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The Transplant Centers belonging to Gruppo Italiano per il Trapianto di Midollo Osseo (GITMO) conducted a survey with the aim of evaluating the effect of SARS-CoV2 pandemic on the allogeneic transplant activity in Italy. The pandemic period from 1/3/2020 to 31/7/2020 was compared with the same period in 2019. Overall, in 2020 there was a 2.4% reduction in the number of allo-HCT cases compared to 2019. Interestingly, this deflection did not affect the acute leukemia cases (+5.7% in 2020). The use of peripheral blood-derived stem cells (+10.7%) and cryopreservation (97.4% of the centers) was highly adopted in 2020. Despite the sanitary emergency, almost all of the surveyed centers declared no impact of SARS-CoV2 pandemic on the transplant timing and outcomes, and the sanitary policy was positively evaluated by the majority of centers. The emergency measures ensured that only a minority of the allo-HCT patients had been infected by SARS-CoV2; however, a mortality of 42.1% among the allo-HCT patients hospitalized for COVID-19 was recorded. This survey gives us the information that the GITMO Group reacted positively to the pandemic. Thanks to the emergency strategies, the Italian allo-HCT activity continued safely, showing only a minor deflection and offering the same probability of cure to the transplanted patients.

BACKGROUND: Balloon pulmonary angioplasty (BPA) represents a therapeutic option for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) in patients who are not eligible for surgical pulmonary endarterectomy (PEA) or with persistent/recurrent symptomatic pulmonary arterial hypertension after PEA. This study evaluated the safety of BPA during 5 years of experience of the only Italian center systematically performing this procedure. METHODS: The BPA program was activated at the S. Orsola Polyclinic in Bologna in June 2015. Life-threatening periprocedural complications were defined as: death

Background Lung transplantation (LT) still remains a treatment option for patients with pulmonary arterial hypertension (PAH) and not operable chronic thromboembolic pulmonary hypertension patients (CTEPH). Purpose The study is intended to compare the survival of transplant recipients (TR) and the survival of not-transplanted (NT) patients since listing. Methods We included all patients with PAH and not-operable CTEPH listed for LT. The survival of NT, TR and of all listed patients was evaluated starting from the date of listing (patients were censored as alive at the time of LT). The survival of TR was also evaluated starting from the date of the LT. Results 125 patients were included (112, 90% had PAH). Fifty-eight (46%) patients were transplanted, after a mean waiting time of 1.5±1.3 years. Forty-one patients (33%) died while on the list and 25 (20%) patients were alive on the list on December 2019. The survival of NT patients at 1, 3 and 5 years after listing was 74%, 42%, 33%, respectively. The survival of TR patients at 1, 3 and 5 years after listing was 90%, 70%, 63%, respectively. The survival of all patients since listing (intention to treat analysis) at 1, 3 and 5 years was 85%, 59%, 48% respectively. The survival of TR at 1, 3 and 5 years since transplantation was 63%, 61%, 59%, respectively. Conclusions Despite biases in the comparison of non-randomized groups, the data confirm a better long-term survival since listing of TR as compared with NT PAH or not-operable CTEPH patients. Funding Acknowledgement Type of funding sources: None.

Dasatinib is a potent BCR-ABL inhibitor effective in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia (ALL) resistant/intolerant to imatinib. In the GIMEMA LAL1205 protocol, patients with newly diagnosed Ph+ ALL older than 18 years (with no upper age limit) received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy. Postremission therapy was free. Fifty-three patients were evaluable (median age, 53.6 years). All patients achieved a complete hematologic remission (CHR), 49 (92.5%) at day 22. At this time point, 10 patients achieved a BCR-ABL reduction to < 10−3. At 20 months, the overall survival was 69.2% and disease-free survival was 51.1%. A significant difference in DFS was observed between patients who showed at day 22 a decrease in BCR-ABL levels to < 10−3 compared with patients who never reached these levels during induction. In multivariate analysis, BCR-ABL levels of < 10−3 at day 85 correlated with disease-free survival. No deaths or relapses occurred during induction. Twenty-three patients relapsed after completing induction. A T315I mutation was detected in 12 of 17 relapsed cases. Treatment was well tolerated; only 4 patients discontinued therapy during the last phase of the induction when already in CHR. In adult Ph+ ALL, induction treatment with dasatinib plus steroids is associated with a CHR in virtually all patients, irrespective of age, good compliance, no deaths, and a very rapid debulking of the neoplastic clone. This trial was registered at [www.clinicaltrials.gov][1] as #[NCT00391989][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00391989&atom=%2Fbloodjournal%2F118%2F25%2F6521.atom

