Comparing 2-day vs 3-day flu-CY lymphodepleting regimens for CD19 CAR T-cell therapy in patients with non-hodgkin's lymphoma.

Introduction: Lymphodepleting chemotherapy (LDC) is critical to CAR T-cell expansion and efficacy. Despite this, there is not a consensus in the literature regarding the optimal LDC regimen, including dose and frequency. Methods: We retrospectively reviewed consecutive patients at a single institution that received LDC prior to treatment with the CD19 directed CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel. Patients treated at our center received fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 for 3 consecutive days prior to May 2019. After this timepoint patients routinely received fludarabine 40 mg/m2 and cyclophosphamide 500 mg/m2 for 2 consecutive days. Clinical data from each cohort were obtained from the electronic medical record and compared for differences in CAR T-cell efficacy and toxicity. Results: From June 2018 to August 2023, LDC was given to 92 patients prior to CD19 directed CAR T-cell therapy for relapsed non-Hodgkin's lymphoma. Twenty-eight patients received a 3-day regimen, and 64 patients received a 2-day regimen. In the total cohort, 75% of patients received axicabtagene ciloleucel and 25% received tisagenlecleucel. The overall response rates in both the 2-day regimen group and the 3-day regimen group were similar (69% vs 75%, p= 0.21) as were the complete response rates (50% vs 54%, p=0.82). There were no significant differences between the 2-day and 3-day regimens for grade 2-4 cytokine release syndrome (55% vs 50%, p=0.82), grade 2-4 immune effector cell associated-neurotoxicity syndrome (42% vs 29%, p=0.25), or time to resolution of neutropenia or thrombocytopenia. The rate of prolonged platelet recovery lasting greater than 60 days was higher with the 3-day regimen (9% vs 27%, p=0.026). Discussion: As the number of patients eligible for CAR T-cell therapy continues to increase, optimizing each component of therapy is necessary. We show that a 2-day regimen of LDC with fludarabine and cyclophosphamide is feasible without significant impact on CAR T-cell efficacy or toxicity. Prospective studies are necessary to further determine the most effective LDC regimen.

Defibrotide Therapy for SARS-CoV-2 ARDS.

BACKGROUND: SARS-CoV-2-related ARDS is associated with endothelial dysfunction and profound dysregulation of the thrombotic-fibrinolytic pathway. Defibrotide is a polyanionic compound with fibrinolytic, antithrombotic, and antiinflammatory properties. RESEARCH QUESTION: What is the safety and tolerability of defibrotide in patients with severe SARS-CoV-2 infections? STUDY DESIGN AND METHODS: We report a prospective, open-label, single-center safety trial of defibrotide for the management of SARS-CoV-2-related ARDS. Eligible participants were 18 years of age or older with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-dimer of more than twice upper limit of normal, and positive polymerase chain reaction-based results for SARS-CoV-2. Defibrotide (6.25 mg/kg/dose IV q6h) was administered for a planned 7-day course, with serum D-dimer levels and respiratory function monitored daily during therapy. RESULTS: Twelve patients (median age, 63 years) were treated, with 10 patients receiving mechanical ventilation and 6 receiving vasopressor support at study entry. The median D-dimer was 3.25 µg/ml (range, 1.33-12.3) at study entry. The median duration of therapy was 7 days. No hemorrhagic or thrombotic complications occurred during therapy. No other adverse events attributable to defibrotide were noted. Four patients met the day 7 pulmonary response parameter, all four showing a decrease in serum D-dimer levels within the initial 72 h of defibrotide therapy. Three patients died of progressive pulmonary disease 11, 17, and 34 days after study entry. Nine patients (75%) remain alive 64 to 174 days after initiation of defibrotide. Day 30 all-cause mortality was 17% (95% CI, 0%-35%). All patients with a baseline Pao2 to Fio2 ratio of ≥ 125 mm Hg survived, whereas the three patients with a baseline Pao2 to Fio2 ratio of < 125 mm Hg died. INTERPRETATION: The use of defibrotide for management of SARS-CoV-2-related ARDS proved safe and tolerable. No hemorrhagic or thrombotic complications were reported during therapy, with promising outcomes in a patient population with a historically high mortality rate. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04530604; URL: www. CLINICALTRIALS: gov.

Impact of Pharmacogenetics on Intravenous Tacrolimus Exposure and Conversions to Oral Therapy.

