Breakthrough invasive fungal infections on isavuconazole prophylaxis in hematologic malignancy & hematopoietic stem cell transplant patients.

BACKGROUND: Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. METHODS: In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. RESULTS: We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 µg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. CONCLUSION: ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

Early administration of SARS-CoV-2 monoclonal antibody reduces the risk of mortality in hematologic malignancy and hematopoietic cell transplant patients with COVID-19.

BACKGROUND: Data on severe acute respiratory distress syndrome coronavirus 2 monoclonal antibody (SARS-CoV-2-specific mAb) use in hematologic malignancy and hematopoietic cell transplantation (HM/HCT) patients are limited. Here, we describe our experience with the use of casirivimab-imdevimab or bamlanivimab for the treatment of coronavirus disease 2019 (COVID-19) in HM/HCT patients. METHODS: This was a retrospective chart review at the University of Miami Hospital and Sylvester Comprehensive Cancer Center for HM/HCT patients with COVID-19 who received casirivimab-imdevimab or bamlanivimab from November 21, 2020, to September 30, 2021. Outcomes measured were mortality, hospital admission, and infusion reaction to SARS-CoV-2-specific mAbs. RESULTS: We identified 59 HM/HCT patients with mild to moderate COVID-19 who received casirivimab-imdevimab or bamlanivimab. Median age was 57 years (interquartile range [IQR]: 45-65). Among the 59 patients, 25 (42%) received cellular therapy: 14 (24%) had undergone allogeneic HCT, nine (15%) autologous HCT, and two (3%) received chimeric antigen receptor T-cell therapy. The median time from COVID-19 symptom onset to SARS-CoV-2-specific mAb administration was 4 (IQR: 3-6) days. Forty-six (78%) patients received SARS-CoV-2-specific mAbs as outpatients and 13 (22%) patients received SARS-CoV-2-specific mAbs during hospitalization. Among patients who received SARS-CoV-2-specific mAbs as outpatients, only four (9%) visited the emergency department at days 10, 11, 15, and 35 after SARS-CoV-2-specific mAb administration. None of these four patients required hospital admission. Among the hospitalized patients, five (38%) were admitted to the hospital with neutropenic fever, four (31%) were already hospitalized for transplantation and cellular therapy, three (23%) were admitted for monitoring of COVID-19 symptoms, and one (8%) was admitted with acute kidney injury. Three hospitalized patients (23%) died at 14, 35, and 59 days after SARS-CoV-2-specific mAb administration; two of these three deaths were attributed to COVID-19 infection. One patient developed an immediate infusion reaction to bamlanivimab, and no infusion reactions were reported to casirivimab-imdevimab use. CONCLUSION: During the alpha and delta variant surges, early administration of bamlanivimab or casirivimab-imdevimab prevented hospitalization and death when given in the outpatient setting. Among patients who received mAbs at or after hospital admission, the risk of COVID-19 disease progression and death remains significant. Larger studies of the use of mAb therapy to treat COVID-19 in this population are needed.

Ehrlichiosis mimicking acute leukemia.

Human monocytic ehrlichiosis is a tickborne disease with a spectrum of presentations ranging from asymptomatic, mild to fatal. Ehrlichiosis can transiently cause white blood cells abnormalities that mimic leukemia/lymphoma and cases have been, on rare occasions, initially mistaken for hematological malignancies. We report a case of Ehrlichia chaffeensis infection suspected to be acute promyelocytic leukemia at presentation, prompting therapy with all-trans-retinoic acid. Physicians should keep tickborne transmitted illnesses on the differential in patients presenting with pancytopenia, especially in endemic areas.

Successful Treatment of Disseminated Disease Due to Highly Resistant Aspergillus calidoustus with a Novel Antifungal Therapy.

Invasive aspergillosis is the most common invasive mold infection following a hematopoietic cell transplant. Widespread use of antifungal prophylaxis has led to the increasing incidence of cryptic Aspergillus species. Aspergillus calidoustus is one of those emerging species and is notorious for multidrug resistance to antifungals. Here, we report a case of disseminated A. calidoustus infection in a hematopoietic stem cell transplant recipient who was successfully treated with combination therapy that included a novel antifungal.

Clostridioides difficile Infection and Risk of Acute Graft-versus-Host Disease among Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Clostridioides difficile infection (CDI) is a major cause of infectious diarrhea among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. The relationship between CDI and acute graft-versus-host disease (aGVHD) has been a topic of interest, as these 2 conditions may influence each other. We studied the temporal relationship of CDI to aGVHD in the first 100 days post-transplantation in a large cohort of allo-HSCT recipients. We performed a retrospective cohort study of adult patients undergoing their first allo-HSCT at our tertiary care medical center between January 1, 2010, and December 31, 2016. Patients were followed for CDI diagnosis, development of aGVHD, and vital status up to day +100 post-transplantation. Descriptive statistics and multivariate Cox models with CDI as a time-varying covariate and aGVHD and high-grade aGVHD as outcomes were used for data analyses. A total of 656 allo-HSCT recipients were included in the analysis. Of these, 419 (64%) developed aGVHD, and 111 (17%) were diagnosed with CDI within the first 100 days post-transplantation. CDI developed before the onset of aGVHD in 72 of the 84 allo-HSCT recipients (85%) with both CDI and aGVHD. Fidaxomicin was used in the treatment of 57 of the 111 CDI cases (50%), whereas vancomycin was used in 52 (47%). Most of the CDI cases (88%) were diagnosed in the peritransplantation period (between day -10 and day +10). The median time to the development of CDI and aGVHD was 3.5 days (range, -7 to 95 days) and 33 days (range, 9 to 98 days) post-transplantation, respectively. Using multivariate Cox model, the following predictors were significantly associated with the development of aGVHD: CDI (adjusted hazard ratio [aHR], 1.52; 95% confidence interval [CI], 1.17 to 1.97; P = .0018), transplantation from a matched related donor (MRD) compared with a matched unrelated donor (aHR, 0.68; 95% CI, 0.54 to 0.85; P = .0003), and myeloablative versus nonmyeloablative conditioning (aHR, 2.45; 95% CI, 1.80 to 3.34; P < .0001), adjusting for age, sex, race, underlying disease, cytomegalovirus CMV serostatus, transplant source, and receipt of antithymocyte globulin (ATG). There was no association between CDI and high-grade aGVHD after adjustment for age, underlying disease, transplant type, intensity of conditioning, and receipt of ATG (aHR, 1.59; 95% CI, 0.95 to 2.66; P = .0755). CDI after allo-HSCT is associated with increased risk of GVHD when no CDI prophylaxis was used. Further studies examining CDI preventive measures, including prophylaxis, as well as the preservation or reconstitution of the gastrointestinal microbiome in the setting of HSCT are warranted.

