TCRαß/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis.

ABSTRACT: TCRαß/CD19 cell depletion is a promising graft manipulation technique frequently used in the context of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of exvivo T-cell depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median, 47.6 months for surviving patients). With a 5-year cumulative incidence of nonrelapse mortality of 5.2% (95% confidence interval [CI], 2.8%-8.8%) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9%-29.2%), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI, 68.6%-80.9%) and 71.6% (95% CI, 64.4%-77.6%), respectively. Cumulative incidence of both grade II-IV acute and chronic graft-versus-host disease were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including type of disease, use of total body irradiation in the conditioning regimen (hazard ratio [HR], 0.5; 95% CI, 0.26-0.98; P = .04), disease status at HSCT (complete remission [CR] ≥3 vs CR 1/2; HR, 2.23; 95% CI, 1.20-4.16; P = .01), and high levels of pre-HSCT minimal residual disease (HR, 2.09; 95% CI, 1.01-4.33; P = .04) were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable on those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted.

Outcomes of children and young adults with B-cell acute lymphoblastic leukemia given blinatumomab as last consolidation treatment before allogeneic hematopoietic stem cell transplantation.

Blinatumomab has remarkable efficacy in patients with relapsed/refractory (r/r) or measurable residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (B-ALL). In many patients, blinatumomab treatment is followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of blinatumomab on HSCT outcomes in children and young adults (YA) remains to be fully elucidated. We conducted a single-center, retrospective analysis on patients given blinatumomab as last treatment before HSCT. Seventy-eight pediatric and YA patients were evaluated. With a median follow-up of 23.23 months, the 2-year disease-free (DFS) and overall survival (OS) probability were 72.2% and 89.2%, respectively, with a 2-year cumulative incidence (CI) of non-relapse mortality (NRM) of 2.6%. A trend toward improved 2-year DFS, but not OS, was noted in patients transplanted in first complete remission (CR1) (92.9%) compared to those in second or greater remission (CR2/3) (68.5%, p=0.18) due to a lower CI of relapse (0% vs. 29.9%, p=0.05). Among CR2/3 patients, those receiving the sequential combination of inotuzumab and blinatumomab had a significantly lower CI of relapse as compared to those who did not receive inotuzumab (9.5% vs. 40.4%, p=0.023). Relapse after HSCT occurred in 16 patients, all exhibiting CD19-positive blasts; 10 of them received anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and 2 inotuzumab as salvage therapy, leading to a 2-year post-relapse OS of 52.7%. Our results indicate that HSCT following blinatumomab in children and YA with B-ALL is highly effective, being associated with low NRM and not affecting the efficacy of subsequent salvage immunotherapies, including CAR-T cells.

Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells implicated in the response to fungal and bacterial infections. Their contribution to restoring T-cell immunity and influencing hematopoietic stem cell transplant (HSCT) outcomes remains poorly understood. We retrospectively studied MAIT-cell recovery in 145 consecutive children and young adults with hematologic malignancies undergoing allogeneic (allo)-HSCT between April 2019 and May 2022, from unrelated matched donor (MUD, N=52), with standard graft-versus-host-disease (GvHD) prophylaxis, or HLA-haploidentical (Haplo, N=93) donor after in vitro αßT/CD19-cell depletion, without post-HSCT pharmacological prophylaxis. With a median follow-up of 33 months (range, 12-49 months), overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) were 79.5%, 72%, and 7%, respectively; GvHD-free relapse-free survival (GRFS) was 63%, while cumulative incidence of relapse was 23%. While αßT cells were reconstituted 1-2 years post HSCT, MAIT cells showed delayed recovery and prolonged functional impairment, characterized by expression of activation (CD25, CD38), exhaustion (PD1, TIM3) and senescence (CD57) markers, and suboptimal ex vivo response. OS, DFS, and NRM were not affected by MAIT cells. Interestingly, higher MAIT cells at day +30 correlated with higher incidence of grade II-IV acute GvHD (19% vs. 7%, P=0.06). Furthermore, a greater MAIT-cell count tended to be associated with a higher incidence of chronic GvHD (cGvHD) (17% vs. 6%, P=0.07) resulting in lower GRFS (55% vs. 73%, P=0.05). Higher MAIT cells also correlated with greater cytomegalovirus (CMV) reactivation and lower late blood stream infections (BSI) (44% vs. 24%, P=0.02 and 9% vs. 18%, P=0.08, respectively). Future studies are needed to confirm the impact of early MAIT-cell recovery on cGvHD, CMV reactivation, and late BSI.