CYP3A5 and CYP3A4 are the predominant enzymes responsible for tacrolimus metabolism; however only a proportion of the population expresses CYP3A5 secondary to genetic variation. CYP3A5 is expressed in both the intestine and the liver and has been shown to impact both the bioavailability and metabolism of orally administered tacrolimus. Increasing the initial tacrolimus dose by 50% to 100% is recommended in patients who are known CYP3A5 expressers; however, whether this dose adjustment is appropriate for i.v. tacrolimus administration is unclear. The objective of this study was to evaluate the impact of CYP3A5 genotype as well as other pharmacogenes on i.v. tacrolimus exposure to determine whether the current genotype-guided dosing recommendations are appropriate for this formulation. In addition, this study aimed to investigate dose conversion requirements among CYP3A5 genotypes when converting from i.v. to p.o. tacrolimus. This study is a retrospective chart review of all patients who underwent allogeneic stem cell transplantation at Michigan Medicine between June 1, 2014, and March 1, 2018, who received i.v. tacrolimus at the time of their transplantation. Secondary use samples were obtained for genotyping CYP3A5, CYP3A4, and ABCB1. Patient demographic information, tacrolimus dosing and trough levels, and concomitant medications received at the time of tacrolimus trough were collected retrospectively from the patients' medical records. The i.v. dose-controlled concentration (C/D) and the i.v.:p.o. exposure ratio was calculated for all tacrolimus doses and patients, respectively. The impact of CYP3A5, CYP3A4, and ABCB1 genotypes on the i.v. C/D were evaluated with linear mixed modeling. The impact of CYP3A5 genotype on the i.v.:p.o. ratio was evaluated while controlling for age and concomitant use of an azole inhibitor. CYP3A5 and CYP3A4 genotypes were significantly associated with the i.v. C/D, with CYP3A5 expressers and CYP3A4 rapid metabolizers having 20% lower tacrolimus exposure. Neither genotype remained significant in the multivariable model, although age, hematocrit, and concomitant use of strong azole inhibitors were associated with increased i.v. C/D. When controlling for patient age and sex, CYP3A5 expressers had significantly higher i.v.:p.o. ratios than CYP3A5 nonexpressers (3.42 versus 2.78; P = .04). Post hoc analysis showed that the i.v.:p.o. ratio may differ among different CYP3A5 genotypes and azole inhibitor combinations. This study demonstrates that the current genotype-guided tacrolimus dose adjustment recommendations are inappropriate for CYP3A5 expressers receiving i.v. tacrolimus. Although CYP3A5 genotype is likely a minor contributor to i.v. tacrolimus exposure, genotype, in addition to capturing concomitant CYP3A inhibitors, would likely improve i.v.:p.o. dose conversion selection. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening in patients with acute myeloid leukemia (AML).

BACKGROUND: Current literature has demonstrated the utility of the MRSA nasal screen as a de-escalation tool to decrease unnecessary anti-MRSA antibiotic therapy. However, data on the applicability of this test in patients with hematologic malignancy is lacking. METHODS: This is a single-center, retrospective cohort study of patients with acute myeloid leukemia (AML) with or without a history of hematopoietic cell transplant (HCT), with pneumonia and MRSA nasal screening with respiratory cultures obtained. The primary outcome was to determine the negative predictive value (NPV) of the MRSA nasal screen for MRSA pneumonia. Secondary outcomes included sensitivity, specificity, positive predictive value (PPV) of the MRSA nasal screen and prevalence of MRSA pneumonia. RESULTS: Of 98 patients with AML and pneumonia, the prevalence of MRSA pneumonia was 4.1% with confirmed positive MRSA respiratory cultures observed in 4 patient cases. In patients with confirmed MRSA pneumonia, 3 had positive MRSA nasal screens while 1 had a false negative result, possibly due to a long lag time (21 days) between MRSA nasal screen and pneumonia diagnosis. Overall, the MRSA nasal screen demonstrated 75% sensitivity and 100% specificity, with a PPV of 100% and a NPV of 98.9%. CONCLUSIONS: Given the low prevalence, empiric use of anti-MRSA therapy in those AML and HCT patients with pneumonia may not be warranted in clinically stable patients. For patients in whom empiric anti-MRSA antibiotics are initiated, nasal screening for MRSA may be utilized to de-escalate anti-MRSA antibiotics in patients with AML with or without HCT.

Incorporating preauthorization into antimicrobial stewardship pharmacist workflow reduces Clostridioides difficile and gastrointestinal panel testing.

