Impact of minimal residual disease response and of status of disease on survival after blinatumomab in B-cell acute lymphoblastic leukemia: results from a real-life study.

Blinatumomab is a bispecific T-cell engager approved for relapsed/refractory and minimal residual disease positive B-cell Acute Lymphoblastic Leukemia. We conducted a retrospective study evaluating the outcome of Blinatumomab. The impact of clinical and treatment-related variables on cumulative incidence of relapse/progression (CIRP), event-free (EFS) and overall survival (OS) was analyzed. From January 2016 to December 2022 50 Ph'- (37) and Ph+ (13) B-ALL patients received Blinatumomab. The median age was 37. Indications to blinatumomab were relapsed/refractory B-ALL in 29 and MRD-positive in 21 patients. Blinatumomab was the 2nd and 3rd line in 40 and in 10 patients, respectively. Twenty patients were treated pre-transplantation, ten were treated for relapse after transplant, twenty were not eligible for transplant. Out of 29 patients treated for relapsed/refractory disease, 16 (55%) achieved complete response and 12 achieved MRD-negativity. Out of 21 patients treated for MRD, 16 (76%) achieved MRD-negativity. At a median follow-up of 46 months the median EFS and OS were 11.5 and 16.2 months. The CIRP was 50%. In univariate analysis age, disease-status (overt vs. minimal disease) at blinatumomab, bridging to transplant after blinatumomab and MRD-response resulted significant for EFS and OS. In multivariate analysis only disease-status and MRD-response retained significance both for EFS and OS. Disease-status and MRD-response resulted significant for EFS and OS also after censoring at HSCT. This retrospective study on B-ALL patients treated with blinatumomab confirms a superior outcome for MRD-responsive over MRD non-responsive patients. Survival depends also on the disease-status prior treatment.

Combined Inhibition of Bcl2 and Bcr-Abl1 Exercises Anti-Leukemia Activity but Does Not Eradicate the Primitive Leukemic Cells.

BACKGROUND: The management of Philadelphia Chromosome-positive (Ph+) hematological malignancies is strictly correlated to the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, these drugs do not induce leukemic stem cells death and their persistence may generate a disease relapse. Published reports indicated that Venetoclax, a selective BCL2 inhibitor, could be effective in Ph+ diseases, as BCL2 anti-apoptotic activity is modulated by BCR-ABL1 kinase. We, therefore, investigated if BCL2 inhibition, alone or combined with Nilotinib, a BCR-ABL1 inhibitor, affects the primitive and committed Ph+ cells survival. METHODS: We used Ph+ cells isolated from leukemic patients at diagnosis. To estimate the therapeutic efficacy of BCL2 and BCR-ABL1 inhibition we employed long-term culture, proliferation and apoptosis assay. Immunoblot was used to evaluate the ability of treatment to interfere with the down-stream targets of BCR-ABL1. RESULTS: Blocking BCL2, we observed reduced proliferation and clonogenic potential of CML CD34-positive cells and this cytotoxicity was improved by combination with BCR-ABL1 inhibitor. However, BCL2 inhibition, alone or in combination regiment with BCR-ABL1 inhibitor, did not reduce the self-renewal of primitive leukemic cells, while strongly induced cell death on primary Ph+ Acute Lymphoblastic Leukemia (ALL). CONCLUSION: Our results suggest that primitive CML leukemic cells are not dependent on BCL2 for their persistence and support that committed CML and Ph + ALL cells are dependent by BCL2 and BCR-ABL1 cooperation for their survival. The antileukemic activity of BCL2 and BCR-ABL1 dual targeting may be a useful therapeutic strategy for Ph+ ALL patients.

Low content of clonogenic progenitors on day+18 is associated with acute graft-versus-host disease and predicts transplant-related mortality.

A marrow reaction associated with acute-graft-versus-host disease (a-GVHD) has been demonstrated in experimental models; its existence in human transplantation is controversial. The aim of the present study was to investigate whether clonogenic marrow precursors are an early marker for a-GVHD and transplant-related mortality (TRM). We prospectively studied 133 patients for colony-forming units-granulocyte-monocyte (CFU-GM) at day +18/+19 posttransplantation. CFU-GM frequency below the 25th percentile was predictive of an acute GVHD score I°-IV° when evaluated in multivariate logistic regression analysis (odds ratio = 13.551, 95% confidence interval [CI]: 1.583-116.031, p = 0.01). In the group with a clonogenic frequency below the 25th percentile, the cumulative incidence of GVHD grades II-IV was significantly more frequent with respect to the group with a frequency greater than the 25th percentile, 86% versus 54% (Gray test: p = 0.02). In multivariate Cox proportional analysis, a CFU-GM frequency below the 25th percentile at day +18 was associated with reduced overall survival (OS) (hazard ratio = 1.778, 95% CI: 1.022-3.093, p = 0.04). Patients with a frequency of CFU-GM greater than the 25th percentile had increased TRM with respect to patients with a clonogenic cell frequency greater than the 25th percentile (33.5% vs. 13.0%, p = 0.01). Patients were divided based on median content of viable CD34+ cells, and measurement of viable CD34+ cells was predictive for OS (p = 0.005) and TRM (p = 0.003). A weak correlation was observed between CFU-GM frequency in marrow at day +18 and levels of IL-2 receptor (IL-2R) in plasma (r = -0.226, p = 0.03). We conclude that marrow progenitor cell counts, on day +18 may be a useful marker for identifying patients at risk for severe a-GVHD, TRM, and inferior survival.