Human leukocyte antigen evolutionary divergence influences outcomes of paediatric patients and young adults affected by malignant disorders given allogeneic haematopoietic stem cell transplantation from unrelated donors.

High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9-10/10 HLA-matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, using the locus median to stratify patients with 'high' or 'low' HED. Patients with high HED-B and -DRB1 showed significantly improved disease-free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED-B + -DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non-relapse-mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED-B + -DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA-DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice.

Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP).

Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.

Amphiregulin, ST2, and REG3α biomarker risk algorithms as predictors of nonrelapse mortality in patients with acute GVHD.

ABSTRACT: Graft-versus-host disease (GVHD) is a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Algorithms containing either the gastrointestinal (GI) GVHD biomarker amphiregulin (AREG) or a combination of 2 GI GVHD biomarkers (suppressor of tumorigenicity-2 [ST2] + regenerating family member 3 alpha [REG3α]) when measured at GVHD diagnosis are validated predictors of NRM risk but have never been assessed in the same patients using identical statistical methods. We measured the serum concentrations of ST2, REG3α, and AREG by enzyme-linked immunosorbent assay at the time of GVHD diagnosis in 715 patients divided by the date of transplantation into training (2004-2015) and validation (2015-2017) cohorts. The training cohort (n = 341) was used to develop algorithms for predicting the probability of 12-month NRM that contained all possible combinations of 1 to 3 biomarkers and a threshold corresponding to the concordance probability was used to stratify patients for the risk of NRM. Algorithms were compared with each other based on several metrics, including the area under the receiver operating characteristics curve, proportion of patients correctly classified, sensitivity, and specificity using only the validation cohort (n = 374). All algorithms were strong discriminators of 12-month NRM, whether or not patients were systemically treated (n = 321). An algorithm containing only ST2 + REG3α had the highest area under the receiver operating characteristics curve (0.757), correctly classified the most patients (75%), and more accurately risk-stratified those who developed Minnesota standard-risk GVHD and for patients who received posttransplant cyclophosphamide-based prophylaxis. An algorithm containing only AREG more accurately risk-stratified patients with Minnesota high-risk GVHD. Combining ST2, REG3α, and AREG into a single algorithm did not improve performance.

Adverse Drug Reactions of Acetaminophen and Ibuprofen in the Paediatric Population: Analysis of the Italian Spontaneous Reporting Database.

BACKGROUND: Acetaminophen and ibuprofen are the only antipyretics drugs approved in children, and are considered safe and well tolerated. However, data regarding the adverse drug reaction (ADR) profile of these drugs in children are scattered. AIM: The aim of our study is to evaluate the ADRs of acetaminophen and ibuprofen through an observational study over a period of 15 years (January 2005-April 2020). Reports of suspected ADRs to the active substances 'acetaminophen' and 'ibuprofen' are listed and accessible through the Italian spontaneous reporting database (RAM system) by AIFA (Pharmacovigilance of the Italian Drug Agency). METHODS: Acetaminophen ADRs in paediatric populations were 15% of cases, with more frequent involvement of skin and soft tissue (54.36%) and gastrointestinal apparatus (44.09%); liver dysfunction accounts for 5.67%. RESULTS: Ibuprofen paediatric ADRs were 26%: skin and soft tissues in 63.16% of cases, gastrointestinal tract in 47.75%, hematemesis and melena in 6.38%; kidney injury in 2.25% of cases. CONCLUSION: Children aged 2 to 11 are more frequently affected by ADRs than infants and adolescents. The risk of gastrointestinal and renal side effects is significantly higher with ibuprofen. Hepatobiliary side effects are more frequently linked to acetaminophen. Potentially fatal ADRs have been reported sporadically for both drugs.

