Publications by authors named "Monica Bocchia"

157 Publications

COVID-19 elicits an impaired antibody response against SARS-CoV-2 in patients with haematological malignancies.

Br J Haematol 2021 Jul 16. Epub 2021 Jul 16.

Università di Torino, Azienda Ospedaliera Città della Salute e della Scienza, Alessandria, Italy.

COVID-19 is associated with high mortality in patients with haematological malignancies (HM) and rate of seroconversion is unknown. The ITA-HEMA-COV project (NCT04352556) investigated patterns of seroconversion for SARS-CoV-2 IgG in patients with HMs. A total of 237 patients, SARS-CoV-2 PCR-positive with at least one SARS-CoV-2 IgG test performed during their care, entered the analysis. Among these, 62 (26·2%) had myeloid, 121 (51·1%) lymphoid and 54 (22·8%) plasma cell neoplasms. Overall, 69% of patients (164 of 237) had detectable IgG SARS-CoV-2 serum antibodies. Serologically negative patients (31%, 73 of 237) were evenly distributed across patients with myeloid, lymphoid and plasma cell neoplasms. In the multivariable logistic regression, chemoimmunotherapy [odds ratio (OR), 3·42; 95% confidence interval (CI), 1·04-11·21; P = 0·04] was associated with a lower rate of seroconversion. This effect did not decline after 180 days from treatment withdrawal (OR, 0·35; 95% CI: 0·11-1·13; P = 0·08). This study demonstrates a low rate of seroconversion in HM patients and indicates that treatment-mediated immune dysfunction is the main driver. As a consequence, we expect a low rate of seroconversion after vaccination and thus we suggest testing the efficacy of seroconversion in HM patients.
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http://dx.doi.org/10.1111/bjh.17704DOI Listing
July 2021

A fatal unsuspected case of acquired A hemophilia. Misleading role of therapy with acetylsalicylic acid?

Intern Emerg Med 2021 Jun 7. Epub 2021 Jun 7.

Hemathology Unit/Coagulative Disorders, "Santa Maria Alle Scotte" University Teaching Hospital of Siena, University of Siena, Siena, Italy.

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http://dx.doi.org/10.1007/s11739-021-02760-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183321PMC
June 2021

Targeting Chronic Myeloid Leukemia Stem/Progenitor Cells Using Venetoclax-Loaded Immunoliposome.

Cancers (Basel) 2021 Mar 15;13(6). Epub 2021 Mar 15.

Department of Clinical and Biological Sciences, University of Turin, 10043 Turin, Italy.

CML is a hematopoietic stem-cell disorder emanating from breakpoint cluster region/Abelson murine leukemia 1 (BCR/ABL) translocation. Introduction of different TKIs revolutionized treatment outcome in CML patients, but CML LSCs seem insensitive to TKIs and are detectable in newly diagnosed and resistant CML patients and in patients who discontinued therapy. It has been reported that CML LSCs aberrantly express some CD markers such as CD26 that can be used for the diagnosis and for targeting. In this study, we confirmed the presence of CD26+ CML LSCs in newly diagnosed and resistant CML patients. To selectively target CML LSCs/progenitor cells that express CD26 and to spare normal HSCs/progenitor cells, we designed a venetoclax-loaded immunoliposome (IL-VX). Our results showed that by using this system we could selectively target CD26+ cells while sparing CD26- cells. The efficiency of venetoclax in targeting CML LSCs has been reported and our system demonstrated a higher potency in cell death induction in comparison to free venetoclax. Meanwhile, treatment of patient samples with IL-VX significantly reduced CD26+ cells in both stem cells and progenitor cells population. In conclusion, this approach showed that selective elimination of CD26+ CML LSCs/progenitor cells can be obtained in vitro, which might allow in vivo reduction of side effects and attainment of treatment-free, long-lasting remission in CML patients.
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http://dx.doi.org/10.3390/cancers13061311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000981PMC
March 2021

First reported case of secondary mixed phenotype acute leukemia after multiple myeloma.

Am J Blood Res 2021 20;11(1):123-131. Epub 2021 Feb 20.