Scedosporium apiospermum fungemia successfully treated with voriconazole and terbinafine.

Scedosporium apiospermum is ubiquitous in the environment and is considered an emerging infection. Immunocompromised hosts can have a wide spectrum of diseases ranging from cutaneous to disseminated disease that may involve pulmonary, central nervous system, or bone. Disseminated disease in immunocompetent hosts is uncommon. Treatment of deep-seated infections is challenging because of the limited susceptibility of the Scedosporium species to all current antifungal drugs. We report a case of Scedosporidium apiospermum fungemia with a presumed pulmonary involvement in an immunocompetent patient. The fungemia was successfully treated with oral voriconazole and terbinafine.

De Novo Acute Myeloid Leukemia with Combined CBFB-MYH11 and BCR-ABL1 Gene Rearrangements: A Case Report and Review of Literature.

Acute myeloid leukemia (AML) with inv(16)(p13.1q22) resulting in CBFB-MYH11 fusion is associated with a favorable prognosis. The presence of a KIT mutation modifies it to an intermediate prognosis. Additionally, inv(16) can cooperate with other genetic aberrations to further increase cell proliferation. Coexistence of inv(16) and t(9;22) is extremely rare (20 cases). We present a case of a 55-year-old male with elevated white blood cell count. Bone marrow evaluation and flow cytometry analysis were compatible with AML with monocytic features. Cytogenetic studies revealed two-related clones, a minor clone with inv(16) and a major clone with concurrent inv(16) and t(9;22) rearrangements. Fluorescent in situ hybridization studies confirmed these rearrangements. Molecular analysis detected a p190 BCR-ABL1 transcript protein. KIT mutations were negative. The patient was initially treated with standard induction regimen; 7 daily doses of cytarabine from day 1-day 7, 3 daily doses of daunorubicin from day 1-day 3, and 1 dose of Mylotarg (gemtuzumab ozogamicin) on day 1. The detection of t(9;22) led to the addition of daily doses of dasatinib (tyrosine kinase inhibitor) from day 7 onwards. The patient achieved complete remission on day 45. During his treatment course, he acquired disseminated Fusarium infection. Day 180 bone marrow evaluation revealed florid relapse with 64% blasts. Cytogenetic study showed clonal evolution of the inv(16) clone with no evidence of the t(9;22) subclone. Eventually, bone marrow transplantation was contraindicated, and the patient was transferred to palliative care. Literature review revealed that AML with co-occurrence of CBFB-MYH11 and BCR-ABL1 gene rearrangements was involved by only a small number of cases with de novo and therapy-related AML. Most cases were in myeloid blast crisis of chronic myeloid leukemia (CML). Treatment and prognosis among the de novo AML cases varied and majority of them achieved clinical remission. In contrast, these cytogenetic abnormalities in the blast phase of CML had a poor prognosis. As the prognosis and management of AML is dependent upon the underlying genetic characteristics of the neoplasm, it is imperative to include clinical outcome with such rare combinations of genetic alterations.

Histoplasmosis-Associated Hemophagocytic Lymphohistiocytosis: A Review of the Literature.

BACKGROUND: Histoplasmosis is an endemic fungal disease with diverse clinical presentations. Histoplasmosis-associated hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with limited data regarding treatment and outcome. We described the clinical features, treatment, and outcomes of five patients in our institution with histoplasmosis-associated HLH. This review also summarizes the current literature about presentation, treatment, and outcome of this infection-related HLH entity. METHODS: We searched the electronic medical records for patients with histoplasmosis-associated HLH at our institution from 1/1/2006 to 9/30/2017. Diagnosis of HLH was confirmed by chart review using the HLH-04 criteria. We also searched the current literature for case reports and case series. RESULTS: Five cases of histoplasmosis-associated HLH were included from our institution. All five patients were diagnosed after 2010. The literature review yielded 60 additional cases of histoplasmosis-associated HLH. The most common underlying condition was HIV in 61% of cases. The majority of histoplasmosis patients (81%) were treated with amphotericin B formulations. Documented specific treatments for HLH were as follows: nine patients received steroids only, six patients received intravenous immunoglobulin (IVIG) only, three patients received dexamethasone and etoposide, two patients received etoposide, dexamethasone, and cyclosporine, two patients received steroids and IVIG, and one patient received Anakinra and IVIG. The inpatient case fatality rate was 31% with most of the deaths occurring within two weeks of hospital admission. CONCLUSIONS: Histoplasmosis-associated HLH among adults is an uncommon but serious complication with high associated mortality. Early antifungal therapy with a lipid formulation amphotericin B is critical. The initiation of immunosuppressive therapy with regimens like HLH-04 in this disease entity should be individualized.