Outcome of 421 adult patients with Philadelphia-negative acute lymphoblastic leukemia treated under an intensive program inspired by the GIMEMA LAL1913 clinical trial: a Campus ALL study.

The introduction of pediatric-inspired regimens in adult Philadelphia-negative acute lymphoblastic leukemia (Ph-ALL) has significantly improved patients' prognosis. Within the Campus ALL network we analyzed the outcome of adult Ph-ALL patients treated according to the GIMEMA LAL1913 protocol outside the clinical trial, to compare the real-life data with the study results. We included 421 consecutive patients, with a median age of 42 years. The complete remission (CR) rate after the first course of chemotherapy was 94% and a measurable residual disease (MRD) negativity after the third course was achieved in 72% of patients. The 3-year overall survival (OS) and disease-free survival (DFS) were 67% and 57%, respectively. In a multivariate analysis, MRD positivity negatively influenced DFS. In a time-dependent analysis including only very high risk (VHR) and MRD positive cases, transplanted (HSCT) patients had a significantly better DFS than non-HSCT ones (P=0.0017). During induction, grade ≥2 pegaspargase-related hepato-toxicity was observed in 25% of patients (vs 12% in the GIMEMA LAL1913 trial, P=0.0003). In this large real-life cohort of Ph-ALL, we confirmed the very high CR rate and a superimposable OS and DFS compared to the GIMEMA LAL1913 clinical trial: CR rate after C1 94% vs 85%, P=0.0004; 3-year OS 67% vs 67%, P=0.94; 3-year DFS 57% vs 63%, P=0.17. HSCT confirms its important role in VHR and MRD-positive patients. The rate of pegaspargase-related toxicity was significantly higher in the real-life setting, emphasizing the importance of dose adjustment in the presence of risk factors to avoid excessive toxicity.

Blinatumomab differentially modulates peripheral blood and bone marrow immune cell repertoire: A Campus ALL study.

Blinatumomab is the first bi-specific T-cell engager approved for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (B-ALL). Despite remarkable clinical results, the effects of blinatumomab on the host immune cell repertoire are not fully elucidated. In the present study, we characterized the peripheral blood (PB) and, for the first time, the bone marrow (BM) immune cell repertoire upon blinatumomab treatment. Twenty-nine patients with B-ALL received blinatumomab according to clinical practice. Deep multiparametric flow cytometry was used to characterize lymphoid subsets during the first treatment cycle. Blinatumomab induced a transient redistribution of PB effector T-cell subsets and Treg cells with a persistent increase in cytotoxic NK cells, which was associated with a transient upregulation of immune checkpoint receptors on PB CD4 and CD8 T-cell subpopulations and of CD39 expression on suppressive Treg cells. Of note, BM immune T-cell subsets showed a broader post-treatment subversion, including the modulation of markers associated with a T-cell-exhausted phenotype. In conclusion, our study indicates that blinatumomab differentially modulates the PB and BM immune cell repertoire, which may have relevant clinical implications in the therapeutic setting.

Myeloid Sarcoma of the Breast as Blast Phase of JAK2-Mutated (Val617Phe Exon 14p) Essential Thrombocythemia: A Case Report and a Systematic Literature Review.

INTRODUCTION: Myeloid sarcoma (MS) is a mass-forming proliferation of myeloid blasts. Frequently, it arises as blast phase of pre-existing myeloproliferative, myelodysplastic disorders or consequent to bone marrow transplant. Its molecular characterization has become an increasingly important requirement for the diagnostic definition of this solid leukemia. CASE PRESENTATION: Our case report concerns an MS arising in the breast of a woman with a previous diagnosis of JAK2-mutated essential thrombocythemia (Val617Phe exon 14p) mimicking, on histology, a lobular carcinoma of the breast. The immunohistochemical study of the neoplasm provided the key that solved the diagnostic doubt and the immunohistochemical evaluation of NPM protein expression, which turn out to be negative, provided a clear indication on the molecular status and prognosis of the disease. A year later, the neoplasm relapsed in the pelvic area. DISCUSSION: This diagnostic challenge led us to review the literature of the past 10 years concerning MS of the breast. To the best of our knowledge, this was the first case of MS of the breast occurring in a patient with a history of essential thrombocythemia and recurred in the pelvic region.

