Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via ß2-adrenergic receptor (ß2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using ß2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

Impact of primary organ site of involvement by peripheral T-cell lymphoma not otherwise specified on survival.

INTRODUCTION: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a rare, highly heterogeneous group of mature T-cell neoplasms that historically has been associated with poor outcomes. We sought to investigate the influence of primary disease site on PTCL-NOS outcomes using a large national cancer registry. METHODS: Baseline clinical and demographic data including primary organ of involvement and Ann Arbor disease stage were extracted from the SEER database. Patients were grouped into nine organ system groups and compared to nodal disease acting as a control. Cox regression models were utilized for adjusted survival analyses. RESULTS: A total of 3095 patients were identified in the SEER database and included in the final analysis. The median age was 61 and a majority of patients were male (60%) and identified as non-Hispanic white (68%). A plurality of patients had stage IV disease (32%). Lymph nodes and spleen were the most common primary disease sites (67%), while central nervous system was the least common (1%). Patients with early-stage PTCL-NOS of the gastrointestinal/genitourinary systems had worse overall survival [HR = 1.97 (1.50-2.59); p < 0.001] and lymphoma-specific survival [HR = 1.74 (1.26-2.40); p < 0.001] which was statistically significant even after adjusting for other variables. Early-stage PTCL-NOS of the central nervous system also had worse overall survival [HR = 1.90 (1.11-3.27); p = 0.020] and lymphoma-specific survival [HR = 2.11 (1.17-3.80); p = 0.013]. Early-stage PTCL-NOS of the skin had better overall survival [HR = 0.54 (0.42-0.68); p < 0.001] and lymphoma-specific survival [HR = 0.388 (0.28-0.53); p < 0.001] which was statistically significant even after adjustments. CONCLUSION: Our findings suggest an association between primary organ involved by PTCL-NOS and both overall and lymphoma-specific survival even after adjusting for common variables. These results warrant validation in future prospective studies.

Impact of Race and Age and their Interaction on Survival Outcomes in Patients With Diffuse Large B-Cell Lymphoma.

BACKGROUND: Advances in treatment for patients with Diffuse Large B-Cell Lymphoma (DLBCL) have led to improved patient outcomes but the magnitude of these disparities remains understudied with regards to improved survival outcomes. We sought to describe changes in DLBCL survival trends over time and explore potential differential survival patterns by patients' race/ethnicity and age. METHODS: We utilized the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with DLBCL from 1980 to 009 and determined 5-year survival outcomes for all patients, categorizing patients by year of diagnosis. We used descriptive statistics and logistic regression, adjusting for stage and year of diagnosis, to describe changes in 5-year survival rates over time by race/ethnicity and age. RESULTS: We identified 43,564 patients with DLBCL eligible for this study. Median age was 67 years (ages: 18-64 = 44.2%, 65-79 = 37.1%, 80 + = 18.7%). Most patients were male (53.4%) and had advanced stage III/IV disease (40.0%). Most patients were White race (81.4%), followed by Asian/Pacific Islander (API) (6.3%), Black (6.3%), Hispanic (5.4%), and American Indian/Alaska Native (AIAN) (0.05%). Overall, the 5-year survival rate improved from 35.1% in 1980 to 52.4% in 2009 across all races and age groups (odds ratio [OR] for 5-year survival with increasing year of diagnosis = 1.05, P < .001). Patients in racial/ethnic minority groups (API: OR = 0.86, P < .0001; Black: OR = 0.57, P < .0001; AIAN: OR = 0.51, P = .008; Hispanic: 0.76, P = 0.291) and older adults (ages 65-79: OR = 0.43, P < .0001; ages 80+: OR = 0.13, P < .0001) had lower 5-year survival rates after adjusting for race, age, stage, and diagnosis year. We found consistent improvement in the odds of 5-year survival for year of diagnosis across all race and ethnicity groups (White: OR = 1.05, P < .001; API: OR = 1.04, P < .001; Black: OR = 1.06, p<.001; AIAN: OR = 1.05, P < .001; Hispanic: OR = 1.05, P < .005) and age groups (ages 18-64: OR = 1.06, P < .001; ages 65-79: OR = 1.04, P < .001; ages 80+: OR = 1.04, P < .001). CONCLUSION: Patients with DLBCL experienced improvements in 5-year survival rates from 1980 to 2009, despite persistently lower survival among patients in racial/ethnic minority groups and older adults.

Prediction of life-threatening and disabling bleeding in patients with AML receiving intensive induction chemotherapy.

Bleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define the incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were retrospectively assessed between day-14 and day +60 of induction treatment according to the World Health Organization (WHO) bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Predictors were considered pretreatment or prior to grade 4 bleeding. Using multivariable competing-risk regression analysis with grade 4 bleeding as the primary outcome, we identified risk factors in the development cohort (n = 341), which were tested in an independent cohort (n = 143). Grade 4 bleeding occurred in 5.9% and 9.8% of patients in the development and validation cohort, respectively. Risk factors that were independently associated with grade 4 bleeding included baseline platelet count ≤40 × 109/L compared with >40 × 109/L, and baseline international normalized ratio of prothrombin time (PT-INR) >1.5 or 1.3 > 1.5 compared with ≤1.3. These variables were allocated points, which allowed for stratification of patients with low- and high-risk for grade 4 bleeding. Cumulative incidence of grade 4 bleeding at day+60 was significantly higher among patients with high- vs low-risk (development: 31 ± 7% vs 2 ± 1%; P < .001; validation: 25 ± 9% vs 7 ± 2%; P = .008). In both cohorts, high bleeding risk was associated with disseminated intravascular coagulation (DIC) and proliferative disease. We developed and validated a simple risk model for grade 4 bleeding, which enables the development of rational risk mitigation strategies to improve early mortality of intensive induction treatment.

Comparing thermal stress reduction strategies that influence MDSC accumulation in tumor bearing mice.

Myeloid derived suppressor cells (MDSCs) are a diverse collection of immune cells that suppress anti-tumor immune responses. Decreasing MDSCs accumulation in the tumor microenvironment could improve the anti-tumor immune response and improve immunotherapy. Here, we examine the impact of physiologically relevant thermal treatments on the accumulation of MDSCs in tumors in mice. We found that different temperature-based protocols, including 1) weekly whole-body hyperthermia, 2) housing mice at their thermoneutral temperature (TT, ~30 °C), and 3) housing mice at a subthermoneutral temperature (ST,~22 °C) while providing a localized heat source, each resulted in a reduction in MDSC accumulation and improved tumor growth control compared to control mice housed at ST, which is the standard, mandated housing temperature for laboratory mice. Additionally, we found that low dose ß-adrenergic receptor blocker (propranolol) therapy reduced MDSC accumulation and improved tumor growth control to a similar degree as the models that relieved cold stress. These results show that thermal treatments can decrease MDSC accumulation and tumor growth comparable to propranolol therapy.

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

PURPOSE: Increased ß-adrenergic receptor (ß-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly ß2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective ß-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. PATIENTS AND METHODS: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. RESULTS: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. CONCLUSIONS: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.

The side effects of immune checkpoint inhibitor therapy on the endocrine system.

Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte-associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary-adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary-adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.

HYPOTHYROIDISM AND GOITER IN A YOUNG MALE WITH SUSPECTED DIETARY IODINE DEFICIENCY FOLLOWED BY THYROTOXICOSIS AFTER IODINE SUPPLEMENTATION.

OBJECTIVE: Iodine deficiency disorders (IDDs) remain a major public health concern in most parts of the world but are extremely rare in North America. We describe a case of goiter in a young male with dietary history and findings suggestive of IDD. METHODS: Laboratory and imaging procedures including thyroid function tests, autoantibodies, urine iodine, thyroid ultrasound, and radioactive iodine (RAI) uptake scan were performed. RESULTS: On initial presentation, thyroid-stimulating hormone (TSH) was 24.4 mIU/L (normal range is 0.4 to 5.0 mIU/L), free thyroxine was <0.4 ng/dL (normal range is 0.8 to 1.8 ng/dL), and thyroid peroxidase antibody was positive at 43 IU/mL (normal range is <35 IU/mL). He reported consuming strawberries and peanut butter sandwiches with no intake of dairy or seafood due to gastrointestinal issues (abdominal pain, bloating, and nausea). Physical exam revealed a diffusely enlarged, palpable thyroid gland (grade II goiter). Ultrasound of the neck showed an enlarged thyroid gland with no nodules. RAI uptake scan showed diffuse increased uptake (91%). Given his poor diet, a 24-hour urinary iodine excretion test was ordered which was suggestive of very low iodine intake. He was started on multivitamins with 150 µg of iodine daily. On follow up, clinical exam showed grade I goiter and TSH had normalized to 0.7 mIU/L and free thyroxine was 1.2 ng/dL. He continued on iodine supplementation and tolerated iodine-rich foods. Six months later, thyroid function tests showed hyperthyroidism with TSH of <0.002 ng/dL and free thyroxine was elevated to 2.8 ng/dL. Iodine supplements were stopped. CONCLUSION: Hypothyroidism and goiter due to IDD should be suspected in the setting of poor dietary intake. IDDs can be rapidly diagnosed in a patient on a restricted diet with multiple urinary iodine determinations and RAI study. Regular thyroid labs should be done to monitor for hyperthyroidism that can develop after iodine supplementation.

Diffuse large B-Cell lymphoma associated with paraneoplastic Guillain-Barré syndrome: A diagnostic and therapeutic challenge.

Paraneoplastic neurological syndromes are a rare manifestation of non-Hodgkin lymphoma and can make treatment of these patients more challenging. We report the case of a 67-year-old man with high grade diffuse large B-cell lymphoma who presented with severe paraneoplastic Guillain-Barré syndrome. He was treated with intravenous immunoglobulin therapy and definitive chemoimmunotherapy, and achieved a full neurological recovery. In this report, we discuss various mechanisms of neurological dysfunction seen in lymphomas. Prompt oncologic treatment and immunotherapy for Guillain-Barré syndrome if instituted concurrently and early in the course of the disease can be associated with the best outcomes.