OBJECTIVE: To evaluate whether incorporating mandatory prior authorization for Clostridioides difficile testing into antimicrobial stewardship pharmacist workflow could reduce testing in patients with alternative etiologies for diarrhea. DESIGN: Single center, quasi-experimental before-and-after study. SETTING: Tertiary-care, academic medical center in Ann Arbor, Michigan. PATIENTS: Adult and pediatric patients admitted between September 11, 2019 and December 10, 2019 were included if they had an order placed for 1 of the following: (1) C. difficile enzyme immunoassay (EIA) in patients hospitalized >72 hours and received laxatives, oral contrast, or initiated tube feeds within the prior 48 hours, (2) repeat molecular multiplex gastrointestinal pathogen panel (GIPAN) testing, or (3) GIPAN testing in patients hospitalized >72 hours. INTERVENTION: A best-practice alert prompting prior authorization by the antimicrobial stewardship program (ASP) for EIA or GIPAN testing was implemented. Approval required the provider to page the ASP pharmacist and discuss rationale for testing. The provider could not proceed with the order if ASP approval was not obtained. RESULTS: An average of 2.5 requests per day were received over the 3-month intervention period. The weekly rate of EIA and GIPAN orders per 1,000 patient days decreased significantly from 6.05 ± 0.94 to 4.87 ± 0.78 (IRR, 0.72; 95% CI, 0.56-0.93; P = .010) and from 1.72 ± 0.37 to 0.89 ± 0.29 (IRR, 0.53; 95% CI, 0.37-0.77; P = .001), respectively. CONCLUSIONS: We identified an efficient, effective C. difficile and GIPAN diagnostic stewardship approval model.

The leukemia strikes back: a review of pathogenesis and treatment of secondary AML.

Secondary AML is associated with a disproportionately poor prognosis, consistently shown to exhibit inferior response rates, event-free survival, and overall survival in comparison with de novo AML. Secondary AML may arise from the evolution of an antecedent hematologic disorder, or it may arise as a complication of prior cytotoxic chemotherapy or radiation therapy in the case of therapy-related AML. Because of the high frequency of poor-risk cytogenetics and high-risk molecular features, such as alterations in TP53, leukemic clones are often inherently chemoresistant. Standard of care induction had long remained conventional 7 + 3 until its reformulation as CPX-351, recently FDA approved specifically for secondary AML. However, recent data also suggests relatively favorable outcomes with regimens based on high-dose cytarabine or hypomethylating agents. With several investigational agents being studied, the therapeutic landscape becomes even more complex, and the treatment approach involves patient-specific, disease-specific, and therapy-specific considerations.

The FOSSIL Study: FLAG or standard 7+3 induction therapy in secondary acute myeloid leukemia.

Patients with secondary acute myeloid leukemia (sAML) have poor outcomes, with CR/CRi rates of 25-35% with standard 7 + 3 induction chemotherapy, while single center non-comparative analyses suggest promising outcomes with FLAG. We conducted a single-center, retrospective cohort study assessing outcomes in treatment-naïve patients with sAML treated with fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG, n = 40) compared with 7 + 3 (n = 66). Median patient age was 63 years (range: 27-82) in the FLAG group and 60 years (range: 21-76) in the 7 + 3 group (P = 0.968). Patients treated with FLAG achieved higher overall response rates (CR + CRi + MLFS) compared to 7 + 3 (70% vs. 48%, P = 0.043). FLAG was well tolerated, with only one induction death (30-day mortality rate, 3% vs. 8%, P = 0.405) and no cases of cerebellar toxicity. Duration of neutropenia was significantly shorter with FLAG (median 16 vs. 23 days, P < 0.001). Half of the FLAG-treated patients proceeded to consolidative therapy compared with only 27% of those who received 7 + 3 (P = 0.022). Overall survival was comparable between groups (8.5 mos, FLAG vs. 9.1 mos, 7 + 3; P = 0.798). Thus, FLAG may represent a low-cost treatment strategy in sAML that produces higher response rates and promising survival outcomes with minimal treatment-related toxicity. Further studies are required to prospectively compare FLAG to the newly FDA-approved CPX-351 in sAML.

Impact of a Statewide Oral Oncolytic Initiative on Five Participating Practices.

PURPOSE: The shift from infusion to oral oncolytic therapy presents challenges to oncology practitioners. The purpose of this study was to describe how a statewide quality-improvement collaborative can enhance quality of care for patients receiving oral oncolytic therapy. METHODS: The Michigan Oncology Quality Consortium hosted a series of learning sessions focused on oral oncolytic quality improvement, providing multiple resources to oncology community practices. The first five participating practices reported which of the evidence-based Michigan Oncology Quality Consortium resources provided were implemented at their site. They also performed prepost self-assessments in October 2013 and April 2015 and another in December 2017 to assess sustainability. Concordance with the ASCO Quality Oncology Practice Initiative oral chemotherapy standards, including documentation (five measures), patient education (seven measures), and follow-up/monitoring (four measures), was compared. RESULTS: All practices showed improvement between 2013 and 2015 in documentation (32% to 88%; P = .03), patient education (37% to 100%; P could not be calculated), and monitoring (40% to 80%; P > .2). Overall, a significant improvement in concordance was observed (36% to 91%; P = .03). Use of resources from each practice varied, and practices that used more resources showed greater improvements. There was a slight decrease in overall concordance between 2015 and 2017, which was not found to be significant (91% to 84%; P = .53). CONCLUSION: Use of tools from a quality-improvement collaborative improved concordance with national standards of care. Large-scale deployment of this model program may provide a clinically efficient and effective mechanism to enhance widespread change.

