Upper and/or Lower Respiratory Tract Infection Caused by Human Metapneumovirus After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.

Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: A multicenter prospective analysis.

Introduction: Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. Methods: We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). Results: Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 109/L, Hb > 80g/L and platelet count > 20 x 109/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 109/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. Discussion: In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.

Outcomes after allogeneic hematopoietic cell transplant in patients diagnosed with blast phase of myeloproliferative neoplasms: A retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year overall survival (OS) was 36% (95% confidence interval [CI], 32-36). Factors associated with lower OS were Karnofsky Performance Score (KPS) <90 (hazard ratio [HR] 1.65, p < .001) and active disease at allo-HCT (HR 1.45, p < .001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression-free survival (PFS). Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p = .008). Active disease at allo-HCT (HR 1.34, p = .03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo-HCT from mismatched related donors were associated with a higher non-relapse mortality (HR 2.66, p = .003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS ≥90 and in CR at transplant had a better prognosis.

Autologous hematopoietic cell transplantation for relapsed multiple myeloma performed with cells procured after previous transplantation-study on behalf of CMWP of the EBMT.

Autologous hematopoietic cell transplantation (auto-HCT) may be performed in multiple myeloma (MM) patients relapsing after a previous auto-HCT. For those without an adequate dose of stored stem cells, remobilization is necessary. This retrospective study included patients who, following disease relapse after the first auto-HCT(s), underwent stem cell remobilization and auto-HCT performed using these cells. There were 305 patients, 68% male, median age at salvage auto-HCT was 59 years. The median time to relapse after the first-line penultimate auto-HCT(s) was 30.6 months, the median follow-up after salvage auto-HCT 31 months. The 2- and 4-year non-relapse mortality (NRM) after the salvage auto-HCT was 5 and 9%, the relapse incidence 56 and 76%, respectively. Overall survival (OS) after 2 and 4 years was 76 and 52%, progression-free survival (PFS) 39 and 15%. In multivariable analysis an increasing interval between the penultimate auto-HCT and relapse was associated with better OS and PFS, later calendar year of salvage auto-HCT with better OS. In conclusion, salvage auto-HCT performed with cells remobilized after a previous auto-HCT was associated with acceptable NRM. The leading cause of failure was disease progression of MM, which correlated with a shorter interval from the penultimate auto-HCT to the first relapse.

Safety and Efficacy of Antibiotic De-escalation and Discontinuation in High-Risk Hematological Patients With Febrile Neutropenia: A Single-Center Experience.

BACKGROUND: There is currently no consensus on optimal duration of antibiotic treatment in febrile neutropenia. We report on the clinical impact of implementation of antibiotic de-escalation and discontinuation strategies based on the Fourth European Conference on Infections in Leukaemia (ECIL-4) recommendations in high-risk hematological patients. METHODS: We studied 446 admissions after introduction of an ECIL-4-based protocol (hereafter "ECIL-4 group") in comparison to a historic cohort of 512 admissions. Primary clinical endpoints were the incidence of infectious complications including septic shock, infection-related intensive care unit (ICU) admission, and overall mortality. Secondary endpoints included the incidence of recurrent fever, bacteremia, and antibiotic consumption. RESULTS: Bacteremia occurred more frequently in the ECIL-4 group (46.9% [209/446] vs 30.5% [156/512]; P < .001), without an associated increase in septic shock (4.7% [21/446] vs 4.5% [23/512]; P = .878) or infection-related ICU admission (4.9% [22/446] vs 4.1% [21/512]; P = .424). Overall mortality was significantly lower in the ECIL-4 group (0.7% [3/446] vs 2.7% [14/512]; P = .016), resulting mainly from a decrease in infection-related mortality (0.4% [2/446] vs 1.8% [9/512]; P = .058). Antibiotic consumption was significantly reduced by a median of 2 days on antibiotic therapy (12 vs 14; P = .001) and 7 daily antibiotic doses (17 vs 24; P < .001) per admission period. CONCLUSIONS: Our results support implementation of ECIL-4 recommendations to be both safe and effective based on real-world data in a large high-risk patient population. We found no increase in infectious complications and total antibiotic exposure was significantly reduced.

Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT.

JAK1/2 inhibitor ruxolitinib (RUX) is approved in patients with myelofibrosis but the impact of pretreatment with RUX on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) remains to be determined. We evaluated the impact of RUX on outcome in 551 myelofibrosis patients who received HSCT without (n = 274) or with (n = 277) RUX pretreatment. The overall leukocyte engraftment on day 45 was 92% and significantly higher in RUX responsive patients than those who had no or lost response to RUX (94% vs. 85%, p = 0.05). The 1-year non-relapse mortality was 22% without significant difference between the arms. In a multivariate analysis (MVA) RUX pretreated patients with ongoing spleen response at transplant had a significantly lower risk of relapse (8.1% vs. 19.1%; p = 0.04)] and better 2-year event-free survival (68.9% vs. 53.7%; p = 0.02) in comparison to patients without RUX pretreatment. For overall survival the only significant factors were age > 58 years (p = 0.03) and HLA mismatch donor (p = 0.001). RUX prior to HSCT did not negatively impact outcome after transplantation and patients with ongoing spleen response at time of transplantation had best outcome.

Mycosis fungoides of the vulva.

Mycosis fungoides (MF) is an indolent form of non-Hodgkin lymphoma and the most common type of primary cutaneous T-cell lymphoma. The overall incidence of MF is approximately 4 per 1 million. Involvement of the vulva by MF is extremely rare, with only seven reported cases in the literature. At the vulva, it is mainly a metastatic lesion and rarely a primary malignancy. We describe a case of vulvar MF and discuss the previous cases. The presentation can easily be confused with benign skin disorders. A vulvar lesion can reflect a systemic disease. When a patient consults for a vulvar lesion it is therefore important not only to look at the vulva but also to examine her in and ask general questions. In a patient with a vulvar mass and cutaneous lesions on other locations MF should be considered in the differential diagnosis.

Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party.

Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR = 6.6; p = 0.001 and OR = 3.3; p = 0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma.

BACKGROUND: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes. METHODS: We performed a database search using the terms "BCMA," "CAR," and "multiple myeloma" for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332). RESULTS: Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0-88.2); 10.5% (6.8-16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3-26.7; I2 = 45%) versus 2.8% (1.3-6.1; I2 = 0%) (p < 0.0001). The pooled overall response rate was 80.5% (73.5-85.9); complete responses (CR) were observed in 44.8% (35.3-54.6). A pooled CR rate of 71.9% (62.8-79.6; I2 = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5-41.1; I2 = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4-17.4) months, which compared favorably to the expected PFS of 1.9 (1.5-3.7) months (HR 0.14; p < 0.0001). CONCLUSIONS: Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT - A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party.

Elevated serum ferritin levels occur due to iron overload or during inflammation and macrophage activation. A correlation of high serum ferritin levels with increased mortality after alloSCT has been suggested by several retrospective analyses as well as by two smaller prospective studies. This prospective multicentric study aimed to study the association of ferritin serum levels before start of conditioning with alloSCT outcome. Patients with acute leukemia, lymphoma or MDS receiving a matched sibling alloSCT for the first time were considered for inclusion, regardless of conditioning. A comparison of outcomes between patients with high and low ferritin level was performed using univariate analysis and multivariate analysis using cause-specific Cox model. Twenty centers reported data on 298 alloSCT recipients. The ferritin cut off point was determined at 1500 µg/l (median of measured ferritin levels). In alloSCT recipients with ferritin levels above cut off measured before the start of conditioning, overall survival (HR = 2.5, CI = 1.5-4.1, p = 0.0005) and progression-free survival (HR = 2.4, CI = 1.6-3.8, p < 0.0001) were inferior. Excess mortality in the high ferritin group was due to both higher relapse incidence (HR = 2.2, CI = 1.2-3.8, p = 0.007) and increased non-relapse mortality (NRM) (HR = 3.1, CI = 1.5-6.4, p = 0.002). NRM was driven by significantly higher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.

The TEMPI syndrome.

