Evaluation of the ATM L2307F germline variant in 121 Italian pedigrees with familial myeloproliferative neoplasms.

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Germline MPL mutations may be a rare cause of "triple-negative" thrombocytosis.

Hereditary thrombocytosis (HT) is a rare inherited disorder with clinical features resembling those of sporadic essential thrombocythemia. This study included 933 patients with persistent isolated thrombocytosis for whom secondary reactive causes were excluded. Of 933 patients screened, 567 were JAK2-mutated, 255 CALR-mutated, 41 MPL-mutated, 2 double-mutated, and 68 were triple-negative. Two patients carried germline non-canonical mutations in exon 10: MPL W515* and MPL V501A. One triple-negative patient carried another germline non-canonical MPL mutation outside exon 10: MPL R102P. As germline MPL mutations may be underlying causes of HT, we recommend screening patients with triple-negative isolated thrombocytosis for non-canonical MPL mutations. Although clear evidence concerning HT treatment is still lacking, individuals with HT should probably be excluded from cytoreductive treatment. Thus, an accurate diagnosis is pivotal in avoiding unnecessary treatments.

Incidence of blast phase in myelofibrosis according to anemia severity.

Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

Human Cytomegalovirus (HCMV) - specific T-cell response after letermovir prophylaxis is predictive for subsequent HCMV reactivation in haematopoietic stem cell transplant recipients.

BACKGROUND: Human Cytomegalovirus (HCMV) is still one of the major concerning infection in hematopoietic stem cell transplant (HSCT) recipients. Letermovir (LTV) has been recently introduced for HCMV prophylaxis in adult patients who received allogeneic HSCT. However, many aspects related to immune reconstitution need to be further explored. The aim of this study was to define the prognostic role of HCMV-specific T-cell frequency measured at the end of LTV prophylaxis in predicting the risk for clinically significant HCMV infection (i.e. infection requiring antiviral treatment) after the stop of the prophylaxis. METHODS: Sixty-six adult patients who underwent allogeneic HSCT were enrolled and HCMV DNAemia was prospectively monitored. Additionally, HCMV-specific T-cell response was evaluated using ELISpot assay against two different antigens (HCMV infected cell lysate and pp65 peptide pool). RESULTS: Ten patients (15.2%) developed at least one positive HCMV DNAemia episode during LTV prophylaxis, whereas 50/66 (75.8%) patients developed at least one positive HCMV DNA event after LTV prophylaxis. Of note, 25 of them (50%) experienced a clinically significant HCMV infection. The median HCMV-specific T-cell response measured against HCMV lysate but not against pp65 peptide pool was lower in patients who developed HCMV clinically significant infection after prophylaxis. A ROC analysis revealed that the level of 0.04 HCMV-specific T cells/µl should be used as cut-off for development of clinically significant HCMV reactivation after prophylaxis. CONCLUSION: Assessment of HCMV-specific immunity upon discontinuation of universal prophylaxis with LTV should be considered as a method for identification of patients at risk for clinically significant HCMV infection.

Assessment of the efficacy and tolerability of ruxolitinib for the treatment of myelofibrosis patients in a real-life setting: An Italian MYNERVA Project.

BACKGROUND: Incorporating real-world data in the drug development process allows the improvement of health outcomes by providing better representation of actual patterns of drug safety and efficacy. AIMS AND METHODS: Here, we present the results of a retroprospective, observational real-life study of 154 patients with myelofibrosis treated with ruxolitinib in a real-life setting in seven Italian centers of the MYNERVA project. RESULTS: Median drug exposure was 29 (range, 3-98) months. Discontinuation rate was 27% after a median time of 13 (range, 3-61). While hematological toxicities were in line with previous findings, infections occurred frequently, representing a not negligible cause of discontinuation and death. Anemia, symptoms, and spleen responses were obtained at any time in 23%, 91%, and 68% of patients, respectively; most patients achieved their responses by week 24. Larger splenomegaly and delayed treatment initiation correlated with lower spleen response at 24 weeks. Spleen response was associated with a superior overall survival, regardless of DIPSS. Of interest, both achievement and loss of spleen response had prognostic implications. DISCUSSION AND CONCLUSION: Overall, our findings provide insights on the efficacy and safety of ruxolitinib in a real-world, multicenter cohort of Italian MF patients.

