Remission of relapsed/refractory classical Hodgkin lymphoma induced by brentuximab vedotin and pembrolizumab combination after allogeneic hematopoietic stem cell transplantation: a case report.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with highly chemorefractory Hodgkin lymphoma (HL). The CD30-targeting antibody-drug conjugate Brentuximab-Vedotin (BV) and programmed cell death protein-1 (PD-1) blocking agents have demonstrated clinical activity with durable responses in relapsed/refractory (r/r) HL. However, patients with a history of allo-HSCT were frequently excluded from clinical trials due to concerns about the risk of graft-versus-host disease (GVHD). We report the clinical history of a patient with refractory classical HL who underwent two allo-HSCTs (first from matched unrelated and second from haploidentical donor) after relapsing on BV and nivolumab and for whom durable remission was finally obtained using BV-pembrolizumab combination for relapse after haploidentical HSCT. Such treatment was associated with the onset of GVHD after only two cycles which led to treatment discontinuation. However, the side effects were rapidly controlled, and after 2 years of follow-up, the patient is still in remission. Our data support the feasibility and efficacy of combining PD-1 blockade with BV to enhance the graft-versus-lymphoma effect after allo-HSCT.

Revisiting Cytomegalovirus Serology in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: Allogeneic hematopoietic cell transplant recipients (allo-HCTRs) with positive cytomegalovirus (CMV) serology may have false-positive results due to blood product transfusion-associated passive immunity. METHODS: This single-center cohort study included allo-HCTRs with negative baseline (at malignancy diagnosis) CMV serology and indeterminate/low-positive (CMV IgG titer, ≥0.6-<50 U/mL) pretransplant CMV serology with negative pretransplant plasma CMV DNAemia. The CMV status of those patients was reclassified from R+ to R- (CMVR- reclassification group). We compared those patients to allo-HCTRs with negative (CMV IgG titer <0.6 U/mL) pretransplant CMV IgG (CMVR- group). We describe the number and type of patients whose pretransplant CMV status was reclassified from indeterminate/positive to negative. We reviewed all plasma CMV DNAemia tests performed during the first 6 months posttransplant in both groups to assess the safety of this approach. RESULTS: Among 246 (84.5%) of 291 transplanted patients identified as CMVR+ pretransplant, 60 (24.4%) were reclassified from CMV serology indeterminate (N:10)/low-positive (N:50) to R-. Only 1 of 60 patients (1.67%) in the CMVR- reclassification group versus 3 of 44 (6.8%; P = .30) in the CMVR- group developed CMV DNAemia during the follow-up period. There were no significant differences in the number of CMV DNAemia tests performed, CMV DNAemia range, and time posttransplant between the 2 groups. CONCLUSIONS: One of 4 allo-HCT CMVR+ may be falsely flagged as R+, with significant impact on donor selection and prophylaxis administration. A 2-step approach including CMV serology testing at hematologic malignancy diagnosis in allo-HCT candidates and careful review of pretransplant CMV IgG titers may help correctly classify CMV serology status.

Routine Infectious Disease Consultation Prior to an Allogeneic Hematopoietic Cell Transplant.

Background: A transplant infectious disease (TID) assessment is essential to select recipients for an allogeneic hematopoietic cell transplant (HCT) and tailor prophylactic and empirical treatment recommendations. Methods: We performed a retrospective single-center study to describe our model of care based on a routine TID consultation prior to an allogeneic HCT between 2018 and 2022 in 292 adult (≥18-year-old) consecutive patients. We describe the performance of a TID consultation, arbitrarily defined as major (HCT postponement, procedure, cytomegalovirus [CMV] recipient serology reinterpretation) and minor interventions. Results: Overall, 765 interventions were observed in 257 of 292 (88%) patients: 88 of 765 (11.5%) major and 677 of 765 (88.5%) minor interventions. Among major interventions, HCT was postponed in 8 of 292 (2.7%) patients and a procedure was requested in 18 of 292 (6.2%) patients. The CMV recipient serostatus was changed from indeterminate/low-titer positive to negative in 60 of 292 (20.5%) patients. Among 677 minor interventions, there were 68 (8.8%) additional consultations with other services requested, 260 (33.7%) additional diagnostic tests requested, 102 (13.2%) additional treatments recommended, 60 (7.8%) non-CMV serology reinterpretations performed, 115 (14.9%) deviations from routine anti-infective prophylaxis, and 72 (9.3%) deviations from routine empirical antibiotic treatment recommendations in case of neutropenic fever. Conclusions: We are proposing a structured, clearly defined, and comprehensive pretransplant checklist for an effective assessment of infectious disease risks and complications prior to an allogeneic HCT. Further studies or experiences like ours could help to define a global strategy or new models of care to be implemented in HCT centers in the future.

