Effect of Levofloxacin Prophylaxis on Rates of Febrile Neutropenia in Patients Receiving DA-EPOCH-R Chemotherapy for Aggressive Lymphomas

Introduction: Febrile neutropenia (FN) is a serious potential adverse event of myelosuppressive chemotherapy. Dose-adjusted EPOCH-R (DA-EPOCH-R: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, with doses adjusted to induce neutropenia of < 0.5 x 10 9/L) is a chemoimmunotherapy regimen used for aggressive lymphomas including diffuse large B-cell lymphoma, double/triple hit, Burkitt, primary mediastinal, and HIV-associated large cell lymphoma. It is associated with high rates of FN (13-25% of cycles) despite use of prophylactic Septra and granulocyte colony stimulating factor (G-CSF). Fluoroquinolone antibiotics have been used in various hematological malignancies to reduce infection rates while on chemotherapy, but this strategy has never been reported with DA-EPOCH-R. This study was conducted to assess the impact of adding routine Levofloxacin prophylaxis on FN and infection rates in patients receiving DA-EPOCH-R. Methods: This is a combined cohort study comparing the patients who received DA-EPOCH-R for newly diagnosed aggressive lymphoma at the London Regional Cancer Program in London, Ontario, Canada before and after the initiation of routine Levofloxacin prophylaxis in July 2020. The prospective cohort received Levofloxacin 500 mg x 7 days with each cycle starting on cycle day 8 in addition to standard supportive care with Septra and G-CSF. The primary objective was the rate of febrile neutropenia. Secondary objectives included days hospitalized, deaths related to infections, and adverse events secondary to Levofloxacin. Results: Thirty patients who received DA-EPOCH-R in the 5 years preceding the initiation of routine prophylactic Levofloxacin were included in the retrospective cohort. Median age was 58 (range 18-79), 66% were male, and 90% had stage III/IV disease. Total number of cycles of DA-EPOCH-R received was 110, with a median of 4 cycles per patient (range: 1-6). FN developed in 14 patients (46%), and complicated a total of 20 cycles (18%) of DA-EPOCH-R. There were 19 hospital admissions due to FN, with a median duration of hospitalization of 12 days (range 3-120). Two patients died, both due to infection. Thirteen patients have been treated so far in the prospective cohort, 12 of whom received levofloxacin prophylaxis. Median age was 59 (range 23-69), 66% were male, and 76% had stage III/IV disease. Total number of cycles of DA-EPOCH-R received was 60, with a median of 5 cycles per patient (range: 1-6 ). Only 1 patient (8%) developed FN, which complicated a total of 3 cycles (5%) of chemotherapy. All 3 episodes of FN resulted in hospitalization for a median duration of 30 days (range 20-49). There have been no deaths due to infection in this cohort thus far. No concerning adverse effects from Levofloxacin have been observed. Conclusions: Although enrollment in the prospective cohort is ongoing, preliminary data are highly encouraging, with significantly lower rates of FN and death due to infection observed since the introduction of routine Levofloxacin prophylaxis. The addition of Levofloxacin to standard prophylaxis with Septra and G-CSF seems to be an effective way to mitigate the risks to patients on DA-EPOCH-R for aggressive lymphomas, and this strategy is worthy of further study. Disclosures Lam: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria.

Prevalence and predictors of pulmonary fungal infections in patients with acute leukemia and aggressive lymphomas: Implications for cancer care in developing countries

