Sierzchulski, Amanda G.

Abstract The reduced-intensity conditioning regimen, fludarabine and melphalan, is frequently used in allogeneic hematopoietic stem cell transplantation (HSCT). Melphalan and the active metabolite of fludarabine, F-ara-A, are excreted via the kidneys. Existing methods to assess clearance in this setting are based on serum creatinine, which has known limitations for glomerular filtration rate (GFR) estimation in patients with malignancy. Measured GFR (mGFR) may better predict drug dosing to mitigate toxicity and increase the chances of successful engraftment. The primary objective of this study was to assess the association between mGFR and risk for nonrelapse mortality (NRM) in patients who have undergone allogeneic HSCT receiving conditioning with fludarabine and melphalan. In the 109 included patients, mGFR <65 mL/min/1.73 m2 predicted a significantly higher rate of overall NRM (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.03-4.35; P = 04) and 1-year incidence of infection (HR, 2.63; 95% CI, 1.54-4.55; P < .001) in addition to a significantly lower 2-year survival (P = .019). Kidney function estimated via estimated GFR (eGFR) and estimated creatinine clearance did not correlate with posttransplant outcomes. These results suggest that mGFR is a promising approach for assessing clearance in patients who have undergone allogeneic HSCT and may be preferred to standard creatinine-based eGFR strategies.

Abstract Study Objective To determine whether there is a drug‐drug interaction precluding the concomitant use of levetiracetam and high‐dose methotrexate (HDMTX). Design Retrospective analysis. Setting Large academic tertiary care medical center. Patients Adult lymphoma patients who received HDMTX as a 4‐h infusion with or without concomitant levetiracetam. Measurements and Main Results Generalized estimating equations clustered on patient were used to assess each outcome. The primary outcome was the incidence of delayed MTX elimination (MTX level >1 µmol/L at 48 h). Secondary outcomes included incidence of acute kidney injury (AKI) and hospital length of stay (LOS). The 430 included patients receiving 1993 doses of HDMTX had a median (IQR) age of 66 (57.5, 72.6) years, 88 (20.5%) received concomitant levetiracetam with at least one dose of MTX, 267 (62.1%) were male, and 397 (92.3%) were Caucasian. HDMTX doses ranged from 1 to 8 g/m 2 . The most common lymphoma diagnoses were systemic diffuse large B‐cell lymphoma (DLBCL; 58.5%) and systemic DLBCL with central nervous system (CNS) involvement (32.8%). Rates of delayed elimination with and without levetiracetam were 13.4% and 16.3%, respectively (OR = 0.80, 95% CI 0.47–1.34, p = 0.39). AKI occurred in 15.6% and 17.0% of patients with and without concomitant levetiracetam, respectively (OR = 0.83, 95% CI 0.52–1.33, p = 0.28). The median LOS with and without levetiracetam was 4.2 and 4.1 days, respectively ( p = 0.039). On multivariable analyses, only age, body surface area, diagnosis of systemic DLBCL with CNS involvement, serum creatinine, hemoglobin, total bilirubin, and dose of HDMTX were associated with delayed elimination. Conclusions High‐dose methotrexate administered with concomitant levetiracetam was not associated with increased risk for delayed MTX elimination or AKI. These results support that levetiracetam and HDMTX are safe for coadministration.

Background: The overall incidence of Pneumocystis Pneumonia (PJP) in lymphoma varies according to diagnosis, host factors and treatment rendered.(Carmona, et al. 2011) A meta-analysis suggested that prophylaxis is appropriate when the chance of incurring PJP is 3.5% or greater.(Green, et al. 2007) Accurately characterizing the incidence of PJP is further complicated by a transition in diagnostic methods from direct immunofluorescence assay (DFA) to a DNA-based polymerase chain reaction (PCR) technique.(Caliendo et al., 1998, Wilson JW, et al., 2011) The incidence of PCR-based diagnosis of PJP and the need for anti-Pneumocystis prophylaxis in patients diagnosed with Hodgkin lymphoma receiving chemotherapy requires further investigation. Methods: This single center, retrospective, observational study was approved by the Mayo Clinic Institutional Review Board and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. Consecutive adult patients with a diagnosis of Hodgkin lymphoma receiving chemotherapy between January 2006 and August 2018 were evaluated. Patients with history of bone marrow transplant were excluded. Kaplan-Meier estimation was used to calculate the cumulative incidence of PJP with a 95% confidence interval. Cox proportional hazard models were used to demonstrate the strength of association between the independent variables and PJP rate. Results: The 506 included patients had a median (IQR) age of 40.3 (28.6, 59.7) years, 287 (56.7%) were male, and 470 (92.9%) were Caucasian. Further baseline demographics and clinical characteristics are described in table 1 with no significant differences between those diagnosed and those free from PJP. Chemotherapy combined with radiation therapy was prescribed for 163 (32.3%) patients while 342 (67.7%) patients received chemotherapy alone. Chemotherapy regimen distribution included 356 patients (70.4%) receiving bleomycin-containing chemotherapy. Median (IQR) total Bleomycin dose was 122 (IQR: 78, 178) Units. Bleomycin-containing combination chemotherapy regimen was not significantly associated with a higher risk for PJP when compared to other combination regimens (HR=1.59, 95% CI 0.55-4.62 p=0.40). Bleomycin-related lung compromise was suspected in 130 (25.7%) patients. Anti-pneumocystis prophylaxis was provided for 97 patients (n=39 a priori, 58 after chemotherapy initiation) and this was not significantly associated with a decreased incidence of PJP (HR=0.51, 95% CI 0.15-1.71, p=0.28). The cumulative incidence of PJP 1 year after start of chemotherapy was 6.2% (95% CI 3.8%-8.5%) and is shown in figure 1. Diagnosis of PJP occurred most commonly during the 2nd (n=8, 30.7%), 3rd (n=8, 30.7%), and 4th (n=7, 26.9%) cycles of chemotherapy. Trimethoprim-sulfamethoxazole was the only agent prescribed as PJP management. There were 10 (38%) patients with PCP that required ICU admission with 9 needing mechanical ventilation, 4 necessitating vasopressor support, and none requiring dialysis. Mortality 30-days from PJP diagnosis was 8% (n=2) with one death attributable to PJP infection. Conclusion: Cumulative incidence of PJP was 6.2% in patients receiving intensive chemotherapy for Hodgkin lymphoma. As the incidence is above the 3.5% threshold previously described, the clinician should consider the potential value of prophylaxis. Defining the overall utility of universal vs. targeted anti-pneumocystis prophylaxis requires further prospective, randomized investigation. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Trimethoprim/Sulfamethoxazole, Pentamidine isethionate, and dapsone will be discussed as prevention of Pneumocystis Pneumonia in the HIV-negative population