The role of ponatinib in adult BCR-ABL1 positive acute lymphoblastic leukemia after allogeneic transplantation: a real-life retrospective multicenter study.

The experience of third-generation tyrosine kinase inhibitor ponatinib treatment in Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph'+ ALL) patients post-allogeneic transplantation is limited. We retrospectively collected data on 25 Ph'+ ALL patients who were started on ponatinib after allogeneic transplantation between July 2015 and July 2019 from nine transplantation centers in Italy. Ponatinib was given in prophylaxis in five (20%), as pre-emptive treatment in seven (28%), and as salvage therapy in thirteen (52%) patients. It was combined with donor leukocyte infusions in ten patients. Half of the patients (12/25) harbored T315I mutation of BCR/ABL1, while in the remaining mutational analysis was negative or not performed. Among the 20 patients who received ponatinib as pre-emptive/salvage treatment, complete molecular response was achieved in 15 (75%) patients. Estimated overall survival at 2-year post-initiation of treatment in the whole cohort was 65% (respectively 60%, 60%, and 78% for the prophylaxis, pre-emptive, and salvage therapy groups). In patients with T315I-positive mutational status, the estimated 2-year survival was 40%. Fourteen patients (56%) experienced toxicity, requiring temporary or definitive suspension of treatment. In conclusion, treatment of Ph'+ ALL patients with ponatinib after transplantation is effective, although the question of adequate drug dose and treatment duration remains unanswered.

The Q-LAMP Method Represents a Valid and Rapid Alternative for the Detection of the BCR-ABL1 Rearrangement in Philadelphia-Positive Leukemias.

Molecular detection of the BCR-ABL1 fusion transcripts is necessary for the genetic confirmation of a chronic myeloid leukemia diagnosis and for the risk classification of acute lymphoblastic leukemia. BCR-ABL1 mRNAs are usually identified using a conventional RT-PCR technique according to the BIOMED-1 method. In this study, we evaluated 122 BCR-ABL1-positive samples with the Q-LAMP assay to establish if this technology may represent a valid alternative to the qualitative BIOMED-1 PCR technique usually employed for the detection and the discrimination of the common BCR-ABL1 transcripts (p190 and p210 isoforms). We found a 100% concordance rate between the two methods. Specifically, the p190- and p210-positive samples were amplified by Q-LAMP with a median threshold time (Tt) of 26.70 min (range: 24.45-31.80 min) and 20.26 min (range: 15.25-34.57 min), respectively. A median time of 19.63 was observed in samples displaying both (e13a2/e14a2) p210 isoforms. Moreover, the Q-LAMP assay allowed recognition of the BCR-ABL1 e13a2 and e14a2 isoforms (median Tts 18.48 for e13a2 vs. 26.08 min for e14a2; p < 0.001). Finally, 20 samples harboring rare BCR-ABL1 isoforms (e1a3, e13a3, e14a3, and e19a2) were correctly identified by the Q-LAMP assay. We conclude that the Q-LAMP assay may represent a faster and valid alternative to the qualitative BIOMED-1 RT-PCR for the diagnosis at BCR-ABL1-positive leukemias, especially when samples are analyzed in centers with restricted resources and/or limited technical expertise.

Mixed T Cell Chimerism After Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen Is Shaped by Persistence of Recipient CD8 T Cells.