Infections by carbapenem-resistant Klebsiella pneumoniae (CRKp) represent a challenging problem after SCT. A retrospective survey (January 2010 to July 2013) involving 52 Italian centers was performed to assess the epidemiology and the prognostic factors of CRKp infections in auto- and allo-SCT. Cases of CRKp infection were reported in 53.4% of centers. CRKp infections were documented in 25 auto-SCTs and 87 allo-SCTs, with an incidence of 0.4% (from 0.1% in 2010 to 0.7% in 2013) and 2% (from 0.4% in 2010 to 2.9% in 2013), respectively. A CRKp colonization documented before or after transplant was followed by an infection in 25.8% of auto-SCT and 39.2% of allo-SCT patients. The infection-related mortality rates were 16% and 64.4%, respectively. A pre-transplant CRKp infection (hazard ratio (HR) 0.33, 95% confidence intervals (CIs) 0.15-0.74; P = 0.007) and a not CRKp-targeted first-line treatment (HR 2.67, 95% CI 1.43-4.99; P = 0.002) were independent factors associated with an increased mortality in allo-SCT patients who developed a CRKp infection. Our study shows challenging findings of CRKp infections in SCT patients in Italy particularly after allo-SCT. The detection of carriers and the definition of early therapeutic strategies represent critical aspects of the management of CRKp infections after SCT. OI Aversa, Franco/0000-0002-8871-6817; de Fabritiis, Paolo/0000-0002-1835-0581; TIRINDELLI, MARIA CRISTINA/0000-0003-4645-4465; cudillo, laura/0000-0002-6828-9707

For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.

La costitutiva attività tirosin-cinasica della proteina chimerica p210bcr-abl ha un ruolo centrale nella patogenesi e nella progressione della Leucemia Mieloide Cronica (LMC). Interagendo con molteplici circuiti di trasduzione del segnale mitogenico essa inibisce l'adesione delle cellule leucemiche allo stroma midollare, abroga i checkpoints del ciclo cellulare e induce resistenza all'apoptosi. Ciò che si osserva è un'abnorme espansione dell'ematopoiesi leucemica sulla controparte normale e l'instabilità genomica che ne condiziona l'evoluzione da un fenotipo normale, caratterizzante la fase cronica, ad un fenotipo trasformato tipico della crisi blastica. I risultati dello studio qui presentato indicano che la costitutiva attività tirosin-cinasica di p210bcr-abl ha effetti su molteplici segnali coinvolti nella via intrinseca e nella via estrinseca della apoptosi e convergenti sulla integrità della membrana mitocondriale. L'espressione di un costrutto sensibile in temperatura di Bcr-Abl in progenitori ematopoietici clonali (32D) e l'esposizione ad un inibitore specifico dell'attività tirosin-cinasica di p210bcr-abl (STI571) ci ha permesso di individuare il ruolo della proteina chimerica nella fase decisionale dell'apoptosi. P210bcr-abl causa l'overespressione dei segnali anti-apoptotici Bcl-2 e Bcl-xL, previene l'attivazione dei segnali pro-apoptotici Bid, Bad e Bax, impedendo la formazione di omodimeri ed eterodimeri tra gli stessi membri della famiglia BcI-2 a livello della membrana mitocondriale. Tale condizione blocca il rilascio di citocromo-c e di altri fattori apoptogeni dal mitocondrio. La formazione dell'apoptosoma risulta pertanto inibita, così come la cascata caspasica mitocondrio-dipendente. La definizione dei circuiti biomolecolari coinvolti nella resistenza alla morte apoptotica ha un impatto importante nel trattamento della LMC: può infatti aiutare ad identificare bersagli farmacologici rilevanti per la terapia della malattia in associazione all'inibizione dell'attività tirosin-cinasica di p210bcr-abl.

Constitutive tyrosine kinase (TK) activity of p210 bcr-abl fusion protein is the causative event of Chronic Myeloid Leukemia (CML). Its inhibition abrogates the proliferative advantage and apoptosis resistance of clonal leukemic progenitors and induces the disease remission and the emergence of normal hematopoiesis. Imatinib mesylate (IM) let hope to have a cure for Ph1-(bcr-abl)-positive leukemias. Unfortunaley, the IM resistance apparent from longer clinical follow-up emerged as the drug major limitation. It imposes the development of combined therapies capable of targeting genes located downstream of bcr-abl and endowed with a bcr-abl-independent role in CML progression towards the fully transformed phenotype of blast crisis. PI3 kinase inhibitors could be considered as very promising drugs as they target AKT pathway. We investigated the in vitro effects of Wortmannin alone or in combination with IM on proliferation and survival of bcr-abl-transducing 32D cell clones. Here we demonstrate that Wortmannin and IM combined treatment is more effective than IM alone in inhibiting the enzymatic activity of Cdk2, the cyclin-dependent kinase mostly responsible for p210 TK-induced acceleration of cell cycle progression. Cdk2 activity was prevented by the enhanced effects of drug combination on Chk2-Cdc25A axis and PI3K/Akt pathway (leading to increased nuclear import of Cdk inhibitors p21 and p27 and to cyclin D downmodulation). In conclusion, the combined use of TK and PI3K inhibitors may prevent IM resistance and, therefore, improve the prognosis of CML at clinical diagnosis, but its advantage in the treatment of IM-resistant CML is likely marginal and conditional upon the mechanisms responsible for IM resistance.