Hepatitis E Virus Infection Epidemiology in Recipients of Allogeneic Hematopoietic Cell Transplant.

Among 292 recipients of allogeneic hematopoietic cell transplant (2018-2022), 64 (21.9%) tested positive for anti-hepatitis E virus (HEV) immunoglobulin G. Among 208 recipients tested by plasma/serum HEV polymerase chain reaction (2012-2022), 3 (1.4%) primary HEV infections were diagnosed; in 1 patient, plasma HEV polymerase chain reaction relapsed positive for 100 days. HEV infection remains rare albeit associated with persistent viral replication.

CMV Infection After Letermovir Primary Prophylaxis Discontinuation in Allogeneic Hematopoietic Cell Transplant Recipients.

In this single-center study of 61 allogeneic hematopoietic cell transplant (HCT) recipients receiving letermovir primary cytomegalovirus (CMV) prophylaxis for the first 100 days, we report 23% incidence of clinically significant CMV infection during the first 100 days after letermovir discontinuation, predominately in haploidentical HCT recipients, without any associations with CMV-DNAemia under letermovir.

Real-world experience of sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for FLT3-ITD AML reveals high rates of toxicity-related treatment interruption.

Sorafenib significantly improves survival of FLT3-ITD mutated AML patients when used as a post-allogeneic HSCT maintenance. Importantly, clinical trials reported a low rate of toxicities requiring sorafenib discontinuation. The aim of our analysis was to evaluate the real-world experience in patients treated with post-allogeneic HSCT sorafenib maintenance therapy for FLT3-ITD AML with a particular focus on tolerability and toxicity-related treatment interruption. We conducted a single-center retrospective study on 30 FLT3-ITD AML patients undergoing allogeneic HSCT in complete remission between 2017 and 2020 and who received sorafenib maintenance. 26 patients (87%) experienced toxicities leading to dose reduction (n=9) or direct interruption (n=17). Average time on sorafenib was 125 days (range 1-765). Most common toxicities were skin, gastrointestinal, and hematologic. Among patients who had a dose reduction, 4 eventually interrupted the drug and 5 were able to continue. Among patients who interrupted sorafenib because of toxicities, 7 were re-challenged with good tolerance in 3 cases. Overall, 18 patients (60% of the entire cohort) definitively discontinued sorafenib because of toxicities. 14 patients were thereafter switched to midostaurin. Importantly, with a median follow-up of 12 months, the median overall survival was not reached suggesting a positive impact of sorafenib maintenance despite the high rates of treatment interruption. In conclusion, our real-world analysis reveals high rates of toxicity-related interruption of sorafenib maintenance after allogeneic HSCT. Interestingly, our results suggest the feasibility of re-challenging with sorafenib and/or of switching to other maintenance approaches in case of intolerance.

Comparative Evaluation of Luminex xTAG® Gastrointestinal Pathogen Panel and Direct-From-Stool Real-Time PCR for Detection of C. difficile Toxin tcdB in Stool Samples from a Pediatric Population.

Detection of Clostridioides difficile toxins in patients with gastroenteritis has increasingly been accomplished through the use of enteric multiplex syndromic panels. Comparisons of the performance of these panels to both direct-from-stool (DFS) and culture-enriched stools followed by polymerase chain reaction (PCR) methods in pediatric populations are limited. Here, we compare the performance of the Luminex xTAG® Gastrointestinal Pathogen Panel (GPP) to our DFS in-house real-time PCR (DFS RT-PCR) assay for the detection of C. difficile toxin gene, tcdB, using 2641 stool specimens collected from children enrolled in the Alberta Provincial Pediatric EnTeric Infection Team (APPETITE) study in Alberta, Canada. We used culture enrichment followed by in-house RT-PCR to resolve discordant results between the two assays. We found excellent agreement (k = 0.89) between the GPP and our DFS RT-PCR assay: the positive percent agreement between the two assays was 97%, and the negative percent agreement was 99%. GPP, a multi-analyte platform can easily be implemented into a routine diagnostic laboratory for detecting enteric pathogens including C. difficile.

Defibrotide Shows Efficacy in the Prevention of Sinusoidal Obstruction Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study.

Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a well-known complication of allogeneic hematopoietic stem cell transplantation (HSCT) associated with a mortality rate of up to 85%.  Defibrotide has shown efficacy in treatment of SOS/VOD. Moreover, evidence exists supporting the efficacy of defibrotide as SOS/VOD prophylaxis. We have previously reported our single center experience on 52 HSCT recipients receiving defibrotide as SOS/VOD prophylaxis, which has shown that the patients did not develop any SOS/VOD under this prophylaxis. The aim of the present study was to see if we can confirm the previous results, mainly on the decrease incidence of SOS/VOD, as well as improve event-free survival (EFS) on a larger study population. We extended our previous study in a single-center retrospective analysis to include 237 consecutive patients (248 transplantations) who underwent transplantation between 1999 and 2009 for hematological diseases and receiving intravenous defibrotide as prophylaxis. This cohort was compared to 241 patients (248 transplantations) treated before 1999 or after 2009 when defibrotide prophylaxis was not routinely used in our center. Median follow-up for the study group was 10 (range 2-16) years and for the control group 2.7 (range 1-18) years. None of the 237 patients in the defibrotide group developed SOS/VOD. The cumulative incidence (CI) of SOS/VOD was 0% in the defibrotide group as compared to 4.8% (95% confidence interval [CI], 2.6-8%; P= .00046) in the control group. There was also a better 1-year EFS with 38% (95% CI, 32%-44%) in the defibrotide group versus 28% (95% CI, 22%-34%) (P= .00969) and decreased cumulative incidence of acute graft-versus-host disease (GvHD) in the defibrotide group 31% (95% CI, 25%-37%) versus 42% (95% CI, 36%-48%) (P= .026). The 1-year overall survival, relapse incidence, and non-relapse mortality were not statistically different. Multivariable analysis, performed taking into account clinical factors known to influence the risk of SOS/VOD, confirmed the favorable impact of defibrotide on SOS/VOD (HR 1.38e-08 [95% CI, 3.28e-09-5.80e-08]; P< .00001). Conversely, multivariable analysis failed to confirm the impact of defibrotide on 1-year EFS or acute GvHD. This large retrospective study on SOS/VOD-prophylaxis with defibrotide suggests that this approach may be of benefit. These results need to be confirmed in a prospective randomized trial.

When and how do we stop antifungal treatment for an invasive mould infection in allogeneic haematopoietic cell transplant recipients?

BACKGROUND: Limited data exist to describe end-of-treatment (EOT) parameters of antifungal therapy for invasive mould infections (IMI). METHODS: In a 10-year cohort of consecutive adult allogeneic haematopoietic cell transplant recipients with proven/probable IMI, we describe treatment duration and patient profile at EOT. RESULTS: There were 61 patients with 66 proven/probable IMI identified: 47/66 (71%) invasive aspergillosis (IA), 11/66 (17%) mucormycosis, and 8/66 (12%) other-IMI. Excluding 5 (8%) patients lost to follow-up, treatment was prematurely discontinued due to death or palliative care in 29/56 (51.8%) patients. Antifungal treatment was completed in 27 (48.2%) patients, for a median duration of 280 days (IQR: 110, 809): 258 (IQR: 110, 1905) and 307.5 (99, 809) days in IA and non-IA IMI, respectively. Treatment was continued after 90 and 180 days in 43/56 (76.8%) and 30/56 (53.6%) patients, respectively. At EOT, most patients were not neutropenic (ANC: 2.12 G/L, IQR: 0.04, 5.3), with CD4+ counts at 99 cells/µl (IQR: 0, 759) and immunoglobulins at 5.6 g/L (IQR: 2.3, 10.6). Most patients (16/27, 59.3%) were not receiving steroids at EOT, while 14/27 (53.9%) were on another type of immunosuppression. Amongst 15 patients with imaging at EOT, 12 (80%) had complete/partial radiologic response. Any chart documentation or an infectious disease consultation on treatment discontinuation was observed in 12/56 (21%) and 11/56 (20%) patients, respectively. CONCLUSIONS: Long treatment courses are observed in patients with IMI, due to prolonged immunosuppression. Although immune reconstitution and radiological response were frequently observed at EOT, consistent documentation of treatment discontinuation based on well-defined parameters is lacking.

Direct Clostridioides difficile ribotyping from stool using capillary electrophoresis.

Clostridioides difficile(C. difficile) genotyping is essential for surveillance of emerging strains, transmissions, and outbreak investigations, but culture is lengthy and may not be routinely performed, which necessitates culture-independent genotyping methods. We aimed to develop a direct from stool C. difficile PCR ribotyping algorithm using capillary electrophoresis. Ribotypes were generated directly from 66.8% of stools with 33.2% requiring broth enrichment. 16S and tcdB cycle thresholds (Ct) were significantly lower (P< 0.001) in directly ribotyped stools compared to enriched stools, and Ct correlated with direct ribotyping (area under the curve: 0.97 and 0.96, respectively). Direct and isolate ribotypes were 94.7% concordant. Mixed C. difficile ribotypes were presumptively identified in 14 (7.5%) samples with 12 (6.4%) mixtures confirmed. We have developed a rapid PCR ribotyping algorithm allowing for direct C. difficile genotyping from stool using capillary electrophoresis with occasional detection of mixed C. difficile populations in stool, which is a limitation of conventional isolate genotyping.

