Evaluation of palonosetron, fosaprepitant, and olanzapine as antiemetic prophylaxis for fludarabine and melphalan-based conditioning regimens prior to allogeneic hematopoietic stem cell transplants.

BACKGROUND: Limited data are available regarding efficacious antiemetic regimens to prevent chemotherapy-induced nausea and vomiting (CINV) for patients undergoing allogeneic hematopoietic stem cell transplant (HSCT). In patients aged 60 years or older, allogeneic HSCT is associated with improved survival, but tolerability of the transplant is a significant barrier. Fludarabine and melphalan (Flu-Mel) is a frequently utilized multi-day reduced intensity conditioning regimen for allogeneic HSCT. However, the optimal CINV prevention regimen is unknown. OBJECTIVE: The purpose of this study was to evaluate the efficacy of a novel CINV prophylaxis regimen prior to allogeneic HSCT with Flu-Mel compared to a historical control group. STUDY DESIGN: This was a retrospective, single-center, cohort review of 123 patients who received a Flu-Mel preparative regimen prior to allogeneic HSCT from January 1, 2019, to September 30, 2022. Fifty-nine patients received high dose ondansetron (HDO) for CINV prevention, while sixty-four patients received a combination of palonosetron, fosaprepitant, and olanzapine (PFO). The primary outcome was average number of rescue antiemetic doses administered per day. A key secondary outcome was time to first rescue antiemetic. RESULTS: The median number of antiemetic doses used per day was significantly lower in patients who received PFO compared to HDO (1.94 doses [0.31-3.60] vs 3.31 doses [1.61-4.92]; p = 0.002). In addition, use of PFO significantly prolonged the median time to first rescue antiemetic compared to HDO (41.3 h [24.3-122.7] vs 26.2 h [14.7-48.1]; p = 0.016). CONCLUSION: The combination of palonosetron, fosaprepitant, and olanzapine is an effective antiemetic regimen for patients receiving a Flu-Mel-based preparative regimen.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Variant Acute Promyelocytic Leukemia Presenting Without Auer Rods Highlights the Need for Correlation with Cytogenetic Data in Leukemia Diagnosis.

Variant acute promyelocytic leukemia (vAPL) is a rare leukemia characterized by rearrangement between RARα and a non-PML partner gene. This type of leukemia can be difficult to recognize by histomorphologic evaluation, particularly in patients with few or no Auer rods, and by flow cytometry, but it can be identified by distinct cytogenetic features. Herein, we report on a patient with vAPL with t(11;17)(q23;q21) who presented an initial diagnostic challenge. Detailed flow cytometry findings are presented for this rare entity. Our case study also presents novel treatment (chemotherapy in combination with venetoclax) chosen based on mechanistic data from preclinical studies.

Gilteritinib: An FMS-like tyrosine kinase 3/AXL tyrosine kinase inhibitor for the treatment of relapsed or refractory acute myeloid leukemia patients.

Acute myeloid leukemia has recently undergone a significant transition into identifying and successfully inhibiting driver mutations leading to disease. One of the most common mutations in acute myeloid leukemia involves the protein FMS-like tyrosine kinase 3 (FLT3), which leads to ligand-independent activation of intracellular signaling cascades leading to the survival and proliferation of the acute leukemia blast cell. Preclinical studies have demonstrated the presence of two dominant types of mutations of this protein: internal tandem duplication and tyrosine kinase domain mutations. Successful inhibition of this protein has proven to be challenging. While FLT3 has been shown to be successfully inhibited and shown to improve overall survival in the frontline therapy of acute myeloid leukemia in combination with cytarabine and anthracycline, relapsed and refractory (R/R) patients have not been shown to be a successful population until recently. A phase III trial (ADMIRAL trial) demonstrated significant overall survival benefit in patients receiving gilteritinib compared to patients receiving salvage chemotherapy. This review will provide an overview of the preclinical, clinical, and practical use of gilteritinib in the treatment of patients with relapsed and refractory acute myeloid leukemia with FLT3 mutation.

