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Descriviamo il caso di una giovane paziente di 39 anni con recidiva ematologica tardiva di leucemia acuta linfoblastica emersa a 23 mesi da fine mantenimento e a due giorni dall’approvazione di brexu-cel in regime di rimborsabilità del Servizio sanitario nazionale. Il particolare nesso temporale favorevole tra i due eventi ci ha permesso di avviare immediatamente la paziente a linfocitoaferesi, terapia bridge con inotuzumab ozogamicin e successivo trattamento con brexu-cel, ottenendo una remissione molecolare di malattia, e successivamente a trapianto allogenico di cellule staminali a consolidamento di tale ottima risposta. Attualmente, a 19 mesi da infusione di brexu-cel e a 15 mesi dal trapianto allogenico, la paziente mantiene la MRD negatività, non presenta graft-versus-host disease e conduce una vita attiva e di ottima qualità.

La terapia cellulare anti-CD19 CAR-T (cellule T con recettore chimerico per l’antigene) brexucabtagene autoleucel (brexu-cel) rappresenta un’opzione terapeutica promettente e disponibile per il paziente affetto da leucemia acuta linfoblastica-B Philadelphia-positiva ricaduta/refrattario, anche dopo molteplici precedenti linee di terapia comprendenti terapie anti-CD19 e precedente trapianto allogenico di cellule staminali ematopoietiche. Nel caso clinico presentato si evidenziano altri aspetti centrali per la gestione corretta, complessa e multidisciplinare di questa categoria di pazienti quali la scelta della terapia bridge, l’importanza della valutazione dell’espressione del CD19, il burden di malattia come predittore di outcome, il ruolo del trapianto allogenico di cellule staminali ematopoietiche di consolidamento.

The PI3K/mTOR pathway is the second most frequently deregulated pathway in a majority of cancers such as breast cancer, lung cancer, and melanomas as well as leukemia. Mutations in the genes coding for receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) are quite common in all forms of acute leukemia. This can be a major cause of deregulation of the PI3K-mTOR pathway. To understand how cells display resistance to the dual PI3K/mTOR inhibitor, we used a panel of 25 acute leukemia cell lines. We observed that while a number of cell lines displayed sensitivity to the dual PI3K/mTOR pathway inhibitor PKI-587, many cells displayed substantial resistance. Cells sensitive to PKI-587 also showed aberrant activation of PI3K/mTOR pathway components such as AKT and S6K and also displayed sensitivity to a panel of various other PI3K/mTOR inhibitors. Using RNA sequencing data, we observed that expression of a G protein-coupled receptor, P2RY14, was upregulated nine-fold in cells showing resistance to the PI3K/mTOR inhibitor. P2RY14 has not been much studied in hematologic malignancies. However, this receptor seems to have a role in the localization of hematopoietic stem cells (HSCs) and in promoting regenerative capabilities following injury. We observed that acute lymphoblastic leukemia (ALL) and FLT3-ITD-positive acute myeloid leukemia (AML) patients with higher expression of P2RY14 mRNA displayed relatively poor survival compared to patients carrying lower expression of P2RY14 suggesting a role of P2RY14 in patient survival. To understand the role of this receptor in cell signaling, we used phospho-protein arrays and observed activation of distinct signaling cascades. Furthermore, array data were verified using murine pro-B cell line Ba/F3 stably transfected with P2RY14. We observed that activation of P2RY14 by its ligand, UDP-glucose, resulted in selective induction of ERK1/2 phosphorylation. Taken together, our data suggest that acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of a GPCR, P2RY14, which has a role in patient survival and also couples to the activation of ERK signaling.

Immunoglobulin gene rearrangements are used as PCR targets for detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). We investigated the occurrence of monoclonal immunoglobulin kappa-deleting element (IGK-Kde) rearrangements by Southern blotting and PCR/heteroduplex analysis at diagnosis, their stability at relapse, and their applicability in real-time quantitative PCR (RQ-PCR) analysis. In 77 selected children with precursor-B-ALL, Southern blotting detected 122 IGK-Kde rearrangements, 12 of which were derived from subclones in six patients (8%). PCR/heteroduplex analysis with BIOMED-1 Concerted Action primers identified 100 of the 110 major IGK-Kde rearrangements (91%). Comparison between diagnosis and relapse samples from 21 patients with PCR-detectable IGK-Kde rearrangements (using Southern blotting, PCR/heteroduplex analysis, and sequencing) demonstrated that 27 of the 32 rearrangements remained stable at relapse. When patients with oligoclonal IGK-Kde rearrangements were excluded, 25 of the 27 rearrangements remained stable at relapse and at least one stable rearrangement was present in 17 of the 18 patients. Subsequently, RQ-PCR analysis with allele-specific forward primers, a germline Kde TaqMan-probe, and a germline Kde reverse primer was evaluated for 18 IGK-Kde rearrangements. In 16 of the 18 targets (89%) a sensitivity of < or =10(-4) was reached. Analysis of MRD during follow-up of eight patients with IGK-Kde rearrangements showed comparable results between RQ-PCR data and classical dot-blot data. We conclude that the frequently occurring IGK-Kde rearrangements are generally detectable by PCR (90%) and are highly stable MRD-PCR targets, particularly where monoclonal rearrangements at diagnosis (95%) are concerned. Furthermore, most IGK-Kde rearrangements (90%) can be used for sensitive detection of MRD (< or =10(-4)) by RQ-PCR analysis.