Hematology Unit, University of Siena, Azienda Ospedaliera Universitaria Senese Siena, Italy.

In recent years the outcome of patients with multiple myeloma (MM) has significantly improved, due to new drugs. However, some agents, i.e. the alkylating drug melphalan, can be associated with an increased incidence of secondary malignancies. Myelodysplastic syndromes and acute myeloid leukemia are reported in the literature, and rarely acute lymphoblastic leukemia. Here we describe a unique case of a 56-years old female patient affected by MM since 2015 in complete remission after autologous stem cell transplant and in lenalidomide maintenance, who developed 2 years later mixed phenotype acute leukemia (MPAL). The patient, refractory to both lymphoblastic and myeloid acute leukemia regimens, achieved complete remission with bi-specific anti-CD19/anti-CD3 monoclonal antibody blinatumomab and with hypomethylating agent azacytidine plus the BCL-2 inhibitor venetoclax. She then underwent hematopoietic stem cell transplantation from HLA-identical sibling donor and she is still in complete remission after 9 months. To the best of our knowledge, there are no cases in the literature describing MPAL after autologous transplant for MM. Our patient was treated with blinatumomab and venetoclax and achieved complete remission 9 months from allogeneic transplant. The mechanism underlying the development of MPAL is not completely understood and therapies are still lacking. In this context the combination of blinatumomab, azacytidine and venetoclax successfully used in this patient may provide food for thought for further studies in this rare setting of patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010609PMC
February 2021

Ibrutinib in association with venetoclax for the treatment of mantle-cell lymphoma: a multicenter case series.

Am J Blood Res 2020 15;10(6):355-359. Epub 2020 Dec 15.

Hematology Unit, Azienda Ospedaliera Universitaria Senese, University of Siena Italy.

Introduction: Mantle-cell lymphoma (MCL) with relapsed/refractory (R/R) disease after intensive chemotherapy have few effective treatment options. Ibrutinib showed a promising median progression-free survival (PFS) with manageable toxicity. The BCL2 inhibitor venetoclax showed encouraging results in R/R MCL patients and preclinical models suggest a potential synergistic effect of dual BTK and BCL2 inhibition. Ibrutinib in association with venetoclax was successfully investigated in a phase II trial.

Case Report: We have retrospectively analyzed 4 patients with R/R MCL receiving daily oral ibrutinib in association with venetoclax. All patients received oral ibrutinib 560 mg per day as monotherapy and subsequently added venetoclax with an initial dose of 50 mg per day, with weekly rump-up until a full dose of 400 mg per day until disease progression. All patients achieved a response, the CR rate was 50%. The aim was to perform an allogeneic SCT (allo-SCT). One patient experienced an early relapse and died because of PD. Allo-SCT was successfully performed in the other 3 patients; ibrutinib and venetoclax were discontinued before allo-SCT. One patient died because of transplant-related complications, while the other 2 cases are alive and in CR. No tumor lysis syndrome occurred.

Discussion: Ibrutinib plus venetoclax represents a promising and feasible treatment option for R/R MCL patients outside clinical trials.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811909PMC
December 2020

Long-Term Safety of Rapid Daratumumab Infusions in Multiple Myeloma Patients.

Front Oncol 2020 21;10:570187. Epub 2020 Dec 21.

Hematology Unit, University of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.

Multiple myeloma survival has significantly improved in recent years, due to novel agents that are available for treatment. The anti-CD38 monoclonal antibody Daratumumab is particularly efficient for patients with relapse/refractory disease, and many studies have shown its unprecedented efficacy also as a first treatment. However, to avoid the incidence of infusion reactions, long infusion schedules of 8 h at first dose and 4 h in the following doses are required, which can reduce the compliance of patients and health care professionals. A reduced infusion time of 90 min has been reported previously, but data are missing on the prolonged safety of this over time as well as the efficacy of this approach. In this work, we investigate the safety of 484 rapid Daratumumab infusions given early after the second dose over a 22 months period in 39 myeloma patients.
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http://dx.doi.org/10.3389/fonc.2020.570187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783633PMC
December 2020

Low-density lipoprotein (LDL) levels and risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib.