Prospective Initiative to Reduce Mucosal Barrier Injuries and Bloodstream Infections in Patients With Hematologic Malignancy Receiving Inpatient Chemotherapy.

PURPOSE: Mucosal barrier injury (MBI) occurs during periods of prolonged neutropenia in patients receiving cytotoxic chemotherapy for hematologic malignancies. This can lead to laboratory-confirmed bloodstream infections (LCBIs) and subsequent complications, including sepsis, organ failure, and possible death. There are no published prevention strategies for MBI. The purpose of our proposal was to decrease our MBI-LCBI events per month by 25%. METHODS: A multidisciplinary team was assembled to achieve this proposal. Cause-and-effect diagrams in addition to Pareto charts were used to investigate potential interventions. Using Plan-Do-Study-Act (PDSA) cycles, multiple tests of change were designed over the course of 3 years. RESULTS: The number of baseline events per month for MBI-LCBIs was 1.1. With the completion of the first PDSA cycle, the MBI-LCBI events dropped to 1.0 event per month. A second PDSA cycle involving implementation of an oral care kit improved to 0.35 events per month. This unfortunately was not sustained, and a root cause analysis demonstrated that physician noncompliance with ordering the oral kit was the main reason. After the change of a physician-driven protocol to a nurse-driven protocol, the third PDSA cycle resulted in a decrease in MBI-LCBI events to 0.89 events per month. CONCLUSION: To our knowledge, this is the first published report of an intervention to prevent MBI-LCBI events. Through a multidisciplinary approach and with quality improvement tools, we were able to demonstrate a significant reduction in MBI-LCBI events.

Evaluation of cardiomyopathy in acute myeloid leukemia patients treated with anthracyclines.

BACKGROUND: Acute myeloid leukemia patients receive anthracycline-containing induction chemotherapy. Anthracyclines cause cardiotoxicity; however, there is a paucity of data reflecting the risk of cardiotoxicity in the acute myeloid leukemia population, and risk factors for development of reduced left ventricular ejection fraction are not well established in this population. METHODS: A retrospective cohort study of adult acute myeloid leukemia patients receiving anthracycline-containing induction chemotherapy between March 2011 and August 2017 was performed. Baseline and all additional cardiac monitoring within one year of induction were collected. Home medications and new medication initiation were determined via the electronic health record and new outpatient prescriptions. RESULTS: Of 97 evaluable patients, 25 (25.8%) developed reduced left ventricular ejection fraction and 18 (18.6%) experienced clinical heart failure within one year of induction. The median difference from baseline to lowest left ventricular ejection fraction was -5.0 percentage points, with a range of +10.0 to -52.5. The median time to onset of reduced left ventricular ejection fraction was 27 days, at a median cumulative anthracycline dose of 270 mg/m2. No patient-specific or medication-specific factors were significantly associated with the risk of developing reduced left ventricular ejection fraction. Of 14 patients started on medical management for reduced left ventricular ejection fraction, 10 (71%) responded to therapy. CONCLUSIONS: In this retrospective analysis, we observed that acute myeloid leukemia patients experienced reduced left ventricular ejection fraction more quickly and at lower doses than previously reported in the solid tumor population. Reduced left ventricular ejection fraction was at least partially reversible in most patients started on medical management. Although no factors were significantly associated with decreased cardiomyopathy risk, future assessment of cardioprotective medications may be warranted.

A prospective study on urine alkalization with an oral regimen consisting of sodium bicarbonate and acetazolamide in patients receiving high-dose methotrexate.