Objectives: Among patients receiving cancer therapy, pulmonary fungal infections (PFIs) are an important cause of morbidity and mortality. Identifying predictors of PFI can direct targeted prophylaxis to improve outcomes, especially in low- and middle-income countries (LMIC) with limited resources. The objectives of the study were to evaluate the predictors of PFI in hospitalized patients with hematological malignancies in the United States and implications for prioritizing anti-fungal care in LMIC. Materials and Methods: Using the 2018 National Inpatient Sample, we conducted a retrospective study of patients ≥18 years, with acute leukemia or aggressive lymphoma. Demographics and outcomes were compared between patients with and without PFI. Predictors of PFI were evaluated by regression analysis. Results: PFI was diagnosed in 1635 (0.8%) of 205,525 eligible hospitalizations and aspergillosis was noted in 1315 (80.4%) of PFI cases. Patients with acute myeloid leukemia (AML) accounted for 64.2% of cases of PFI. Patients with PFI, when compared with those without PFI, were younger, had higher Charlson comorbidity index, were more likely to be non-Caucasian, and to have AML. Patients with PFI had higher odds of respiratory failure, sepsis, and in-hospital mortality. Variables associated with PFI were Hispanic or native American origin (OR = 1.71; 95% CI: 1.21–2.42), Charlson comorbidity index ≥3 (OR = 1.52; 95% CI: 1.16–2.00), neutropenia (OR = 1.97; 95% CI: 1.58–2.46), malnutrition (OR = 2.30; 95% CI: 1.75–3.01), bone marrow transplant status (OR = 2.28, 95% CI: 1.53–3.39), and AML diagnosis (OR = 3.12; 95% CI: 2.40–4.05). Conclusions: This study identified variables associated with PFI in patients diagnosed with acute leukemia and aggressive lymphomas. In LMIC, where resources are scarce, patients with cancer who have the identified high-risk characteristics should be given priority for antifungal prophylaxis.

Pulmonary fungal infections in acute leukemias and aggressive lymphomas: Analysis of the United States National Inpatient Database.

e19042 Background: For patients undergoing intensive chemotherapy, pulmonary fungal infections (PFI) represent a major cause of morbidity and mortality. Our study examined predictors and outcomes of PFI in hospitalized patients (pts) with hematological malignancies in the current era of antifungal prophylaxis for high-risk patients. Methods: Using the 2018 National Inpatient Sample (NIS) database, we conducted a retrospective study of hospitalized pts aged ≥ 18 years, with acute leukemias or aggressive lymphomas. Hospitalizations were selected using International Classification of Disease, Tenth Revision (ICD-10) codes for leukemias, lymphomas and PFI (candidiasis, aspergillosis, cryptococcus, and mucormycosis). Demographics, comorbidities, and outcomes were compared between pts with and without PFI using Chi-squared test. Multivariable logistic regression was performed to explore predictors associated with PFI. Results: Of 205,525 hospitalizations that met the inclusion criteria, PFI was diagnosed in 1635 (0.8%). Frequent infections were aspergillosis (80%) and candidiasis (11%). Pts with acute myeloid leukemia (AML) accounted for 64% of all PFI. The PFI group, compared to non-PFI, were more likely to be non-Caucasian (39% vs 32%, p<0.05), have higher Charlson comorbidity index (CI) [64% vs 55%, p<0.01], longer mean length of stay (23 vs 9 days, p<0.001), and more likely to have AML (64% vs 33%, p<0.001). Pts with PFI had higher odds of acute respiratory failure, severe sepsis, and in-hospital mortality. Mortality rates for PFI and non-PFI group were 17% and 6% respectively (p<0.001). Predictors associated with PFI were Hispanic or Native American race, Charlson CI ≥ 3, neutropenia, malnutrition, bone marrow transplant status and diagnosis of AML (Table). Conclusions: Our study identified clinical variables that predicted for PFI in patients with acute leukemias and aggressive lymphomas. Pts with these high-risk characteristics should get priority for close surveillance, mold-specific prophylaxis, and antifungal therapeutic drug monitoring. Selected predictors associated with pulmonary fungal infections. Adjusted Odds ratio (OR).[Table: see text]

Strategies for introducing palliative care in the management of relapsed or refractory aggressive lymphomas

Recent advances in treatment of patients with aggressive lymphomas ranging from chimeric antigen receptor T-cell therapy to combination of antibody–drug conjugates with chemotherapy have improved survival outcomes. Despite these significant advances, patients with relapsed or refractory disease experience high physical and psychological symptom burden, and a substantial proportion still die of their lymphoma. In addition, end-of-life care outcomes are suboptimal with high rates of intensive end-of-life health care use and low rates of timely hospice enrollment. Integrating palliative care concurrently with disease-directed care for this patient population has strong potential to improve their symptom burden, quality of life, and end-of-life care. Multiple factors, including heightened prognostic uncertainty in the setting of relapsed/refractory disease, pose challenges to timely provision of palliative care. This article reviews benefits of primary and specialty palliative care for patients with relapsed/refractory aggressive lymphomas and barriers to such care. It also highlights strategies for effectively integrating palliative care for patients with relapsed/refractory aggressive lymphomas.