Ann Hematol 2021 Aug 3;100(8):2005-2014. Epub 2021 Jan 3.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12 months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200 mg/dL and LDL > 70 mg/dL 3 months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P = 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P < 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P = 0.008; HR = 3.5; 95% CI = 1.4-8.7 and P < 0.001; HR = 4.4; 95% CI = 2-9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins.Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.
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http://dx.doi.org/10.1007/s00277-020-04392-wDOI Listing
August 2021

Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of -ITD in Mutated AML, Irrespectively of -ITD Allelic Burden.

Cancers (Basel) 2020 Dec 24;13(1). Epub 2020 Dec 24.

Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, 16132 Genova, Italy.

The mutations of and -ITD represent the most frequent genetic aberration in acute myeloid leukemia. Indeed, the presence of an mutation reduces the negative prognostic impact of -ITD in patients treated with conventional "3+7" induction. However, little information is available on their prognostic role with intensified regimens. Here, we investigated the efficacy of a fludarabine, high-dose cytarabine and idarubicin induction (FLAI) in 149 consecutive fit AML patients (median age 52) carrying the and/or -ITD mutation, treated from 2008 to 2018. One-hundred-and-twenty-nine patients achieved CR (86.6%). After a median follow up of 68 months, 3-year overall survival was 58.6%. Multivariate analysis disclosed that both mut ( < 0.05) and ELN 2017 risk score ( < 0.05) were significant predictors of survival. -mutated patients had a favorable outcome, with no significant differences between patients with or without concomitant -ITD ( = 0.372), irrespective of -ITD allelic burden. Moreover, in landmark analysis, performing allogeneic transplantation (HSCT) in first CR proved to be beneficial only in ELN 2017 high-risk patients. Our data indicate that FLAI exerts a strong anti-leukemic effect in younger AML patients with mut and question the role of HSCT in 1st CR in mut patients with concomitant -ITD.
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http://dx.doi.org/10.3390/cancers13010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796342PMC
December 2020

Daratumumab efficacy in extramedullary orbital myeloma.

Clin Case Rep 2020 Dec 28;8(12):3652-3653. Epub 2020 Oct 28.

Hematology Azienda Ospedaliera Universitaria Siena Italy.

Daratumumab is very efficacious in multiple myeloma. Few reports are present about efficacy in extramedullary myeloma. We report here daratumumab efficacy in extramedullary ocular myeloma in a young 46-year-old man diagnosed 3 years earlier and relapse refractory to five previous lines of therapy.
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http://dx.doi.org/10.1002/ccr3.3458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752422PMC
December 2020

A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation.

J Clin Med 2020 Nov 17;9(11). Epub 2020 Nov 17.

Hematology Unit, Fondazione Policlinico Universitario Gemelli IRCCS, 00168 Rome, Italy.

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported-281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months-65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.
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http://dx.doi.org/10.3390/jcm9113692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698481PMC
November 2020

The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians.

J Clin Med 2020 Oct 21;9(10). Epub 2020 Oct 21.

Departmental Simple Unit of Pediatric Rheumatology, AUSL-IRCSS Reggio Emilia, 42123 Reggio Emilia, Italy.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30-50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β -3.34, 95%CI -6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.
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http://dx.doi.org/10.3390/jcm9103379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589625PMC
October 2020

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia.

Clin Case Rep 2020 Oct 7;8(10):2000-2002. Epub 2020 Jul 7.

Hematology Unit Azienda Ospedaliera Universitaria Senese University of Siena Siena Italy.

A case of an early-relapsed high-risk T-ALL with high BCL-2 expression on leukemic blasts was successfully treated with decitabine and venetoclax, achieving a CR. We suggest decitabine and venetoclax should be synergistic in BCL2-positive ALL.
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http://dx.doi.org/10.1002/ccr3.3041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562845PMC
October 2020

Minimal Residual Disease in Multiple Myeloma: State of the Art and Applications in Clinical Practice.

J Pers Med 2020 Sep 10;10(3). Epub 2020 Sep 10.

Division of Hematology, University of Siena, 53100 Siena, Italy.