PURPOSE: Intravenous (IV) sodium bicarbonate is typically used in alkalization regimens for the safe use of the chemotherapeutic agent high-dose methotrexate (HDMTX). Urine parameters including urine output and pH are important in order to minimize the risk of kidney injury, which increases adverse effects and hospital length of stay following HDMTX. IV sodium bicarbonate has been on shortage, and there are limited literature describing the safety of alternative regimens. PATIENTS AND METHODS: A single institution, prospective analysis of non-Hodgkin's lymphoma and acute lymphoblastic leukemia patients receiving HDMTX for central nervous system (CNS) prophylaxis or disease. Patients received an oral (PO) regimen of sodium bicarbonate and acetazolamide to achieve a urine pH >7. This cohort was compared to a subsequent IV sodium bicarbonate control cohort. Multiple co-primary safety outcomes assessed the incidences of acute kidney injury and delayed methotrexate clearance as well as change in liver function tests. Secondary outcomes included time to urine pH, time to urine output, and length of stay. RESULTS: A total of 126 encounters were studied for the primary safety outcome. There was no difference between AKI incidence in patients receiving the PO alkalization regimen compared to patients receiving IV sodium bicarbonate (14.5% vs 9.3%, respectively, P=0.41). There was no difference in methotrexate clearance between the PO and IV groups (26.5% vs 37.2%, respectively, P=0.21). The use of PO alkalization regimen is estimated to have saved 2002 vials of IV sodium bicarbonate and was approximately US$226 less expensive per encounter. CONCLUSION: This analysis supports the use of PO regimens to achieve urine alkalization necessary for safe administration of HDMTX during periods of IV sodium bicarbonate shortage. Further studies may determine optimal dosing strategies that decrease length of stay and ensure noninferiority of efficacy outcomes with PO regimens for urine alkalization with HDMTX.

Multidisciplinary Effort to Decrease Time From Admission to Chemotherapy on an Inpatient Oncology Unit.

There are no national standards for time between patient arrival and the initiation of scheduled chemotherapy (time to chemotherapy [TTC]). Delays in this process have a negative impact on patient care and the use of health care resources. At the University of Virginia Cancer Center, mean TTC in 2015 was 12.1 hours and mean length of stay (LOS) was 5.45 days at baseline. We formed a multidisciplinary team that participated in ASCO's Quality Training Program. We aimed to improve TTC by 10% over 6 months. We used Plan-Do-Study-Act (PDSA) cycles as quality improvement (QI) models and used XmR charts to evaluate the interventions. The first PDSA cycle involved amending the chemotherapy consent process; mean TTC and LOS improved to 9.3 hours and 4.65 days, respectively. The second PDSA cycle involved shifting pharmacist review of chemotherapy orders to before admission rather than after patient arrival. Mean TTC remained at 9.4 hours (net 22% improvement from baseline) and LOS improved to 4.33 days (net 21% improvement). Our team surpassed the 10% improvement goal for TTC. This QI project faced a few limitations. Our baseline data set was a retrospective cohort review. In addition, oncology patients have a wide range of individual clinical needs that may have an impact on TTC. Delays in TTC have an impact on oncologic care at many medical centers. Our project highlights the need for guidance on this issue. We recommend that other institutions form multidisciplinary teams and also use QI tools to assess delays and implement changes.

Establishing an Antifungal Program to Reduce Invasive Fungal Infections in Patients With Acute Myeloid Leukemia Receiving Induction and Reinduction Chemotherapy.

PURPOSE:: Twenty percent of patients with acute myeloid leukemia (AML) undergoing induction or reinduction chemotherapy at the University of Virginia Health System from May 2011 to August 2014 had a proven or probable invasive fungal infection (IFI). The purpose of our initiative was to reduce the percentage of proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy at the University of Virginia Health System to 10% or less by June 2017, in concordance with national averages. METHODS:: A multidisciplinary team was formed to lead the comprehensive quality improvement (QI) initiative. The team generated both current process state and ideal process state workflow diagrams, a cause-and-effect diagram, and a Pareto diagram to determine the most relevant etiology for proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy. RESULTS:: Analysis led to the creation of a program standardizing antifungal prophylaxis in this patient population, along with a suggested work-up for recalcitrant fevers. Through two tests of change (Plan-Do-Study-Act cycles 1 and 2), the QI initiative was able to effectively reduce the proven or probable IFI rate to 0% since program implementation in August 2016, thus surpassing both QI initiative goals and national rates of IFI. Mean length of stay (LOS) decreased by 3.4 days, and median intensive care unit LOS decreased by 2 days. CONCLUSION:: Creation of a standardized antifungal prophylaxis program led to a marked decrease in LOS and the proven or probable IFI rate of patients with AML undergoing induction or reinduction chemotherapy.