Prevention of graft-versus-host disease (GVHD) is paramount for allogeneic hematopoietic stem cell transplantation (HSCT) to treat nonmalignant diseases. We previously reported that allogeneic HSCT for severe aplastic anemia (SAA) using the fludarabine, cyclophosphamide, and alemtuzumab (Campath-1H) (FCC) regimen is associated with a very low risk of GVHD and excellent clinical outcomes. We now report a single-center study of 45 patients with longer follow-up and investigation of lymphocyte recovery. Overall survival (OS) was 93%, and event-free survival (EFS) was 90.7%. Acute and chronic GVHD each occurred in 6 patients (13.3%), and only 1 case was severe. Mixed T cell chimerism was frequent and persisted after cessation of immunosuppression. T cells were extensively depleted, representing only 11.3% of lymphocytes at day 30 and rising to 43.8% by 1 year, but still significantly below normal levels (67.2%; P = .018), and deficiency persisted after immunosuppressive therapy (IST) withdrawal. Depletion of CD4 T cells was particularly profound, causing inversion of the normal CD4:CD8 T cell ratio. T cell subset composition was also abnormal, with memory and effector T cells predominating for at least 6 months after FCC HSCT. Analysis of T cell subset chimerism showed that CD4 T cells were predominantly donor-derived at 1 year, whereas recipient-derived CD8 T cells shaped mixed chimerism with a notable contribution of recipient effector CD8 T cells. The prolonged mixed T cell chimerism after IST withdrawal and low incidence of GVHD indicates the establishment of mutual tolerance, but the low incidence of viral disease suggests maintenance of antiviral immunity. Our study shows that despite the abnormal T cell profile after allogeneic HSCT for SAA using the FCC regimen, this regimen is conducive to an excellent clinical outcome.

Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned.

The natural history of Fanconi anemia remains hard to establish because of its rarity and its heterogeneous clinical presentation; since 1994, the Italian Fanconi Anemia Registry has collected clinical, epidemiological and genetic data of Italian Fanconi Anemia patients. This registry includes 180 patients with a confirmed diagnosis of Fanconi anemia who have either been enrolled prospectively, at diagnosis, or later on. After enrollment, follow-up data were periodically collected to assess the clinical course, possible complications and long-term survival; the median follow up was 15.6 years. The main goal of the study was to describe the natural history of Fanconi anemia, focusing on the following variables: family history, disease presentation, development of hematological manifestations, development of malignancies, occurrence of hematopoietic stem cell transplantation and survival. Typical morphological and/or hematological abnormalities and/or growth retardation were the most common manifestations at diagnosis; the majority of patients (77%) exhibited hematological abnormalities at the initial presentation, and almost all (96%) eventually developed hematological manifestations. More than half of the patients (57%) underwent a bone-marrow transplant. The occurrence of cancer was quite rare at diagnosis, whereas the cumulative incidence of malignancies at 10, 20 and 30 years was 5%, 8% and 22%, respectively, for hematological cancers and 1%, 15% and 32%, respectively, for solid tumors. Overall survival at 10, 20 and 30 years were 88%, 56% and 37%, respectively; the main causes of death were cancer, complications of the hematological presentation and complications of transplantation. These data clearly confirm the detrimental outcome of Fanconi anemia, with no major improvement in the past decades.

Nonmyeloablative peripheral blood haploidentical stem cell transplantation for refractory severe aplastic anemia.

New transplant approaches are urgently needed for patients with refractory severe aplastic anemia (SAA) who lack a matched sibling or unrelated donor (UD) or who have failed UD or cord blood transplant. Patients with refractory SAA are at risk of later clonal evolution to myelodysplastic syndrome and acute leukemia. We report our pilot findings with haploidentical hematopoietic stem cell transplantation (haploHSCT) using uniform reduced-intensity conditioning with postgraft high-dose cyclophosphamide in 8 patients with refractory SAA or patients who rejected a prior UD or cord blood transplant. Six of 8 patients engrafted. Graft failure was associated with donor-directed HLA antibodies, despite intensive pre-HSCT desensitization with plasma exchange and rituximab. There was only 1 case of grade II skin graft-versus-host disease. We show that haploHSCT can successfully rescue refractory SAA patients who lack donor-directed HLA antibodies but not in the presence of donor-directed HLA antibodies. This novel protocol for haploHSCT for SAA has been adopted by the European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party for a future noninterventional, observational study to further evaluate its efficacy.

Deregulation of New Cell Death Mechanisms in Leukemia.