Novel drugs have revolutionized multiple myeloma therapy in the last 20 years, with median survival that has doubled to up to 8-10 years. The introduction of therapeutic strategies, such as consolidation and maintenance after autologous stem cell transplants, has also ameliorated clinical results. The goal of modern therapies is becoming not only complete remission, but also the deepest possible remission. In this context, the evaluation of minimal residual disease by techniques such as next-generation sequencing (NGS) and next-generation flow (NGF) is becoming part of all new clinical trials that test drug efficacy. This review focuses on minimal residual disease approaches in clinical trials, with particular attention to real-world practices.
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http://dx.doi.org/10.3390/jpm10030120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565263PMC
September 2020

Prognostic impact of tumor-associated macrophages, lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma.

Am J Blood Res 2020 25;10(4):97-108. Epub 2020 Aug 25.

Unit of Pathology, Department of Medical Biotechnologies, University of Siena Siena, Italy.

Introduction: Microenvironment has a prognostic influence in diffuse large B-cell lymphoma (DLBCL); among its components, tumor-associated macrophages (TAM) play a leading role. TAM can be classified into M1 (anti-tumor) and M2 (pro-tumor). Another prognostic factor could be represented by lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR).

Objective: The aim of the study is to evaluate the prognostic impact of M1 and M2 TAM subtypes, LMR and NLR in DLBCL.

Methods: We analyzed 37 consecutive patients between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP/CHOP-like regimens, 9/37 (24.4%) less intensive therapies. Immunohistochemistry was performed with antibodies against CD68 and CD163. We divided our cohort into 2 categories according to the Steidl score. TAM who coexpressed CD68 and CD163 were considered as M2. For LMR and NLR we used previously published cut-offs of 2.71 and 2.81.

Results: CR rate was 70.3%; we did not record a significant correlation between CD68+ TAM, CD163+ TAM, CD68+/CD163+ TAM, LMR, NLR and CR. We observed a reduced PFS in patients with IPI ≥ 2 and high M2 TAM expression and a trend between higher expression of CD68+ TAM and improved PFS.

Conclusion: M2 TAM could have a prognostic role for IPI ≥ 2 DLBCL patients receiving R-CHOP, which thus warrants further investigation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486489PMC
August 2020

The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19.

Leukemia 2020 10 2;34(10):2815-2816. Epub 2020 Sep 2.

Division of Hematology, University of Siena, Siena, Italy.

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http://dx.doi.org/10.1038/s41375-020-01038-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467142PMC
October 2020

How to manage early-stage follicular lymphoma.

Expert Rev Hematol 2020 10 20;13(10):1093-1105. Epub 2020 Sep 20.

Unit of Hematology, Azienda Ospedaliera Universitaria Senese & University of Siena , Siena, Italy.

Introduction: Early-stage follicular lymphoma (FL) is characterized by good prognosis and can be cured with involved-field radiotherapy (IF-RT) in most cases. PET scan is a milestone of diagnostic work-up, with the aim of identifying a truly localized disease; however, staging in most of the studies was without PET.

Areas Covered: We have searched in MEDLINE (inclusive dates 1994-2020) data about localized FL management. While high-quality evidence is lacking, current guidelines recommend IFRT or involved-site RT as first-line treatment in limited stages FL. Since a significant proportion of disease relapse occurred in non-irradiated areas, it has been hypothesized that occult disease could be present at diagnosis and could persist after RT, contributing to relapse. Available treatment options include watch-and-wait, chemotherapy, RT plus chemo- or chemo-immunotherapy, and RT combined with rituximab (R).

Expert Opinion: RT combined with chemotherapy could increase PFS, but a clear OS benefit is lacking and toxic effects could be unacceptable. A promising strategy is represented by R combined with IF-RT, with low relapse rate outside the radiation fields and without the toxicity reported with chemotherapy. The study of prognostic factors in PET-staged patients, the reduction of RT fields and doses, and a response-adapted strategy represent new perspectives to investigate.
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http://dx.doi.org/10.1080/17474086.2020.1818226DOI Listing
October 2020

Ruxolitinib Rapidly Reduces Acute Respiratory Distress Syndrome in COVID-19 Disease. Analysis of Data Collection From RESPIRE Protocol.