Mechanism-based treatment of cancer with immune checkpoint inhibitor therapies.

Immune checkpoints are cell surface molecules that initiate regulatory pathways which have powerful control of CD8+ cytolytic T cell activity. Antagonistic and agonistic antibodies engaging these molecules have demonstrated profound impact on immune activation and have entered clinical use for the treatment of a variety of diseases. Over the past decade, antagonistic antibodies known as immune checkpoint inhibitors have become a new pillar of cancer treatment and have reshaped the therapeutic landscape in oncology. These agents differ in their mechanism of action and toxicity profiles compared to more traditional systemic cancer treatments such as chemo- and targeted therapies. This article reviews the pharmacology of this new class of agents.

Impact of concomitant medication use and immune-related adverse events on response to immune checkpoint inhibitors.

Aim: Patients receiving checkpoint inhibitors (CPI) are frequently on other medications for co-morbidities. We explored the impact of concomitant medication use on outcomes. Materials & methods: 210 metastatic cancer patients on CPI were identified and association between concomitant medication use and immune-related adverse events with clinical outcomes was determined. Results: Aspirin, metformin, ß-blockers and statins were not shown to have any statistically significant difference on clinical benefit. 26.3% patients with clinical benefit developed rash versus 11.8% without clinical benefit (p < 0.05) on multivariate analysis. Conclusion: Use of common prescription and nonprescription medications in patients with multiple co-morbidities appears safe and does not have an adverse effect on CPI efficacy. The presence of rash predicted for a better response.

Metastatic sarcomatoid renal cell carcinoma treated with immune checkpoint inhibitors.

Introduction: Renal cell carcinoma (RCC) with sarcomatoid component carries a poor prognosis. Immune checkpoint inhibitors (CPIs) have been approved for the treatment of metastatic RCC, but their efficacy in patients with sarcomatoid component is not known. Materials and Methods: We conducted a retrospective chart review of 30 consecutive patients at our center who were treated for metastatic RCC with sarcomatoid component. Results: Ten patients were treated with CPI group while 20 patients were in No-CPI group. There were no significant differences in age, sex, race, and stage at diagnosis between the two groups. After a median follow-up of 35 months, 3 of 10 patients in CPI arm and 5 of 20 patients in No-CPI group were alive. The median overall survival was 33.8 m in immunotherapy group compared to 8.8 m in nonimmunotherapy group (p = .001). Discussion: In our experience, CPI therapy resulted in better outcomes compared to traditional therapy with molecular-targeted agents or chemotherapy in these patients.

Mechanism of resistance to immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) have revolutionized the management of cancer over the last decade. Instead of targeting the cancer cell directly these agents work by augmenting the immune response towards tumor. Although they are associated with improved responses compared to traditional treatments in several malignancies, a majority of the patients don't respond to ICIs even when used in the frontline setting. In patients who do respond, a significant number eventually develop resistance. We will review ICI mechanisms of action and resistance. We will also discuss new therapeutic options and combinations with other agents that are currently being evaluated to overcome resistance to ICI.

Challenges faced when identifying patients for combination immunotherapy.

In 1996, Jim Allison demonstrated that blocking the immune regulatory molecule CTLA-4 with anit-CTLA4 antibody led to enhance tumor responses in mice. It would take an additional 15 years for human studies to confirm the potency and clinical efficacy of anti-CTLA4, ultimately leading to US FDA approval of the first checkpoint inhibitor, ipilimumab. Now with a plethora of immune-modulating agents demonstrating single agent safety and benefit across many tumor types, investigation on the optimal combination of immune-based therapies has begun in earnest. While there are many challenges, a central one is how to select which combination for which patient is the best. Here we review the current approaches that a practitioner can use to achieve this therapeutic goal.

Remission of Severe, Relapsed, and Refractory TTP after Multiple Cycles of Bortezomib.

Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by autoantibodies against a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Uncleaved von Willebrand factor (VWF) multimers accumulate and bind to platelets which causes spontaneous microthrombi ultimately causing microangiopathic hemolytic anemia, thrombocytopenia, and end-organ ischemia. Plasma exchange (PEX) with or without steroids constitutes standard first-line therapy with rituximab typically reserved for refractory cases. Therapies beyond rituximab lack strong evidence for routine use. Recently, bortezomib, a proteasome inhibitor used commonly in patients with multiple myeloma, was shown to induce remission in patients with refractory TTP. Here, we report a case of severe, relapsed TTP that was refractory to PEX, steroids, and rituximab that underwent remission following three cycles of bortezomib. We discuss the salient features of our case, the mechanism of action of bortezomib, and the very few other similar reports that exist in the literature. We conclude that bortezomib should be considered for patients with TTP refractory to PEX, steroids, and rituximab due to its efficacy and relatively favorable side effect profile.