Hodgkin’s lymphoma (HL) is a heterogeneous lymphoid malignancy curable in more than 80% of cases. Its morbility and mortality are mostly contingent upon chemo- and radio-therapy side effects including cardiovascular or pulmonary diseases, infections and second malignancies. Indeed, the high incidence of secondary cancers and leukemias in potentially cured LH patients supports that genomic instability and defective DNA repair system have a crucial role in secondary cancerogenesis/leukemogenesis processes as they let the emergence of genomic aberrations and clonal cell evolution towards a transformed phenotype. The aim of our study was to define the genomic profile associated with HL evolution towards secondary leukemia. To the purpose, formalin-fixed/paraffin-embedded biopsies from 4 LH patients who developed a secondary acute myeloid leukemia (AML) were analyzed by mean of array-based comparative genomic hybridization (aCGH). This method allows the identification of changes in DNA sequence copy number (amplifications or deletions) at high resolution. The microarrays used in our study contain 287 genomic targets involved in most human cancers, including oncogenes, tumor-suppressor genes and DNA sequences localized within chromosomal regions most frequently rearranged. DNAs from lymphonode biopsies of LH patient who developed AML were compared with pooled DNAs from reactive and LH lymphonodes (comparable for histotype and follow-up) from cured patients. CGH profiles of single LH patients were extensively altered. However, they shared a common pattern of structural genomic alterations. Bioinformatic analysis of CGH results performed with dedicated softwares let distinguish statistatically significant (ratio >1,2) amplifications relative to 3 DNA sequences (AFM137XA11, FGFR1, PPABP) and statistatically significant (ratio< 0,83) deletions in 4 (AFM217YD10, FGR(SRC2), GATA3, TOP1, WT1). CGH data relative to the above mentioned sequences were further validated by FISH and immunohistochemistry. In spite of the low number of LH patients our results suggest that the evolution to AML in LH patients may be genetically determined. The role of single genes in leukemic transformation requires further investigation.

Covalent modifications of the core histone tails, includind acetylation, methylation, phosphorylation, ADP-ribosylation and ubiquitination govern the chromatine accessibility and create binding surfaces for protein recognition (such as the bromodomain far acetylated lysines and the chromodomain for methylated lysines), therefore dictating the rate of gene transcription. We investigated the impact of p210 bcr-abl tyrosine kinase of chronic myeloid leukemia (CMLl) on the acetylation and methylation at individual lysine residues within the NH2-terminal tails of histone H4, an integral component of transcriptional competence at the onset of S phase. To the purpose, we used RP-HPLC coupled with electrospray mass spectrometry (LCMS) to resolve the single H4 species (non-acetylated and mono-, di- or three-acetylated) and enzymatic digestion coupled with MALDI mass spectrometry to define the individuai lysine residues involved in acetylation and methylation processes. In single cell clones generated from the murine myeloid 32D cell line transducing a temperature-sensitive (ts) p210 bcr-abl construct (that owns constitutive tyrosine kinase activity at the permissive temperature of 33°C, but lacks it at the non- permissive temperature of 39°C) the inhibition of p210 bcr-abl tyrosine kinase induced by 1 M STI571 was associated with a significant (p

The possible prognostic value of the position of the breakpoint within the M-BCR in patients with Phl+ CML is still being debated. We analyzed the DNA rearrangements and the transcript types of 244 patients and tried to correlate the data obtained with prognostic features, defined according to Sokal's risk index, and with chronic phase and/or survival duration. The exact location of the breakpoint, either 5' or 3' to the Hind III restriction site within the M-BCR was identified. Moreover, the exact M-BCR subregion was also identified. As a whole, 150 pts were rearranged in the 5' part and 94 in the 3' part of the M-BCR. No correlation was observed between the site of rearrangement on the one hand and the Sokal's prognostic index and survival, on the other. Transcript analysis was performed in 130 patients; 59 carried an a2b2 and 69 an a2b3 pattern. Two patients carried both transcripts. Of the patients rearranged in the 5' area, according to Southern blotting, 29.2% showed an a2b3 transcript. Therefore, R...