Front Med (Lausanne) 2020 4;7:466. Epub 2020 Aug 4.

Hematology Unit, Università of Siena, Azienda Ospedaliero Universitaria Senese, Siena, Italy.

The Coronavirus disease (COVID-19) pandemic is causing millions of infections and hundreds of thousands of deaths worldwide. Cumulative clinical and laboratory evidence suggest that a subset of patients with severe COVID-19 may develop a cytokine storm syndrome during the course of the disease, with severe respiratory impairment requiring ventilatory support. One field of research nowadays is to identify and treat viral-induced hyperinflammation with drugs used in other clinical conditions characterized by an hyperinflammation status. These drugs might help to reduce COVID19 mortality. Ruxolitinib, a JAK1 and JAK2 inhibitor, has been successfully used to treat severe immune-mediated diseases, such as graft vs. host disease and Hemophagocytic lymphohistiocytosis. We used ruxolitinib in 18 patients with clinically progressive COVID-19 related acute respiratory distress syndrome, with a primary endpoint to rapidly reduce the degree of respiratory impairment and as a secondary endpoint to rapidly restore the PaO/FiO ratio, as an evaluation of clinical status, and monitoring of drug related Adverse Events. Parameters of inflammation responses and organ functions were assessed and monitored. The treatment plan was ruxolitinib 20 mg bid for the first 48 h and subsequent two-step de-escalation at 10 mg bid and 5 mg bid for a maximum of 14 days of treatment. Our data collection shows a rapid clinical response with no evolution from to mechanical ventilation in 16/18 patients and no response in two patients (overall response rate-ORR 89%). Already after 48 h of ruxolitinib treatment 16/18 patients showed evident clinical improvement, and after 7 days of treatment 11/18 patients showed fully recovered respiratory function (pO > 98% in spontaneous breathing), 4/18 patients had minimal oxygen requirement (2-4 L/m), 1/18 patient showed stable disease, and 2/18 patient showed progressive disease. After 14 days, 16/18 patients showed complete recovery of respiratory function (ORR 89%). Compliance to ruxolitinib planned treatment was 100% and no serious adverse event was recorded. In our case series of 18 critically ill patients with COVID-19 and ARDS, administration of ruxolitinib resulted in a clinical improvement that concurred to modify the standard course of disease. Ruxolitinib can be a therapeutic option for patients with respiratory insufficiency in COVID-19 related ARDS. RESPIRE Study (uxolitinib for the treatment of acute rratory distss syndrome, ClinicalTrials.gov Identifier: NCT04361903).
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http://dx.doi.org/10.3389/fmed.2020.00466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417512PMC
August 2020

Efficacy and safety of eltrombopag during conception and first trimester of pregnancy in a case of refractory severe immune thrombocytopenia.

Blood Coagul Fibrinolysis 2020 Sep;31(6):416-418

Hematology Unit, Azienda Ospedaliera Universitaria Senese e Università di Siena, Siena, Italy.

: Immune thrombocytopenia (ITP) is a relatively frequent cause of thrombocytopenia during pregnancy. Thrombopoietin receptor agonists (TPO-RAs) are the most recent drugs approved for second-line treatment of ITP. Limited data are available about their use in pregnancy with only a few published cases; yet no data exist about their effect when administered only during conception and first trimester of gestation. We describe the case of a woman with refractory ITP who took eltrombopag during conception and first trimester of pregnancy. No fetal or maternal complications were reported. Moreover, the patient remained in complete response after delivery despite therapy discontinuation. The analysis of this case and the revision of the available literature suggest that the use of TPO-RAs, thanks to their short time to response, may be effective and feasible during the first trimester of pregnancy, even if not yet recommended by current guidelines.
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http://dx.doi.org/10.1097/MBC.0000000000000936DOI Listing
September 2020

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study.

Lancet Haematol 2020 Oct 13;7(10):e737-e745. Epub 2020 Aug 13.

