Publications by authors named "Cristina Bucelli"

34 Publications

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study.

Front Oncol 2021 12;11:637116. Epub 2021 Mar 12.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Lack of demonstrable mutations affecting , or driver genes within the spectrum of -negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5-10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the gene (55.0%), followed by (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.
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http://dx.doi.org/10.3389/fonc.2021.637116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006378PMC
March 2021

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge.

J Clin Med 2021 Feb 1;10(3). Epub 2021 Feb 1.

Hematology, Department of Translational and Precision Medicine, Sapienza University, Policlinico Umberto 1, 00161 Rome, Italy.

The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with tyrosine kinase inhibitor (TKI) development, which allows a near-normal life expectancy. However, long-term TKI exposure has been associated with persistent adverse events (AEs) which negatively impact on quality of life (QoL) and have the potential to cause significant morbidity and mortality. In clinical practice, TKI dose reduction is usually considered to reduce AEs and improve QoL, but dose optimization could have also another aim, i.e., the achievement and maintenance of cytogenetic and molecular responses. While therapy cessation appeared as a safe option for about half of the patients achieving an optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. The present review is focused on the most recent evidences for TKIs dose modifications in CML clinical studies and in the real-life setting. It will consider TKI dose modifications in newly diagnosed patients, dose reduction for AEs, or in deep molecular response, either as a prelude to treatment-free remission (TFR) or as continuous maintenance therapy in those patients not wishing to attempt TFR. In addition, it will focus on patients not achieving a molecular response deep enough to go to TFR, and for whom dose reduction could be an option to avoid AEs.
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http://dx.doi.org/10.3390/jcm10030515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867069PMC
February 2021

Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial.

Lancet Haematol 2021 Mar 18;8(3):e175-e184. Epub 2021 Jan 18.

Unità Operativa di Ematologia e Trapianto Midollo Osseo, IRCCS Ospedale San Raffaele, Milan, Italy.

Background: There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone.

Methods: In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 μg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325.

Findings: Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred.

Interpretation: Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera.

Funding: AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.
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http://dx.doi.org/10.1016/S2352-3026(20)30373-2DOI Listing
March 2021

Cytogenetic study in primary myelofibrosis at diagnosis: Clinical and histological association and impact on survival according to WHO 2017 classification in an Italian multicenter series.

Hematol Oncol 2021 Feb 4;39(1):123-128. Epub 2020 Oct 4.

Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

We analyzed cytogenetic data at diagnosis in 395 primary myelofibrosis (PMF) patients to evaluate any possible association between karyotype and WHO 2017 classification and its impact on prognosis. All the cases were diagnosed and followed at five Italian Hematological Centers between November 1983 and December 2016. An abnormal karyotype (AK) was found in 69 patients and clustered differently according to bone marrow fibrosis grade as it was found in 31 (27.0%) cases with overt fibrotic and 38 (13.6%) with pre-fibrotic PMF (p = 0.001). Sex, anemia, thrombocytopenia, circulating blasts ≥1%, higher lactate dehydrogenase, and International Prognostic Scoring System risk classes were all significantly associated with karyotype. At a median follow-up of >6 years, 101 deaths were recorded. Survival was different between AK and normal karyotype (NK) patients with an estimated median overall survival (OS) of 11.6 and 25.7 years, respectively (p = 0.0148). In conclusion, in our cohort around 20% of patients had an AK, more frequently in subjects with an advanced bone marrow fibrosis grade and clinical-laboratory features indicative of a more aggressive disease. This study shows that an AK confers a more severe clinical phenotype and impacts adversely on OS, thus representing an additional parameter to be considered in the evaluation of PMF prognosis.
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http://dx.doi.org/10.1002/hon.2808DOI Listing
February 2021

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy.

Int J Mol Sci 2020 Aug 13;21(16). Epub 2020 Aug 13.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called "masked PV", as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients' prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors.
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http://dx.doi.org/10.3390/ijms21165805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461104PMC
August 2020

Use of generic imatinib as first-line treatment in patients with chronic myeloid leukemia (CML): the GIMS (Glivec to Imatinib Switch) study.

Blood Res 2020 Sep;55(3):139-145

Hematology Division and Bone Marrow Unit, Ospedale San Gerardo, ASST-Monza, Monza, Italy.

Background: Generic formulations of imatinib mesylate have been introduced in Western Europe since 2017 to treat patients with chronic myeloid leukemia (CML). However, results on the safety and efficacy of generic formulations are contrasting. The aim of this study was to investigate the safety and efficacy of generic imatinib in CML patients treated in 12 Italian institutes.

Methods: This is an observational, retro-prospective analysis of patients with CML for whom the treatment was switched from brand to generic imatinib. We analyzed and compared the variation in quantitative PCR values before and after the switch, and the proportion of patients who maintained molecular response after changing from brand to generic imatinib. Adverse events (AEs) were also evaluated.