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues for counteracting blood disorders. Chemotherapy-resistant leukemic clones activate molecular processes for biological survival, preventing the activation of regulated cell death pathways, leading to cancer progression. In the past decade, leukemia research has predominantly centered around modulating the well-established processes of apoptosis (type I cell death) and autophagy (type II cell death). However, the development of therapy resistance and the adaptive nature of leukemic clones have rendered targeting these cell death pathways ineffective. The identification of novel cell death mechanisms, as categorized by the Nomenclature Committee on Cell Death (NCCD), has provided researchers with new tools to overcome survival mechanisms and activate alternative molecular pathways. This review aims to synthesize information on these recently discovered RCD mechanisms in the major types of leukemia, providing researchers with a comprehensive overview of cell death and its modulation.

Limited efficacy of 3 + 7 plus gemtuzumab ozogamycin in newly diagnosed fit intermediate genetic risk acute myeloid leukemia patients.

BACKGROUND: Gemtuzumab-ozogamycin (GO) is approved in combination with high-dose chemotherapy for treatment-naïve low- and intermediate-risk acute myeloid leukemia (AML). AIMS: In this retrospective real-life multicenter study, we reported efficacy and safety of GO plus high-dose chemotherapy in newly diagnosed AML patients. METHODS AND RESULTS: A total of 31 fit low- and intermediate-risk AML patients treated with GO-based regimens were retrospectively included in this real-life multicenter study, and results were compared with a control cohort treated with 3 + 7 alone. Complete remission (CR) rate after induction was 77%, and most responders (45%) underwent two GO-based consolidation, and minimal residual disease (MRD) negativity was observed in 17 cases (55%) after the end of consolidation. Low genetic risk was associated with increased CR rate compared with intermediate-risk AML (88% vs. 33%; p < .001), as well as prolonged overall survival (OS; hazard ratio, 0.16; 95% confidential interval, 0.02-0.89; p < .001). GO addition resulted in a survival benefit for low-risk AML (median OS not reached vs. 25 months; p = .19) while not for intermediate-risk subjects (10 vs. 13 months; p = .92), compared with the control group. Moreover, GO-treated patients experienced fever of unknown origin or sepsis in 42% or 36% of cases, respectively, with one death during induction due to septic shock, with similar rates compared with the control group (p = .3480 and p = .5297, respectively). No cases of veno-occlusive disease after allogeneic transplantation were observed. CONCLUSIONS: Our real-life multicenter study confirmed GO-based treatment efficacy with high MRD negativity rates in fit newly diagnosed AML patients, especially in those with low genetic risk and core binding factor, while limited benefits were observed in intermediate-risk AML. However, further validation on larger prospective cohorts is required.

Long-term real world evidence of CPX-351 of high-risk AML patients identified high rate of negative MRD and prolonged OS.

CPX-351 has been approved for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). No extensive data are available on MRD and long-term clinical outcome using CPX-351 in AML in real-life. We retrospectively collected data from 168 patients in 36 centers in France and Italy who had received one or two cycles of induction with CPX-351. All patients were older than 18 years and had newly diagnosed, untreated t-AML or MRC-AML. With a median follow-up of 3 years, median OS was 13.3 months. Median OS was 20.4 months vs. 12.9 months for patients with MRD below or above 10-3, respectively (p=0.006). In a multivariate analysis, only MRD >10-3 was associated with a poorer OS (hazard ratio [HR]=2.6, 95% CI 1.2-5.5, p=0.013). We also observed a trend towards a better median OS in patients who underwent HSCT with MRD <10-3 (not reached vs. 26.0 months, p=0.06). Achievement of MRD negativity contributed to the improvement of OS in the overall population and, maybe, in transplanted patients. These data provide the rationale for the two ongoing studies evaluating CPX-351 vs. 7+3 in non-MRC-AML and non-t-AML using MRD as the primary endpoint for ALFA-2101 phase II clinical trial and event-free survival for AMLSG 30-18 phase III clinical trial.