The TEMPI syndrome is a rare and acquired disorder characterized by 5 salient features, which compose its name: (1) telangiectasias; (2) elevated erythropoietin and erythrocytosis; (3) monoclonal gammopathy; (4) perinephric fluid collections; and (5) intrapulmonary shunting. Complete resolution of symptoms following treatment with plasma cell-directed therapy supports the hypothesis that the monoclonal antibody is causal and pathogenic. Understanding the basis of the TEMPI syndrome will depend on the identification of additional patients and a coordinated international effort.

Incidence and outcome of Kaposi sarcoma after hematopoietic stem cell transplantation: a retrospective analysis and a review of the literature, on behalf of infectious diseases working party of EBMT.

The incidence, the clinical characteristics, and the outcome of Kaposi sarcoma (KS) in patients after hematopoietic stem cell transplantation (HSCT) were assessed. During the period 1987-2018, 13 cases of KS were diagnosed, 3 females and 10 males, median age of 50 years, median time from HSCT of 7 months. KS had an incidence of 0.17% in allogeneic and 0.05% in autologous HSCT. HHV-8 was documented in eight of nine tumor tissue samples assessed. The organ involvement was: skin in nine, lymph nodes in six, oral cavity in four, and visceral in three patients, respectively; seven patients had >1 organ involved. Five patients had immunosuppression withdrawn, whereas four and three patients received radiotherapy and chemotherapy, respectively. Eight patients are alive (median follow-up 48 months, range 5-128), whereas five patients died after a median time of 8 months from the diagnosis of KS. However, no death was caused by KS. We conclude that the incidence of KS after HSCT is very low. Although KS can be managed with the reduction of immunosuppression, visceral forms may require chemotherapy and/or radiotherapy. The low prevalence of KS indicates that screening for HHV-8 serology and surveillance for HHV-8 viremia are not indicated in HSCT patients.

Association of uric acid levels before start of conditioning with mortality after allogeneic hematopoietic stem cell transplantation - a prospective, non-interventional study of the EBMT Transplant Complication Working Party.

Uric acid is a danger signal contributing to inflammation. Its relevance to allogeneic stem cell transplantation (alloSCT) derives from preclinical models where the depletion of uric acid led to improved survival and reduced graft-versus-host disease (GvHD). In a clinical pilot trial, peri-transplant uric acid depletion reduced acute GvHD incidence. This prospective international multicenter study aimed to investigate the association of uric acid serum levels before start of conditioning with alloSCT outcome. We included patients with acute leukemia, lymphoma or myelodysplastic syndrome receiving a first matched sibling alloSCT from peripheral blood, regardless of conditioning. We compared outcomes between patients with high and low uric acid levels with univariate- and multivariate analysis using a cause-specific Cox model. Twenty centers from 10 countries reported data on 366 alloSCT recipients. There were no significant differences in terms of baseline comorbidity and disease stage between the high- and low uric acid group. Patients with uric acid levels above median measured before start of conditioning did not significantly differ from the remaining in terms of acute GvHD grades II-IV incidence (Hazard ratio [HR] 1.5, 95% Confidence interval [CI]: 1.0-2.4, P=0.08). However, they had significantly shorter overall survival (HR 2.8, 95% CI: 1.7-4.7, P<0.0001) and progression free survival (HR 1.6, 95% CI: 1.1-2.4, P=0.025). Non-relapse mortality was significantly increased in alloSCT recipients with high uric acid levels (HR 2.7, 95% CI: 1.4-5.0, P=0.003). Finally, the incidence of relapse after alloSCT was increased in patients with higher uric acid levels (HR 1.6, 95% CI: 1.0-2.5, P=0.04). We conclude that high uric acid levels before the start of conditioning correlate with increased mortality after alloSCT.

Tandem Autologous Stem Cell Transplantation Improves Outcomes in Newly Diagnosed Multiple Myeloma with Extramedullary Disease and High-Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (n = 373), tandem autologous (n = 84), or autologous-allogeneic transplant (n = 31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (n = 202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (P = .06 and P = .30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; P = .003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, .46 and .64; P = .02 and P = .03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, .31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.

Impact of antithymocyte globulin on outcomes of allogeneic hematopoietic cell transplantation with TBI.

The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P < .001), grade III-IV aGVHD (HR, 0.21; P < .001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate.