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.

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.

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.

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.

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.

Pseudoaneurysm of the aortic root following aortic valve endocarditis - a case with 2 rare life - threatening complications.

Infective endocarditis can have peri-annular spread and involve the valvular annulus and adjacent cardiac structures, leading to tissue necrosis and peri-annular abscess. This process may cause pseudoaneurysm formation and other rare and potentially life-threatening complications, so their identification and correct diagnosis are crucial. We describe a case of an 81-year-old woman, with a history of aortic valve replacement and worsening of symptoms, that presents at the imaging a pseudoaneurysm of the aortic root complicated at the same time by 2 life-threatening conditions: fistulization in the Right Ventricular Outflow Tract (RVOT) and the compression of Right Coronary Artery (RCA). This case underlines the importance of imaging, especially Coronary Computed Tomography Angiography (CCTA), in the diagnosis and follow-up of infective endocarditis and its complications, especially in a patient not eligible for surgery.

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.

A rare case of a giant circumflex coronary artery aneurysm 10 years after bentall surgery.

In this paper, we describe a rare case of coronary artery aneurysms occasionally found on a pre interventional Coronary Computed Tomography Angiography performed on a 67-year-old man with a history of aneurysm of the ascending aorta previously treated with Bentall surgery, who arrived at our hospital to have a percutaneous valve-in-valve implantation procedure. Even though the patient was considered not eligible for the procedure, due to his many comorbidities, and conservatively managed, at 1-year followup his angiographic condition remained stable.

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.

Lymphocytes, Interleukin 6 and D-dimer Cannot Predict Clinical Outcome in Coronavirus Cancer Patients: LyNC1.20 Study.

BACKGROUND/AIM: Knowledge of Coronavirus 19 (COVID19) pathogenetic mechanisms is necessary to provide new treatment strategies. This study aims to assess how oncological disease impacts on the clinical course of COVID-19 patients. PATIENTS AND METHODS: From 1st March to 30th April 2020, 96 COVID-19 patients were classified according to clinical outcome as severe (n=67) and moderate (n=29). Demographic data, medical history, admission lymphocytes, procalcitonin (PCT), c-reactive-protein (CRP), D-dimer, and Interleukin-6 (IL-6) were collected. RESULTS: A statistically significant association was found between hypertension (p=0.007) and three or more comorbidities with severe outcomes (p=0.034). No statistical differences were found between the severe and moderate groups with regards to the rate of patients with past oncological history. However, no patient allocated in the moderate group had received oncological treatment within 12 months. Higher values of CRP, IL-6, D-Dimer and lower values of lymphocytes were reported in the severe group (p=0.0007, p=0.00386, p=0.041, and p=0.007, respectively). Using binary logistic regression, higher values of CRP (OR=8.861; p=0.012) and PCT were associated with a higher risk of severe outcome (OR=21.075; p=0.008). Within the oncological population, D-Dimer and IL-6 did not confirm their prognostic significance as in the general population (p>0.05). CONCLUSION: Specific prognostic factors for oncological patients should be designed for COVID-19 clinical practice.

CPX-351 treatment in secondary acute myeloblastic leukemia is effective and improves the feasibility of allogeneic stem cell transplantation: results of the Italian compassionate use program.

Secondary acute myeloid leukemia (sAML) poorly responds to conventional treatments and allogeneic stem cell transplantation (HSCT). We evaluated toxicity and efficacy of CPX-351 in 71 elderly patients (median age 66 years) with sAML enrolled in the Italian Named (Compassionate) Use Program. Sixty days treatment-related mortality was 7% (5/71). The response rate at the end of treatment was: CR/CRi in 50/71 patients (70.4%), PR in 6/71 (8.5%), and NR in 10/71 (19.7%). After a median follow-up of 11 months relapse was observed in 10/50 patients (20%) and 12 months cumulative incidence of relapse (CIR) was 23.6%. Median duration of response was not reached. In competing risk analysis, CIR was reduced when HSCT was performed in first CR (12 months CIR of 5% and 37.4%, respectively, for patients receiving (=20) or not (=30) HSCT, p = 0.012). Twelve-months OS was 68.6% (median not reached). In landmark analysis, HSCT in CR1 was the only significant predictor of longer survival (12 months OS of 100 and 70.5%, for patients undergoing or not HSCT in CR1, respectively, p = 0.011). In conclusion, we extend to a real-life setting, the notion that CPX is an effective regimen for high risk AML patients and may improve the results of HSCT.

Full donor chimerism without graft-versus-host disease: the key factor for maximum benefit of pre-emptive donor lymphocyte infusions (pDLI).