ObjectiveSelected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on.Design53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core‐related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy.ResultsTwo cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values.ConclusionsPegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.

Chronic infection with hepatitis B virus (HBV) leads to an increased risk of death from cirrhosis and hepatocellular carcinoma. Functional cure rates are low with current treatment options (nucleos(t)ide analogs (NAs) and pegylated interferons). Bepirovirsen is an antisense oligonucleotide targeting all HBV messenger RNAs; in cell culture and animal models, bepirovirsen leads to reductions in HBV-derived RNAs, HBV DNA and viral proteins. This phase 2 double-blinded, randomized, placebo-controlled trial is the first evaluation of the safety and activity of an antisense oligonucleotide targeting HBV RNA in both treatment-naïve and virally suppressed individuals with chronic HBV infection. The primary objective was to assess the safety and tolerability of bepirovirsen in individuals with chronic hepatitis B (CHB) (NCT02981602). The secondary objective was to assess antiviral activity, including the change from baseline to day 29 in serum hepatitis B surface antigen (HBsAg) concentration. Participants with CHB infection ≥6 months and serum HBsAg ≥50 IU ml −1 were enrolled from seven centers across Hong Kong and the Republic of Korea and randomized (3:1 within each dose cohort) to receive bepirovirsen or placebo via subcutaneous injection twice weekly during weeks 1 and 2 (days 1, 4, 8 and 11) and once weekly during weeks 3 and 4 (days 15 and 22). Participants were then followed for 26 weeks. Twenty-four participants were treatment-naïve and seven were receiving stable NA therapy. Treatment-emergent adverse events were mostly mild/moderate (most commonly injection site reactions). Eleven (61.1%) and three (50.0%) treatment-naïve participants experienced one or more treatment-emergent adverse event in the bepirovirsen and placebo groups, respectively. In participants receiving NA therapy, the corresponding numbers were three (60.0%) and one (50.0%). Transient, self-resolving alanine aminotransferase flares (≥2× upper limit of normal) were observed in eight treatment-naïve participants and three participants on stable NA regimens in the bepirovirsen treatment arms. HBsAg reductions were observed and were significant versus placebo for treatment-naïve participants receiving bepirovirsen 300 mg ( P  = 0.001), but not for the bepirovirsen 150 mg group ( P  = 0.245) or participants receiving stable NA therapy ( P  = 0.762). Two participants in each of the 300 mg dose groups achieved HBsAg levels below the lower limit of quantitation by day 29 ( n  = 3) or day 36 ( n  = 1). Bepirovirsen had a favorable safety profile. These preliminary observations warrant further investigation of the safety and activity of bepirovirsen in a larger CHB patient population. A first-in-human study of an antisense oligonucleotide targeting hepatitis B virus (HBV) RNA provides initial insights into this potential new therapeutic modality for individuals with chronic HBV infection.

In a phase 2 trial involving participants taking a nucleoside or nucleotide analogue, 23% of those assigned to receive xalnesiran plus pegylated interferon alfa-2a had HBsAg loss at 24 weeks after the end of treatment.

Preventing mother-to-child transmission of hepatitis B virus is an opportunity to prevent lifelong infection and associated complications. This randomized, placebo-controlled trial in Thailand assessed tenofovir to prevent HBV infection in infants.

Perinatal hepatitis B virus (HBV) infection carries a significant risk of chronicity and complications while making infected people reservoirs for further transmission. Hepatitis B immunization in infants, with or without hepatitis B immune globulin (HBIG), has proven effective in preventing mother-to-child transmission. Nevertheless, some newborns of mothers with high viremia testing positive for hepatitis B e antigen (HBeAg) may not benefit from HBV immunoprophylaxis. Nineteen (10.2 %) of 186 infants born to HBV-infected mothers were HBV DNA-positive. HBV genotypes, serotypes, and hepatitis B surface antigen (HBsAg) sequences were comparable in most mother-cord blood-infant sample pairings, indicating that the infants' HBV strains originated from their mothers. Three (15.3 %) infants had overt HBV infection, whereas 16 (84.2 %) had occult HBV infection (OBI). The HBV isolates from infants exhibited 26 mutations: 38.5 % in the ‘a’ determinant and 61.5 % in the rest of HBsAg. Mutations were identified in B-cell and T-cell epitopes, impairing humoral and cellular responses to detect or neutralize the virus. This rendered immunoprophylaxis and diagnostics ineffective while inducing tolerance to the infection. HBV strains with these mutations can persist and cause complications, but they can be transmitted undetected by HBsAg tests commonly used in community healthcare. This study reveals the risk of HBV transmission from HBsAg mutant-infected mothers to newborns despite having received the birth dose with HBIG and complete hepatitis B vaccination. •HBV S protein mutation can impair detection and immune neutralization of the virus•HBV mutants can persist in fully vaccinated infants and spread unnoticed•Babies born to mothers infected with HBV mutants may not be prevented by vaccination and HBIG•Vaccine escape and diagnosis failure are challenges to the efficacy of vaccination