Outcomes of previously untreated elderly patients with AML: a propensity score-matched comparison of clofarabine vs. FLAG.

The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.

Predictors for requiring re-induction chemotherapy in acute myeloid leukemia patients with residual disease on day 14 bone marrow assessment.

PURPOSE: Day 14 bone marrow (BM) biopsies following standard induction in acute myeloid leukemia (AML) have a suboptimal ability to predict complete remission (CR). The decision to administer re-induction chemotherapy with residual disease on day 14 is variable and lacks clear guidance. METHODS: We retrospectively compared clinical and laboratory characteristics of adult patients with newly diagnosed, previously untreated AML who underwent 3+7 induction chemotherapy from January 2004 until February 2017. RESULTS: Of 90 patients with a positive day 14 BM biopsy, 53 did not receive immediate re-induction chemotherapy. Twenty-seven (51%) of those patients achieved a CR upon count recovery. Favorable risk cytogenetics was found to be highly significant for attaining a CR at repeat BM biopsy. CONCLUSIONS: Day 14 BM evaluations following 3+7 induction are unable to accurately predict the ability to achieve a CR. Many patients will attain a CR despite no further chemotherapy. The decision to re-induce can be safely delayed in many patients, especially those with favorable risk cytogenetics.

Cockcroft-Gault revisited: New de-liver-ance on recommendations for use in cirrhosis.

The Cockcroft-Gault (CG) equation has become perhaps the most popular practical approach for estimating renal function among health care professionals. Despite its widespread use, clinicians often overlook not only the limitations of the original serum creatinine (SCr) based equation, but also may not appreciate the validity of the many variations used to compensate for these limitations. For cirrhotic patients in particular, the underlying pathophysiology of the disease contributes to a falsely low SCr, thereby overestimating renal function with use of the CG equation in this population. We reviewed the original CG trial from 1976 along with data surrounding clinician specific alterations to the CG equation that followed through time. These alterations included different formulas for body weight in obese patients and the "rounding up" approach in patients with low SCr. Additionally, we described the pathophysiology and hemodynamic changes that occur in cirrhosis; and reviewed several studies that attempted to estimate renal function in this population. The evidence we reviewed regarding the most accurate manipulation of the original CG equation to estimate creatinine clearance (CrCl) was inconclusive. Unfortunately, the homogeneity of the patient population in the original CG trial limited its external validity. Elimination of body weight in the CG equation actually produced the estimate closest to the measure CrCl. Furthermore, "rounding up" of SCr values often underestimated CrCl. This approach could lead to suboptimal dosing of drug therapies in patients with low SCr. In cirrhotic patients, utilization of SCr based methods overestimated true renal function by about 50% in the literature we reviewed.

Risk factors and impact of Clostridium difficile recurrence on haematology patients.

Objectives: The incidence of Clostridium difficile infection (CDI) in adults with malignancy is 7%-14% compared with 1%-2% in the general hospitalized population. Despite the increased incidence of CDI in this population, a major concern is the propensity of CDI to recur, leading to delays in therapy impacting outcomes. We conducted a retrospective case-control study to identify risk factors for recurrent CDI (rCDI) and to determine the impact of rCDI on adult patients with a haematological malignancy. Methods: Adult haematology patients with CDI from June 2010 to December 2014 were divided into two groups: rCDI and non-rCDI. Multivariable models using logistic regression were constructed to identify risk factors for rCDI. Results: A total of 100 patients in our study yielded a 41% recurrence rate. CDI impacted chemotherapy significantly more in the rCDI group (53.7% versus 11.9%, P <0.001), primarily due to interruptions in established treatment plans (46.3% versus 10.3%, P <0.001). Risk factors for rCDI identified at index included salvage lymphoma chemotherapy (OR 9.64, 95% CI 1.02-91.15, P = 0.048) and severe CDI (OR 4.82, 95% CI 1.31-17.66, P = 0.018). Longitudinal risk factors included exposure to fluoroquinolones (OR 3.96, 95% CI 1.04-15.15, P = 0.044), ceftriaxone (OR 18.93, 95% CI 1.27-281.95, P = 0.033) and piperacillin/tazobactam (OR 10.4, 95% CI 1.81-59.64, P = 0.009). Conclusions: Haematology patients exhibit a higher rate of rCDI than general hospitalized patients. Utilization of this multivariable model to guide index CDI therapy at index may help to decrease the rCDI and prevent delays or interruptions in chemotherapy.