Case Report: Trichosporon japonicum Fungemia in a Pediatric Patient With Refractory Acute B Cell Lymphoblastic Leukemia.

Trichosporon japonicum is a very rare opportunistic yeast causing fungal disease in humans, especially in immunocompromised hosts. Here, we describe a new case of T. japonicum isolated from the blood of a pyrexial pediatric patient with refractory acute B cell lymphoblastic leukemia and acute respiratory distress. Prompt diagnosis through early clinical suspicion and appropriate molecular microbiology analysis allowed the yeast to be accurately identified at species level. Subsequent drug susceptibility testing and focused antifungal treatment with voriconazole and amphotericin B led to a complete clinical and mycological resolution of the infection, which represents the second successful case of T. japonicum bloodstream infection described in literature to date.

Testing for fecal gluten immunogenic peptides: a useful tool to evaluate compliance with gluten-free diet by celiacs.

BACKGROUND: Although experts agree that strict dietary compliance is fundamental for the health of celiac patients, there are no evidence-based recommendations on the best way to assess dietary compliance. Detection of gluten immunogenic peptides (GIPs) in feces was recently proposed as an effective method of assessing the dietary compliance of celiac patients. METHODS: Fifty-five consecutive celiac patients (27 adults and 28 children, age 6-72 years), who had been on a gluten-free diet for at least 2 years, were enrolled. All patients were evaluated clinically for symptoms, physical parameters and laboratory parameters. Dietary compliance was assessed with the Biagi questionnaire and serum anti-tissue transglutaminase (tTG) IgA antibodies were measured. GIPs were determined by immunoenzymatic assay on an automated Chorus analyzer (DIESSE Diagnostica Senese), after extraction of fecal samples by the method developed by DIESSE. RESULTS: Eight patients tested positive for GIPs (GIPs+); 71.4% of GIP-positive patients were asymptomatic; tTG antibodies were detected in 3/8 GIP+ patients. The Biagi score was significantly associated with fecal positivity for GIPs (P=0.02). However, according to the Biagi score, 57.1% of GIP+ patients followed the diet strictly and 5.4% of GIP- subjects did not comply with the diet or made substantial mistakes. CONCLUSIONS: Assay of fecal GIPs identified more patients who did not comply with the diet than did the Biagi questionnaire, evaluation of symptoms or anti-tTG antibodies. Detection of fecal GIPs offers a direct, objective, quantitative assessment of even occasional exposure to gluten and is confirmed as a practical way to check dietary compliance.

Fecal gluten immunogenic peptides as indicators of dietary compliance in celiac patients.

BACKGROUND: It is important to have methods for evaluating dietary compliance in patients with celiac disease (CD). Determination of fecal gluten immunogenic peptides (GIPs) was recently proposed as a method of detecting gluten intake. The aim of this study was to evaluate whether determination of GIPs can be used as an indicator of compliance with a gluten-free diet (GFD). METHODS: Twenty-five persons with CD on a gluten-free diet for at least one year were enrolled in the study. Compliance with the diet was assessed by the Biagi questionnaire, evaluation of symptoms and assay of IgA anti-tissue transglutaminase antibodies (IgA anti-tTG). GIPs were determined by iVYLISA GIP-S test (Biomedal S.L., Seville, Spain) on an automated Chorus analyzer (DIESSE Diagnostica Senese, Siena, Italy), after extraction of fecal samples by the method developed by DIESSE. RESULTS: Four patients tested positive for GIPs (GIP+), two of whom complied strictly with the gluten-free diet according to the Biagi questionnaire. None of the four GIP-positive patients manifested symptoms. IgA anti-tTG was significantly higher in GIP+ than in GIP- subjects. CONCLUSIONS: Assay of fecal GIPs identified more patients who were not complying with the diet than the Biagi questionnaire or evaluation of symptoms. The anti-tTG and GIP results agreed perfectly; however, since anti-tTG antibodies remain high for longer and are not a completely reliable marker of GFD intake, detection of fecal GIPs offers a direct, objective, quantitative assessment of exposure, even occasional, to gluten and could be used to check dietary compliance.