Hematology, University Hospital Sant'Andrea, Sapienza, Rome, Italy; Department of Clinical and Molecular Medicine, Sapienza, University of Rome, Rome, Italy.

Background: Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19.

Methods: This multicentre, retrospective, cohort study included adult patients (aged ≥18 years) with diagnosis of a WHO-defined haematological malignancy admitted to 66 Italian hospitals between Feb 25 and May 18, 2020, with laboratory-confirmed and symptomatic COVID-19. Data cutoff for this analysis was June 22, 2020. The primary outcome was mortality and evaluation of potential predictive parameters of mortality. We calculated standardised mortality ratios between observed death in the study cohort and expected death by applying stratum-specific mortality rates of the Italian population with COVID-19 and an Italian cohort of 31 993 patients with haematological malignancies without COVID-19 (data up to March 1, 2019). Multivariable Cox proportional hazards model was used to identify factors associated with overall survival. This study is registered with ClinicalTrials.gov, NCT04352556, and the prospective part of the study is ongoing.

Findings: We enrolled 536 patients with a median follow-up of 20 days (IQR 10-34) at data cutoff, 85 (16%) of whom were managed as outpatients. 440 (98%) of 451 hospitalised patients completed their hospital course (were either discharged alive or died). 198 (37%) of 536 patients died. When compared with the general Italian population with COVID-19, the standardised mortality ratio was 2·04 (95% CI 1·77-2·34) in our whole study cohort and 3·72 (2·86-4·64) in individuals younger than 70 years. When compared with the non-COVID-19 cohort with haematological malignancies, the standardised mortality ratio was 41·3 (38·1-44·9). Older age (hazard ratio 1·03, 95% CI 1·01-1·05); progressive disease status (2·10, 1·41-3·12); diagnosis of acute myeloid leukaemia (3·49, 1·56-7·81), indolent non-Hodgin lymphoma (2·19, 1·07-4·48), aggressive non-Hodgkin lymphoma (2·56, 1·34-4·89), or plasma cell neoplasms (2·48, 1·31-4·69), and severe or critical COVID-19 (4·08, 2·73-6·09) were associated with worse overall survival.

Interpretation: This study adds to the evidence that patients with haematological malignancies have worse outcomes than both the general population with COVID-19 and patients with haematological malignancies without COVID-19. The high mortality among patients with haematological malignancies hospitalised with COVID-19 highlights the need for aggressive infection prevention strategies, at least until effective vaccination or treatment strategies are available.

Funding: Associazione italiana contro le leucemie, linfomi e mieloma-Varese Onlus.
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http://dx.doi.org/10.1016/S2352-3026(20)30251-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426107PMC
October 2020

Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors.

Ann Hematol 2020 Jul 30;99(7):1525-1530. Epub 2020 May 30.

Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rd TKIs.
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http://dx.doi.org/10.1007/s00277-020-04102-6DOI Listing
July 2020

Coexistence of Serum Monoclonal Gammopathy of Uncertain Significance and Hodgkin Lymphoma.

Indian J Hematol Blood Transfus 2020 Apr 12;36(2):390-392. Epub 2019 Dec 12.

1Hematology Unit, University Hospital, Azienda Ospedaliera Universitaria Senese, Viale Bracci, 16, 53100 Siena, Italy.

An uncommon association between multiple myeloma and Hodgkin lymphoma (HL) was observed in some case reports, while an association with monoclonal gammopathy of uncertain significance (MGUS) is exceedingly rare. We have diagnosed 110 HL cases from 2008 to 2018; here we report 4 HL cases associated with MGUS. MGUS was diagnosed before HL (1 case), together with HL (1 case) or after HL (2 cases). M-component was IgG/k (3 cases) and IgG/k and IgG/λ (1 case), MGUS was not influenced by HL treatment (2 cases), raised after therapy (1 case), while in the last case MGUS appeared after ASCT while HL was in complete remission. We suggest to further study a possible link between MGUS and HL and to perform serum immunofixation if protein electrophoresis shows a suspected discrete band. The comprehension of pathophysiology of this association and a possible role of cytokines such as IL-6 and antilymphoma therapies such as nivolumab or ASCT to MGUS development could represent an interesting research field that requires further investigations.
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http://dx.doi.org/10.1007/s12288-019-01242-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229058PMC
April 2020

Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia.