Treatment of severe mitral annulus calcification: An attractive alternative!

Surgical treatment of mitral valve disease with severe mitral annular calcifications (MACs) is challenging, with reported high morbidity and mortality. Transcatheter treatment options are feasible, however, still far from being optimal alternatives. We report our positive experience with the off-label implant of a BioIntegral Injectable BioPulmonic valve fitted on a circumferential pericardial skirt for the treatment of severe MAC.

Intravascular Complications of Central Venous Catheterization by Insertion Site in Acute Leukemia during Remission Induction Chemotherapy Phase: Lower Risk with Peripherally Inserted Catheters in a Single-Center Retrospective Study.

The basilic/brachial (BBV), internal jugular (IJV), and subclavian veins (SCV) are commonly used as central venous catheter (CVC) sites. A BBV approach [peripherally inserted central catheter (PICC)] is increasingly used for short- to intermediate-term CVCs for acute leukemias undergoing cytotoxic intensive regimens. In this retrospective study, the catheterization of the BBV, IJV, and SCV in patients with previously untreated acute leukemia was assessed. The primary outcome was the composite incidence of catheter-related symptomatic deep-vein thrombosis (sDVT) and bloodstream infection (BSI) from catheterization up to 30 days later. In a 10-year period, 336 CVC were inserted in the BBV (n = 115), IJV (n = 111), and SCV (n = 110) in 336 patients suffering from AML (n = 201) and ALL (n = 135) and undergoing induction chemotherapy. The primary outcome events were 8, 20, and 27 in the BBV, SCV and IJV cohorts (2.6, 6.9, and 9.6 per 1000 catheter-days, respectively; p = 0.002). The primary outcome risk was significantly higher in the IJV-cohort than in the BBV-cohort (HR, 3.6; 95% CI, 1.6 to 7.9; p = 0.001) and in the SCV-cohort than in the BBV-cohort (HR, 2.6; 95% CI, 1.2 to 5.9; p = 0.02). PICC was a valid CVC for the induction chemotherapy of acute leukemia for the lowest risk of sDVT and BSI.

Role of computed tomography in transcatheter replacement of 'other valves': a comprehensive review of preprocedural imaging.

Transcatheter procedures for heart valve repair or replacement represent a valid alternative for treating patients who are inoperable or at a high risk for open-heart surgery. The transcatheter approach has become predominant over surgical intervention for aortic valve disease, but it is also increasingly utilized for diseases of the 'other valves', that is the mitral and, to a lesser extent, tricuspid and pulmonary valve. Preprocedural imaging is essential for planning the transcatheter intervention and computed tomography has become the main imaging modality by providing information that can guide the type of treatment and choice of device as well as predict outcome and prevent complications. In particular, preprocedural computed tomography is useful for providing anatomic details and simulating the effects of device implantation using 3D models. Transcatheter mitral valve replacement is indicated for the treatment of mitral regurgitation, either primary or secondary, and computed tomography is crucial for the success of the procedure. It allows evaluating the mitral valve apparatus, the surrounding structures and the left heart chambers, identifying the best access route and the landing zone and myocardial shelf, and predicting obstruction of the left ventricular outflow tract, which is the most frequent postprocedural complication. Tricuspid valve regurgitation with or without stenosis and pulmonary valve stenosis and regurgitation can also be treated using a transcatheter approach. Computer tomography provides information on the tricuspid and pulmonary valve apparatus, the structures that are spatially related to it and may be affected by the procedure, the right heart chambers and the right ventricular outflow tract.

Transcatheter aortic valve implantation in patients with unruptured aortic root pseudoaneurysm: an observational study.

