpoint inhibitor therapy.

BACKGROUND: Murine model suggests programmed cell death-1 (PD-1), an immune checkpoint not only plays role in tumor escape but is also a tumor suppressor for T-cells. But until, no reports of secondary T-cell lymphoma postuse of immune checkpoint inhibitors (ICIs) has been reported. Herein, we present a hitherto unreported phenomenon of secondary T-cell lymphoma when PD-1 inhibitor was used in a patient diagnosed with a tumor of epithelial origin. CASE REPORT: A man in mid-70s presented with biopsy-proven metastatic tumor of epithelial origin. Patient received carboplatin in combination with paclitaxel for four cycles leading to partial remission. The patient was subsequently switched to pembrolizumab due to persistent disease in the mediastinum. After four cycles of PD-1 inhibitor, patient presented with progression of disease and was diagnosed with biopsy-proven peripheral T-cell lymphoma-not otherwise specified. Based on the reported tumor suppressor function of PD-1 in murine models, we hypothesized that the use of PD-1 inhibitor caused clonal proliferation of abnormal T-cell clone leading to T-cell lymphoma. T-cell receptor (TCR) sequencing was performed by TCRß sequencing and T-cell clones from pre-ICI treatment specimen were compared with post-ICI treatment specimens. We show that one of the T-cell clones present in pre-ICI treatment specimen at a low frequency of had massive expansion to become most dominant clone in post-ICI treatment specimens leading to lymphoma. Moreover, targeted exome sequencing revealed a new TET2 mutation in the clone representing the lymphoma.Next, we retrospectively reviewed the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), the pharmacovigilance database from 2012 to 2018 to find the reported incidence of this phenomenon and calculated the reporting OR (ROR) for disproportionality analysis for risk of T-cell lymphoma due to checkpoint inhibitors compared with other drugs. In FAERS, the incidence of T-cell lymphoma post-ICIs (pembrolizumab, nivolumab and ipilimumab) was found to be 0.02% with 17% mortality. The ROR probability of risk of T-cell lymphoma compared with other drugs in pharmacovigilance database was increased at 1.91. CONCLUSIONS: T-cell lymphoma is a rare sequela of ICIs with high mortality. Larger studies with long-term follow-up of patients receiving ICIs is needed.

Mycobacterial Infections With Ruxolitinib: A Retrospective Pharmacovigilance Review.

BACKGROUND: Ruxolitinib is a selective Janus kinase inhibitor (JAKI) 1/2 approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV). These patients may be at risk for developing opportunistic infections. We assessed the number of patients that developed typical (Mycobacterium tuberculosis [MTB]) and atypical mycobacterial infections (AMI) while on treatment with ruxolitinib by utilizing the United States Food and Drug Administration (FDA) adverse events reporting system (FAERS). MATERIALS AND METHODS: This is a retrospective study utilizing FAERS, a pharmacovigilance database. We queried FAERS for cases of MTB and AMI secondary to ruxolitinib between January 1, 2011 and December 31, 2018. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). ROR was considered significant when the lower limit of 95% confidence interval (CI) was > 1. RESULTS: There were 91 reported cases of MTB associated with ruxolitinib compared with 4575 cases from all other drugs. The ROR was significant at 9.2 (95% CI, 7.5-11.4). There were 23 reports of AMI with ruxolitinib compared with 1287 reported with all other drugs. The ROR was significant at 8.3 (95% CI, 5.5-12.6). Twelve (13.2%) patients with MTB and 8 (34.8%) with AMI died. CONCLUSION: Patients on ruxolitinib are at increased risk of developing MTB and AMI. Clinicians should be aware of this risk and consider screening patients for latent MTB prior to initiating ruxolitinib.

A Case of Histiocytic Sarcoma Arising from Mycosis Fungoides.

Histiocytic sarcoma (HS) is an uncommon malignant neoplasm arising from mature histiocytes and most commonly characterized by the immunophenotypic expression of CD68, CD163, or lysozyme. Although rare, HS arising as a second primary malignancy following hematolymphoid neoplasms has been reported. To our knowledge, this is the first reported case of HS occurring as a second primary malignancy in a patient with mycosis fungoides (MF), with the retained immunophenotype markers CD30 and CD4.