Evaluation of Disease Risk Comorbidity Index after Allogeneic Stem Cell Transplantation in a Cohort with Patients Undergoing Transplantation with In Vitro Partially T Cell Depleted Grafts.

Outcomes of hematopoietic stem cell transplantation (HSCT) are influenced by comorbidities, disease type, and status at transplantation. Several prognostic scores can be used, such as the disease risk index (DRI) or the hematopoietic cell transplantation-specific comorbidity index (HCT-CI). Recently, a new prognostic tool, the disease risk comorbidity index (DRCI), combining the DRI and the HCT-CI, was published. The DRCI determines 6 patient groups (very low risk [VLR], low risk [LR], intermediate risk 1 [IR-1], intermediate risk 2 [IR-2], high risk [HiR], and very high risk [VHR]) with a significant predictive value for overall survival (OS), disease-free survival (DFS), relapse incidence (RI), and graft-versus-host disease-free/relapse-free survival (GRFS). However, the DRCI has not been evaluated for patients allografted with partially in vitro T cell depleted (pTDEP) grafts. In our center, we offer pTDEP to reduce graft-versus-host disease for patients in complete remission at transplant time. In this retrospective study, we investigated the DRCI in 404 adult patients (including 37.6% pTDEP) undergoing a first HSCT for hematological malignancies from 2008 to 2018. Because of the small number of patients in LR, VLR and LR were combined for analysis. In the entire cohort, 2-year OS was 84.4% (95% CI, 71.6% to 97.2%) for LR, 61.6% (54.8% to 68.4%) for IR-1, 45.7% (33.3% to 58.1%) for IR-2, 31% (19.4% to 42.6%) for HiR, and 30.9% (14.5% to 47.3%) for VHR (P < .001). In addition, the DRCI was predictive of DFS, RI, and GRFS but not of nonrelapsed mortality and graft-versus-host disease. Our study confirms similar results with the original publication but gives less accurate prognosis information than the DRI and HCT-CI when used separately. In conclusion, the DRCI does not seem to offer more relevant information than the DRI and HCT-CI to help physicians and patients for the HSCT decision.

Macrophage activation syndrome as an unusual presentation of paucisymptomatic severe acute respiratory syndrome coronavirus 2 infection: A case report.

RATIONALE: Macrophage activation syndrome (MAS) is a rare life-threatening condition characterized by cytokine-mediated tissue injury and multiorgan dysfunction. PATIENT CONCERNS: We describe the unique case of young man who developed MAS as the sole manifestation of an otherwise paucisymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DIAGNOSES: Clinical and biological criteria led to the diagnosis of MAS; cytokine profile was highly suggestive reverse transcription polymerase chain reaction for SARS-CoV-2 in nasopharyngeal swabs was negative, but serum anti-SARS-CoV-2 immunoglobulin A and immunoglobulin G resulted positive leading to the diagnosis of SARS-CoV-2 infection. INTERVENTIONS: The patient was treated with empiric antibiotic and hydroxychloroquine. OUTCOMES: Clinical improvement ensued. At follow-up, the patient is well. LESSON: SARS-CoV-2 infection may trigger develop life-threatening complications, like MAS. This can be independent from coronavirus disease 2019 gravity.

Management of superior vena cava syndrome in critically ill cancer patients.

PURPOSE: The purpose of this study is to describe the management and outcome of critically ill cancer patients with Superior Vena Cava Syndrome (SVCS). METHODS: All cancer patients admitted to the medical intensive care unit (ICU) of the Saint-Louis University Hospital for a SVCS between January 2004 and December 2016 were included. RESULTS: Of the 50 patients included in the study, obstruction of the superior vena cava was partial in two-thirds of the cases and complete in one-third. Pleural effusion was reported in two-thirds of the patients, pulmonary atelectasis in 16 (32%), and pulmonary embolism in five (10%). Computed tomography of the chest showed upper airway compression in 18 (36%) cases, while echocardiography revealed 22 (44%) pericardial effusions. The causes of SVCS were diagnosed one (0-3) day after ICU admission, using interventional radiology procedures in 70% of the cases. Thirty (60%) patients had hematological malignancies, and 20 (40%) had solid tumors. Fifteen (30%) patients required invasive mechanical ventilation, seven (14%) received vasopressors, and renal replacement therapy was implemented in three (6%). ICU, in-hospital, and 6-month mortality rates were 20, 26, and 48%, respectively. The cause of SVCS was the only factor independently associated with day 180 mortality by multivariate analysis. Patients with hematological malignancies had a lower mortality than those with solid tumors (27 versus 80%) (odds ratio 0.12, 95% confidence interval (0.02-0.60), p < 0.01). CONCLUSION: Airway obstruction and pleural and pericardial effusions contributed to the unstable condition of cancer patients with SVCS. The vital prognosis of SVCS was mainly related to the underlying diagnosis.