AIMS: Unruptured aortic root pseudoaneurysm (UARP) is a rare complication of aortic valve endocarditis. Infectious spread to the valvular annulus or myocardium can cause septic complications that manifest as wall thickening, and spontaneous abscess drainage leads to pseudoaneurysm formation. We report the first patient series in which transcatheter aortic valve implantation (TAVI) using a single valve-resolved aortic valvulopathy associated with UARP was performed. METHODS: At our center, from December 2017 to October 2019, 138 patients underwent TAVI for aortic valve stenosis and/or regurgitation, 20 of whom (12 female patients, 8 male patients) had associated incidental UARP and were considered as our study population. The average age of these patients was 76.9 ±â€Š5.2 years. All patients were assessed using preprocedural and postprocedural multimodality imaging, including transthoracic echocardiography, transesophageal echocardiography, and cardiac computed tomography angiography (CCTA). RESULTS: In all cases, the final angiographic examination showed correct valve positioning with complete coverage of the false aneurysm. Post-TAVI CCTA showed presence of total or subtotal UARP thrombosis. The mean follow-up period was 17.5 months (12-23 months). During follow-up, imaging showed normal prosthetic valve function, no significant leakage (trace or mild), and complete UARP exclusion in all patients, without any complications. CONCLUSION: In conclusion, percutaneous valve positioning can simultaneously solve pseudoaneurysm complications by excluding the sac and promoting thrombosis.

Hypomethylating Agents (HMAs) as Salvage Therapy in Relapsed or Refractory AML: An Italian Multicentric Retrospective Study.

Data on the use of azacytidine and decitabine as salvage therapy for acute myeloid leukemia are limited. We retrospectively reviewed clinical records of 100 patients treated with hypomethylating agents (HMA) as salvage therapy in nine Italian institutions. A total of 24% of patients obtained a response to HMA (CR, PR, or CRi), while 26% showed a stable disease (SD); 50% of patients experienced progressive disease. Median OS was 6.5 months. OS in patients with de novo AML was 6.1 months, while OS in patients with secondary AML (sAML) was 12.3 months (p = 0.037). Median OS after HMA in patients with SD as best response to HMA was similar to median OS in patients with response to HMA (10.6 months vs. 13 months). On multivariate analysis, OS difference between patients who obtained a response versus patients who did not was significant (p = 0.0037). OS difference in sAML was significantly better than in de novo AML (p < 0.00001). HMA showed a remarkable efficacy in terms of response rate and OS in a subgroup of patients (sAMLs), historically characterized by a poor outcome. Therefore, 5Azacitidine and decitabine may represent a good clinical option in a selected patient population with relapsed or refractory AML, unsuitable for allo-HSCT.

Relationship between septo-valvular angle and risk of pacemaker implantation after transcatheter aortic valve implantation: a preliminary study.

AIM: Pre-transcatheter aortic valve implantation (TAVI) computed tomography (CT) has proven to be crucial in identifying pre- and post-procedural predicting factors predisposing the onset of major arrhythmias that require permanent pacemaker (PPM) implantation caused by the compressive effects of the prostheses on the conduction system at the membranous septum (MS) and the muscular crest of the interventricular septum.Our analysis aims to verify if the pre-TAVI assessment of the angle between the MS and the aortic annulus (SVA) might be a predictive factor for the onset of arrhythmias that requires PPM. METHODS: Two cardiovascular specialist radiologists retrospectively and double-blind evaluated a randomized list of preprocedural CT of 57 patients who underwent TAVI with a self-expandable valve from April 2019 to February 2020. Two anatomical features were measured by readers: width of the SVA and MS length (MSL). RESULTS: A PPM was implanted in 18 patients (31%) after the procedure. There was no significant difference in the anatomical measurements performed between the two observers, regarding both anatomical measurements (intraclass correlation coefficient was 0.944 for the SVA and 0.774 for the MSL]. Receiver-operating characteristic curves (ROC) performed for both measurements have documented: for the SVA sensitivity 94% and Negative predictive value (NPV) 96% (area under the curve: 0.77; 95% confidence interval 0.66-0.90). The MSL ROC was not significant. The mean SVA value stratified for patients who did not undergo PPM implantation and patients who did resulted as significant (P < 0.005). CONCLUSION: Measurement of the SVA performed in preprocedural CT scans has proven to be related to the onset of major arrhythmias after TAVI requiring permanent pacemaker implantation with high sensitivity (94%) and NPV (96%).