Compared to standard-conditioned regimens, reduced-intensity conditioning and T-cell depletion deliver lower transplant-related mortality and decreased graft-vs-host disease after allogeneic hematopoietic stem-cell transplantation. These advantages may however be mitigated by increased relapse rates and delays in achievement of full donor chimerism (FDC). Pre-emptive donor lymphocyte infusions (pDLI) facilitate the conversion of mixed (MDC) to FDC. However, there is a lack of published data on the risk/benefit analysis of this intervention. We performed a retrospective analysis of 119 patients who received 276 pDLI doses for falling CD3 chimerism, CD3 < 50% or mixed XX/XY karyotype. 71/119(60%) Patients achieved FDC, with only one reverting to MDC. Cumulative incidence (CI) of relapse at 5 years was significantly lower in the FDC group (16.0 vs 41.4%, p < 0.001). Those patients who achieved FDC had improved EFS (p < 0.001) and OS (p < 0.001). Interestingly, patients with FDC who developed DLI-induced graft-vs-host disease (GvHD) showed a similar outcome to those with MDC. The majority of patients who receive pDLI convert to FDC and retain that status. Achievement of FDC after pDLI impacts on survival, and those patients who achieve FDC without GvHD, experience maximum clinical benefit. Strategies to minimise DLI-induced GvHD should be considered to maximise the therapeutic potential of this intervention.

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.

Similar outcomes of alemtuzumab-based hematopoietic cell transplantation for SAA patients older or younger than 50 years.

Survival after allogeneic hematopoietic cell transplantation (HSCT) for severe aplastic anemia (SAA) among older patients remains poor and associated with increased risk for graft-versus-host disease (GVHD). In this retrospective study of 65 consecutive patients with acquired SAA who were transplanted using fludarabine, low-dose cyclophosphamide, and alemtuzumab (FCC), outcomes of 27 patients aged at least 50 years were compared with those of 38 patients younger than 50 years. The median age of the older cohort was 61 years (range, 51-71 years); 21 (78%) patients were transplanted from unrelated donors (3 of 21 from HLA 9/10 mismatch donors) and 6 from matched sibling donors. One-year GVHD-free, relapse-free survival (GRFS) was comparable to that of patients younger than 50 years (84% vs 94%, respectively; P = .23). Both groups showed low rates of acute (5% vs 4%) and chronic (18% vs 14%) GVHD, with no cases of severe GVHD among matched donor transplants, and similar 1-year transplant-related mortality (14% vs 5.4%, older vs younger; P = .23). HSCT comorbidity index (HTC-CI) scores were similar between the groups, but overall survival with an HCT-CI of at least 3 was lower compared with a score less than 3 (76% vs 98%; P = .005). Median donor T-cell chimerism among older patients was 64% and 60% at 1 and 3 years, respectively, and was similar to that of younger patients. Increased B regulatory cells potentially contributed to low alloreactivity and mutual donor-recipient tolerance in older patients. Effect of comorbidities rather than age alone may be a more important determinant of suitability for FCC HSCT in older patients.

Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis.

Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi-center study enrolled 20 adult patients with intermediate- or high-risk primary MF, post- polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib-hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow-up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF.

A Frontline Approach With Peripherally Inserted Versus Centrally Inserted Central Venous Catheters for Remission Induction Chemotherapy Phase of Acute Myeloid Leukemia: A Randomized Comparison.

BACKGROUND: The incidence of peripherally inserted central catheter (PICC)-related adverse events has been uncertain in the setting of acute myeloid leukemia (AML) compared with the incidence of centrally inserted central catheter (CICC) adverse events. PATIENTS AND METHODS: We conducted a monocentric, randomized trial of patients with previously untreated AML. Of the 93 patients, 46 had received a PICC and 47 had received a CICC as frontline intravascular device. Thereafter, all patients underwent intensive chemotherapy for hematologic remission induction. The primary endpoint was catheter-related (CR)-bloodstream infection (BSI) and venous thrombosis (VT) rate. The secondary endpoints catheter malfunction, catheter removal, and patient overall survival. RESULTS: The CR-BSI and CR-VT rate in the PICC and CICC groups was 13% and 49%, respectively, with a difference of 36 percentage points (relative risk for CR-BSI or CR-VT, 0.266; P = .0003). The CR-BSI incidence was 1.4 and 7.8 per 1000 catheters daily in the PICC and CICC groups, respectively. Among the CR thromboses, the symptomatic VT rate was 2.1% in the PICC group and 10.6% in the CICC group. In the CICC group, 16 of the 47 patients (34%) had the catheter removed for BSI (n = 5), septic thrombophlebitis (n = 4), VT (n = 2), or malfunction (n = 5) a median of 7 days after insertion. In the PICC group, only 6 of the 46 patients (13%) required catheter removal for VT (n = 2) or malfunction (n = 4). At a median follow-up of 30 days, 6 patients in the CICC group died of CR complications versus none of the patients in the PICC group (P = .012). Using PICCs, the reduction in BSI and symptomatic VT decreased mortality from CR infection and venous thromboembolism. In contrast, the CICC approach led to early catheter removal mostly for difficult-to-treat infectious pathogens. CONCLUSION: Our data have confirmed that BSI and symptomatic VT are the major complications affecting frontline central intravascular device-related morbidity in the leukemia setting. The use of a PICC is safer than that of a CICC and maintains the effectiveness for patients with AML undergoing chemotherapy, with an approximate fourfold lower combined risk of infection or thrombosis at 30 days.