Targeting the Glucagon Receptor Signaling Pathway As a Novel Strategy to Counteract PI3K Inhibitor Induced Hyperglycemia While Sustaining Tumor PI3K Inhibition

Pathologic activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is an oncogenic driver for many malignancies, including lymphomas1. Although validated as a therapeutic oncologic target, the PI3K signaling pathway is also implicated in normal glucose homeostasis. Specifically, since the PI3K subunit p110α is chiefly responsible for downstream insulin receptor (INSR) signaling, PI3K signaling inhibition that includes p110α leads to severe hyperglycemia. Both compensatory endogenous insulin release as well as treatment of hyperglycemia with exogenous insulin/insulin mimetics activate INSR-associated PI3K signaling, ultimately limiting blockade of tumor associated PI3K signaling2. Aggressive lymphomas driven by pathologic PI3K signaling respond to combined PI3Kα and δ/γ inhibition, but this is likely submaximal due to endogenous insulin feedback, and more intense dosing is difficult to achieve safely due to severe hyperglycemia3. Therefore, a novel strategy to maintain blockade of tumor associated PI3K signaling while reducing hyperglycemia is needed. We hypothesized that inhibition of glucagon receptor (GCGR) signaling, a pathway that does not depend on PI3K, may normalize PI3K inhibitor induced hyperglycemia without disrupting antitumor PI3K blockade. GCGR blockade with a GCGR specific monoclonal antibody (REMD-477, a human anti-GCGR antibody, or REMD2.59c, a murine equivalent) may allow for the safer use of more potent PI3K inhibitors or more intensive dosing schedules in the treatment of aggressive lymphomas. The effect of GCGR blockade on PI3K inhibitor induced hyperglycemia was first evaluated in a non-tumor bearing mouse model using REMD2.59c. The PI3K inhibitor copanlisib was administered by tail vein injection to CB17 SCID mice in the control group every other day at the reported MTD of 15 mg/kg. REMD2.59c was administered by intraperitoneal injection to the treatment group intermittently on the day prior to copanlisib injection. Blood glucose levels were measured 2 hours after copanlisib injection. Significant hyperglycemia was observed after copanlisib treatment, and this was corrected by REMD2.59c pretreatment, confirming the effectiveness of GCGR blockade (Figure A-B). Having demonstrated that GCGR blockade controls hyperglycemia caused by PI3K inhibition with copanlisib in a mouse model, we next treated a 54 year old non-diabetic woman with relapsed and refractory peripheral T cell lymphoma (PTCL) on an IRB-approved clinical pilot study of copanlisib in combination with REMD-477. Following copanlisib 60mg IV alone, glucose increased from a baseline of 100mg/dl to a maximum of 592 mg/dl at 5 hours. For the following weekly doses of copanlisib, she was pre-treated with 70mg REMD-477 SQ, and copanlisib induced hyperglycemia was significantly ameliorated (Figure C). The patient tolerated treatment with REMD-477 well without significant episodes of hypoglycemia. With improved glycemic control on REMD-477, our patient did not require dose reductions or treatment delays, and experienced clinical improvement in lymphadenopathy on copanlisib. She had previously progressed through 6 lines of therapy, including duvelisib, a selective PI3K δ/γ inhibitor which necessitated dose reduction due to gastrointestinal toxicity. Our study of the GCGR mAb REMD-477 as a novel strategy to counteract PI3K inhibitor induced hyperglycemia and insulin feedback is an important advance that may allow for more effective and safer use of potent PI3K inhibitors in the treatment of aggressive lymphomas. References 1. Alzahrani AS. PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside. Semin Cancer Biol. 2019;59(April):125-132. doi:10.1016/j.semcancer.2019.07.009 2. Hopkins BD, Pauli C, Du X, et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature. 2018;560(7719):499-503. doi:10.1016/j.physbeh.2017.03.040 3. Cheson BD, O'Brien S, Ewer MS, et al. Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas. Clin Lymphoma, Myeloma Leuk. 2019;19(3):135-141. doi:10.1016/j.clml.2018.11.021 Figure 1. Disclosures Calzone: REMD Biotherapeutics: Current equity holder in private company. Yan:REMD Biotherapeutics: Current Employment, Current equity holder in private company. Thai:REMD Biotherapeutics: Current Employment, Current equity holder in private company. Lyerly:REMD Biotherapeutics: Consultancy, Current equity holder in private company. OffLabel Disclosure: Copanlisib in the treatment of peripheral T cell lymphoma