Arginase-1+ bone marrow myeloid cells are reduced in myeloproliferative neoplasms and correlate with clinical phenotype, fibrosis, and molecular driver.

INTRODUCTION: Philadelphia-negative myeloproliferative neoplasms (MPN) are clonal myeloid proliferative disorders characterized by sustained systemic inflammation. Despite its renowned importance, the knowledge concerning the inflammatory pathophysiology of these conditions is currently limited to studies on serum cytokines, while cellular immunity has rarely been investigated. METHODS: In the present study, we targeted Arginase-1 immunosuppressive myeloid cells in the bone marrow of MPN patients and healthy controls and investigated their clinical and prognostic significance. We demonstrated that MPN are characterized by a significant reduction of bone marrow immunosuppressive cells and that the number of these cells significantly correlates with several clinical and histopathological features of diagnostic and prognostic importance. Moreover, we identified an unreported correlation between a reduction of Arginase-1+ bone marrow cells and the presence of CALR mutations, linking tumor-promoting immunity and molecular drivers. Finally, we postulate that the reduction of bone marrow Arginase-1+ immunosuppressive cells may be due to the migration of these cells to the spleen, where they may exert systemic immunomodulatory function. CONCLUSION: Altogether, this study preliminary investigated the contribution of cellular immunity in the pathogenesis of myeloproliferative neoplasms and identified a possible interesting therapeutic target as well as a set of new links that may contribute to unraveling the biological mechanisms behind these interesting hematological neoplasms.

COVID-19 in Patients with Hematologic Diseases.

The COVID-19 outbreak had a strong impact on people's lives all over the world. Patients with hematologic diseases have been heavily affected by the pandemic, because their immune system may be compromised due to anti-cancer or immunosuppressive therapies and because diagnosis and treatment of their baseline conditions were delayed during lockdowns. Hematologic malignancies emerged very soon as risk factors for severe COVID-19 infection, increasing the mortality rate. SARS-CoV2 can also induce or exacerbate immune-mediated cytopenias, such as autoimmune hemolytic anemias, complement-mediated anemias, and immune thrombocytopenia. Active immunization with vaccines has been shown to be the best prophylaxis of severe COVID-19 in hematologic patients. However, the immune response to vaccines may be significantly impaired, especially in those receiving anti-CD20 monoclonal antibodies or immunosuppressive agents. Recently, antiviral drugs and monoclonal antibodies have become available for pre-exposure and post-exposure prevention of severe COVID-19. As adverse events after vaccines are extremely rare, the cost-benefit ratio is largely in favor of vaccination, even in patients who might be non-responders; in the hematological setting, all patients should be considered at high risk of developing complications due to SARS-CoV2 infection and should be offered all the therapies aimed to prevent them.

Haematological malignancies in relatives of patients affected with myeloproliferative neoplasms.

In a cohort of 3131 patients with myeloproliferative neoplasms (MPNs), we identified 200 patients (6.4%) who reported a second case of haematological malignancies (HM) in first- or second-degree relatives. The occurrence of a second HM in the family was not influenced by MPN subtype, sex or driver mutation, while it was associated with age at MPN diagnosis: 8.5% of patients diagnosed with MPN younger than 45 years had a second relative affected with HM compared to 5.5% of those diagnosed at the age of 45 years or older (p = 0.003), thus suggesting a genetic predisposition to HM with early onset.

Human Cytomegalovirus-Specific T-Cell Reconstitution and Late-Onset Cytomegalovirus Infection in Hematopoietic Stem Cell Transplantation Recipients following Letermovir Prophylaxis.