Impact of blinatumomab on patient outcomes in relapsed/refractory acute lymphoblastic leukemia: evidence to date.

Relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is associated with a poor prognosis in both children and adults. Traditionally, there were limited options for salvage therapy, which consisted mostly of conventional chemotherapy. However, in the past 5 years, novel agents have changed our treatment strategies in this population. Blinatumomab, a bispecific CD19 directed CD3 T-cell engager, has shown to be effective in both minimal residual disease and R/R B-cell ALL. In R/R B-cell ALL, blinatumomab was associated with an improved median overall survival of 7.7 months vs 4.0 months with traditional chemotherapy (HR for death, 0.71; 95% CI, 0.55-0.93; P=0.01). It has distinctive side effects as compared to chemotherapy, specifically cytokine release syndrome and neurological toxicities. When compared to standard of care chemotherapy, patients have higher quality of life scores and less financial burden. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, blinatumomab-treated patients fared better and had a longer time to deterioration or death (global health status/quality of life subscale: HR 0.66; 95% CI 0.48-0.92; P=0.009) compared to conventional chemotherapy. Using an incremental cost effective ratio threshold of US$150,000 per quality adjusted life year, blinatumomab was determined to be more cost effective compared to chemotherapy with a probability of 73.7%. This review summarizes the current and future data with blinatumomab in R/R B-cell ALL in the adult and pediatric population.

Risk of Major Bleeding with Ibrutinib.

BACKGROUND: The Bruton tyrosine kinase inhibitor, ibrutinib, is an effective therapy against mature B-cell malignancies. Although generally well tolerated, serious bleeding emerged during developmental clinical trials as an unexpected, although uncommon, adverse event. As the use of ibrutinib increases outside of the clinical trial setting and in patients with more comorbidities, the rate of major bleeding could be greater. MATERIALS AND METHODS: A retrospective analysis the data from all patients at our center and its regional clinics who had been prescribed ibrutinib from January 2012 to May 2016 were reviewed for demographic data, comorbid illnesses, bleeding events, and concurrent medications. RESULTS: We identified 70 patients. Bleeding of any grade occurred in 56% of patients, mostly grade 1 to 2 bruising and epistaxis. Major bleeding, defined as grade ≥ 3, occurred in 19% of patients, greater than previously reported. Anemia (hemoglobin < 12 g/dL; hazard ratio [HR], 5.0; 95% confidence interval [CI], 1.4-18.2; P = .02) and an elevated international normalized ratio (> 1.5; HR, 9.5; 95% CI, 2.7-33.5; P < .01) at ibrutinib initiation were associated with an increased risk of major bleeding. Of those with major bleeding, most patients were also taking an antiplatelet agent (70%), an anticoagulant (17%), or a CYP 3A4 inhibitor (7%), with 13% taking both antiplatelet and anticoagulant medications. The use of both antiplatelet and anticoagulant therapy significantly increased the risk of a major bleed event (HR, 19.2; 95% CI, 2.3-166.7; P < .01). CONCLUSION: The results of the present study have demonstrated a greater rate of major bleeding with ibrutinib use in a standard clinical setting than previously reported. Patients with anemia or an elevated international normalized ratio or requiring anticoagulant and/or antiplatelet medications during ibrutinib therapy have a significantly increased risk of major bleeding. Careful consideration of the risks and benefits for this population is needed. The combination of antiplatelet and anticoagulation medications with ibrutinib therapy is of particular concern.

Pharmacokinetics and antitumor efficacy of XMT-1001, a novel, polymeric topoisomerase I inhibitor, in mice bearing HT-29 human colon carcinoma xenografts.

PURPOSE: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors. EXPERIMENTAL DESIGN: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography-tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT. RESULTS: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11. CONCLUSIONS: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11.