Eur J Haematol 2020 Sep 22;105(3):286-291. Epub 2020 May 22.

Department of Translational and Precision Medicine, University "La Sapienza" of Rome, Rome, Italy.

Background: Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined.

Methods: Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated.

Results: Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed.

Conclusions: Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.
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http://dx.doi.org/10.1111/ejh.13436DOI Listing
September 2020

Real word evidence on rituximab utilization: Combining administrative and hospital-pharmacy data.

PLoS One 2020 12;15(3):e0229973. Epub 2020 Mar 12.

Department of Medical Science, Surgery and Neuroscience, University of Siena, and Azienda Ospedaliera Universitaria Senese, Siena, Italy.

Purpose: To describe patterns of utilization, survival and infectious events in patients treated with rituximab at the University Hospital of Siena (UHS) to explore the feasibility of combining routinely collected administrative and hospital-pharmacy data for examining the real-world use of intravenous antineoplastic drugs.

Methods: A retrospective, longitudinal cohort study was conducted using data from the Hospital Pharmacy of Siena (HPS) and the Regional Administrative Database of Tuscany (RAD). Patients aged ≥18 years with ≥1 rituximab administration recorded between January 2012 and June 2016 were identified in the HPS database. Anonymized patient-level data were linked to RAD. Rituximab utilization during the first year of treatment was described using HPS. Hospital diagnoses of adverse infectious events that occurred during the first year of follow-up and four-year survival were observed using RAD.

Results: A total of 311 new users of rituximab were identified: 264 patients received rituximab for non-Hodgkin's lymphoma (NHL) and 47 were treated for chronic lymphocytic leukemia (CLL). Among new users with one complete year of follow-up (n = 203) over 95% received rituximab as the first-line treatment, and approximately 70% of them received 5-8 doses. No patient in the CLL group received >8 administrations. Four-year survival was approximately 70% in both CLL and NHL patients. Sepsis was the most frequent infectious event observed (5.1%).

Conclusion: HPS and RAD provided complementary information on rituximab utilization, demonstrating their potential for future pharmacoepidemiological studies on antineoplastic medications administered in the Italian hospital setting. Overall, this general description of the real-world utilization of rituximab in patients treated for NHL and CLL at UHS was in line with treatment guidelines and current knowledge on the rituximab safety profile.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229973PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067445PMC
June 2020

Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study.

Blood 2020 02;135(8):534-541

Department of Hematology, Ospedale San Carlo, Potenza, Italy.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.
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http://dx.doi.org/10.1182/blood.2019002969DOI Listing
February 2020

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP.

Blood Adv 2019 12;3(24):4280-4290

Università Federico II, Naples, Italy.

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.
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http://dx.doi.org/10.1182/bloodadvances.2019000865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929396PMC
December 2019

Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper.

J Hematol Oncol 2019 12 5;12(1):131. Epub 2019 Dec 5.

Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

BCR-ABL1 kinase domain (KD) mutation status is considered to be an important element of clinical decision algorithms for chronic myeloid leukemia (CML) patients who do not achieve an optimal response to tyrosine kinase inhibitors (TKIs). Conventional Sanger sequencing is the method currently recommended to test BCR-ABL1 KD mutations. However, Sanger sequencing has limited sensitivity and cannot always discriminate between polyclonal and compound mutations. The use of next-generation sequencing (NGS) is increasingly widespread in diagnostic laboratories and represents an attractive alternative. Currently available data on the clinical impact of NGS-based mutational testing in CML patients do not allow recommendations with a high grade of evidence to be prepared. This article reports the results of a group discussion among an ad hoc expert panel with the objective of producing recommendations on the appropriateness of clinical decisions about the indication for NGS, the performance characteristics of NGS platforms, and the therapeutic changes that could be applied based on the use of NGS in CML. Overall, these recommendations might be employed to inform clinicians about the practical use of NGS in CML.
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http://dx.doi.org/10.1186/s13045-019-0815-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894351PMC
December 2019
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