Letermovir (LTV), recently approved for the prophylaxis of human cytomegalovirus (HCMV) reactivation after hematopoietic stem cell transplantation (HSCT), has been shown to decrease the rate of infection in the first months post-transplantation. The aim of this study was to evaluate the impact of LTV prophylaxis on immune reconstitution and late-onset infection. We studied HCMV infection and HCMV-specific T cell reconstitution in 2 matched groups of HSCT recipients, those treated with LTV prophylaxis (n = 30; LTV group) and those receiving preemptive therapy (n = 31; PET group). We analyzed the rates of graft-versus-host disease (GVHD), neutropenia, baseline disease recurrence, and overall survival in the 2 groups. Clinically significant infections necessitating preemptive therapy showed a similar rate in the 2 groups (PET: 21 of 31 [68%]; LTV: 17 of 30 [57%]; P = .434) but occurred significantly later (after prophylaxis discontinuation) in the LTV group. There was no between-group difference in peak HCMV DNAemia level (P = .232). HCMV-specific T cell recovery was delayed by approximately 100 days in the LTV group. HCMV-specific CD4 and CD8 T cell counts were significantly lower in the LTV group at days 120 to 360 and days 90 to 120, respectively. A lower rate of chronic GVHD (P = .024) was seen in the LTV group. Time to engraftment, rate of disease relapse, and 1-year survival were not different between the 2 groups, whereas trends toward a lower rate of neutropenia (P = .124) and a higher rate of acute GVHD grade III-IV (P = .103) were observed in the LTV group. Because LTV prophylaxis delays HCMV infection and HCMV-specific immune reconstitution, immunologic and virologic monitoring should be implemented after discontinuation of prophylaxis. The potential effect of LTV prophylaxis in reducing chronic GVHD should be evaluated in prospective studies.

Philadelphia chromosome-negative myeloproliferative neoplasms in younger adults: A critical discussion of unmet medical needs, with a focus on pregnancy.

Myeloproliferative neoplasms (MPN) are traditionally regarded as a disease of older adults, though a not negligible fraction of cases occurs at a younger age, including women of childbearing potential. MPN in younger patients, indeed, offer several challenges for the clinical hematologist, that goes from difficulties in reaching a timely and accurate diagnosis to a peculiar thrombotic risk, with a relatively high incidence of thromboses in unusual sites (as the splanchnic veins or the cerebral ones). Moreover, the issue of pregnancy is recently gaining more attention as maternal age is rising and molecular screening are widely implemented, leading to a better recognition of these cases, both before and during pregnancy. In the present work we aim at discussing four clinical topic that we identified as areas of uncertainty or true unmet medical needs in the management of younger patients with MPN, with a particular focus on the topic of pregnancy. For each of these topics, we critically reviewed the available evidence that support treatment decisions, though acknowledging that recommendations in this field are mostly based on expert opinion or derived from guidelines of other clinical conditions that share with MPN a high vascular risk, as antiphospholipid syndrome. Taking into consideration both the lack of evidence-based data and the clinical heterogeneity of MPN, we support an individualized strategy of counseling and management for both young patients and for expectant mother with MPN.

Eradication of Measurable Residual Disease in AML: A Challenging Clinical Goal.

In non-promyelocytic (non-M3) AML measurable residual disease (MRD) detected by multi-parameter flow cytometry and molecular technologies, which are guided by Consensus-based guidelines and discover very low leukemic cell numbers far below the 5% threshold of morphological assessment, has emerged as the most relevant predictor of clinical outcome. Currently, it is well-established that MRD positivity after standard induction and consolidation chemotherapy, as well as during the period preceding an allogeneic hematopoietic stem cell transplant (allo-HSCT), portends to a significantly inferior relapse-free survival (RFS) and overall survival (OS). In addition, it has become absolutely clear that conversion from an MRD-positive to an MRD-negative state provides a favorable clinical outcome similar to that associated with early MRD negativity. Thus, the complete eradication of MRD, i.e., the clearance of the few leukemic stem cells-which, due to their chemo-radiotherapy resistance, might eventually be responsible of disease recurrence-has become an un-met clinical need in AML. Nowadays, this goal might potentially be achieved thanks to the development of novel innovative treatment strategies, including those targeting driver mutations, apoptosis, methylation patterns and leukemic proteins. The aim of this review is to analyze these strategies and to suggest any potential combination able to induce MRD negativity in the pre- and post-HSCT period.