Diurnal mouthpiece ventilation and nocturnal non-invasive ventilation versus tracheostomy invasive ventilation in patients with amyotrophic lateral sclerosis.

BACKGROUND: Respiratory disorders are a major cause of morbidity and mortality in amyotrophic lateral sclerosis (ALS). Current guidelines suggest the provision of noninvasive ventilation (NIV) for symptomatic hypoventilation in patients with ALS. Inspite of these results the proportion of ALS patients on tracheostomy invasive ventilation (TIV) is relatively high. METHODS: Thirty-two patients were included in the study: 16 patients were treated with nocturnal NIV associated with diurnal mouthpiece ventilation (MPV) and 16 with TIV .The primary endpoint of the study was to evaluate survival in the two groups. Secondary endpoints were to evaluate differences in the two populations in terms of clinical outcomes and quality of life (HRQoL). RESULTS: Cox analysis survival data shows no statically difference in the hazard function of the two groups. The comparison between the two groups showed a significant improvement in the average value of gas indices (paO2, paCO2) in the group treated with TIV in comparison to the group treated with MPV/NIV. Conversely, the evaluation of the questionnaires on HRQoL showed a higher score in patients treated with MPV/NIV compared to those treated with TIV. CONCLUSIONS: Ventilatory treatment with MPV and TIV did not demonstrate significant differences in survival. Patients treated with MPV reported a better HRQoL, although TIV group showed higher ventilatory parameters improvement than MPV group.

Successful switch from enzyme replacement therapy to miglustat in an adult patient with type 1 Gaucher disease: a case report.

BACKGROUND: Gaucher disease is one of the most common lipid-storage disorders, affecting approximately 1 in 75,000 births. Enzyme replacement therapy with recombinant glucocerebrosidase is currently considered the first-line treatment choice for patients with symptomatic Gaucher disease type 1. Oral substrate reduction therapy is generally considered a second-line treatment option for adult patients with mild to moderate Gaucher disease type 1 who are unable or unwilling to receive lifelong intravenous enzyme infusions. The efficacy and safety of the oral substrate reduction therapy miglustat (Zavesca®) in patients with Gaucher disease type 1 have been established in both short-term clinical trials and long-term, open-label extension studies. Published data indicate that miglustat can be used as maintenance therapy in patients with stable Gaucher disease type 1 switched from previous enzyme replacement therapy. CASE PRESENTATION: We report a case of a 44-year-old Caucasian man with Gaucher disease type 1 who was initially treated with enzyme replacement therapy but, owing to repeated cutaneous allergic reactions, had to be switched to miglustat after several attempts with enzyme replacement therapy. Despite many attempts, desensitization treatment did not result in improved toleration of imiglucerase infusions, and the patient became unwilling to continue with any intravenous enzyme replacement therapy. He subsequently agreed to switch to oral substrate reduction therapy with miglustat 100 mg twice daily titrated up to 100 mg three times daily over a short period. Long-term miglustat treatment maintained both hemoglobin and platelet levels within acceptable ranges over 8 years. The patient's spleen volume decreased, his plasma chitotriosidase levels stayed at reduced levels, and his bone mineral density findings have remained stable throughout follow-up. The patient's quality of life has remained satisfactory. Miglustat showed good gastrointestinal tolerability in this patient, and no adverse events have been reported. CONCLUSIONS: Oral miglustat therapy proved to be a valid alternative treatment to intravenous enzyme replacement therapy for long-term maintenance in this patient with Gaucher disease type 1, who showed persistent allergic intolerance to imiglucerase infusions. This report exemplifies the type of patient with Gaucher disease type 1 who can benefit from switching from enzyme replacement therapy to substrate reduction therapy.

Anaesthesiological implications of Kimura's disease: a case report.

INTRODUCTION: Kimura's disease is a chronic inflammatory condition belonging to the angio-lymphatic proliferative group of disorders, usually affecting young men of Asian race, but is rare in Western countries. It is a benign but locally injurious disease, of unknown aetiology, whose classical clinical features are a tumour-like swelling, usually in the head and neck, with or without satellite lymphadenopathy, often accompanied by eosinophilia and elevated serum IgE. CASE PRESENTATION: We report the case of a 33-year-old Caucasian woman with an atypical localization of Kimura's disease, discussing the anaesthesiological implications and reviewing the current literature on Kimura's disease. CONCLUSIONS: The diagnosis of Kimura's disease can be difficult and misleading, and anaesthesiological precautions could be ignored. Patients with this disease are often evaluated for other disorders: unnecessary diagnostic tests and investigations, or even surgery, may be avoided by just being aware of Kimura's disease.