Results: Two hundred patients were enrolled. The median PCR value after the switch was reduced by 0.25 compared to the values before the switch. A significant difference was found between median PCR values before and after the switch in favor of generic imatinib (=0.003). Molecular responses remained stable in 69.0%, improved in 25.5%, and worsened in 5.5% of patients. AEs were similar in the pre- and post-switch periods; however, a significant difference was found in favor of generic imatinib for muscular cramps (<0.0001), periorbital edema (=0.0028), edema of the limbs (<0.0001), fatigue (=0.0482), and diarrhea (=0.0027).

Conclusion: Our data indicate that generic imatinib does not have deleterious effects on CML control and present an acceptable safety profile, similar or better than brand imatinib.
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http://dx.doi.org/10.5045/br.2020.2020130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536566PMC
September 2020

Management of Myelofibrosis: from Diagnosis to New Target Therapies.

Curr Treat Options Oncol 2020 04 30;21(6):46. Epub 2020 Apr 30.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.

Opinion Statement: Myelofibrosis (MF) is a clonal disorder of the pluripotent hematopoietic stem cell, whose clinical manifestations can be extremely heterogeneous, including cytopenias, organomegaly, constitutional symptoms, and cachexia. Median survival ranges from approximately 3.5 to 5.5 years; while the most frequent cause of death is the evolution to acute myeloid leukemia, also other conditions such as progression without transformation, complications due to cytopenias including infections or bleeding, and cardiovascular events may be fatal. Myelofibrosis is still orphan of curative treatments: allogeneic hematopoietic stem cell transplant (HSCT), the only therapeutic approach that has clearly demonstrated an impact on disease progression, is associated with relevant morbidity and mortality and only a minority of patients is eligible for such an intensive procedure. While the discovery of the crucial role of JAK2 mutations and the consequent clinical use of JAK inhibitors has led to a dramatic improvement of symptoms control and quality of life, yet these drugs do not significantly modify the natural history of the disease. A better understanding of the molecular pathogenesis will hopefully foster the development of new targeted therapies aimed at improving MF prognosis. Herein, we review the most recent advances about JAK inhibitors and other molecules which are under investigation.
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http://dx.doi.org/10.1007/s11864-020-00734-yDOI Listing
April 2020

A randomized double-blind trial of 3 aspirin regimens to optimize antiplatelet therapy in essential thrombocythemia.

Blood 2020 07;136(2):171-182

Hematology Project Foundation, Vicenza, Italy.

Essential thrombocythemia (ET) is characterized by abnormal megakaryopoiesis and enhanced thrombotic risk. Once-daily low-dose aspirin is the recommended antithrombotic regimen, but accelerated platelet generation may reduce the duration of platelet cyclooxygenase-1 (COX-1) inhibition. We performed a multicenter double-blind trial to investigate the efficacy of 3 aspirin regimens in optimizing platelet COX-1 inhibition while preserving COX-2-dependent vascular thromboresistance. Patients on chronic once-daily low-dose aspirin (n = 245) were randomized (1:1:1) to receive 100 mg of aspirin 1, 2, or 3 times daily for 2 weeks. Serum thromboxane B2 (sTXB2), a validated biomarker of platelet COX-1 activity, and urinary prostacyclin metabolite (PGIM) excretion were measured at randomization and after 2 weeks, as primary surrogate end points of efficacy and safety, respectively. Urinary TX metabolite (TXM) excretion, gastrointestinal tolerance, and ET-related symptoms were also investigated. Evaluable patients assigned to the twice-daily and thrice-daily regimens showed substantially reduced interindividual variability and lower median (interquartile range) values for sTXB2 (ng/mL) compared with the once-daily arm: 4 (2.1-6.7; n = 79), 2.5 (1.4-5.65, n = 79), and 19.3 (9.7-40; n = 85), respectively. Urinary PGIM was comparable in the 3 arms. Urinary TXM was reduced by 35% in both experimental arms. Patients in the thrice-daily arm reported a higher abdominal discomfort score. In conclusion, the currently recommended aspirin regimen of 75 to 100 once daily for cardiovascular prophylaxis appears to be largely inadequate in reducing platelet activation in the vast majority of patients with ET. The antiplatelet response to low-dose aspirin can be markedly improved by shortening the dosing interval to 12 hours, with no improvement with further reductions (EudraCT 2016-002885-30).
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http://dx.doi.org/10.1182/blood.2019004596DOI Listing
July 2020

Outcome of very elderly chronic myeloid leukaemia patients treated with imatinib frontline.

Ann Hematol 2019 Oct 7;98(10):2329-2338. Epub 2019 Aug 7.

Institute of Hematology, Università Cattolica SacroCuore, Rome, Italy.

Very elderly (> 75 years) chronic myeloid leukaemia (CML) patients at diagnosis are sometimes treated with different doses of imatinib (IM) based on concomitant diseases and physicians' judgement. However, data on long-term follow-up of these patients are still lacking. To investigate treatment response and outcome, we retrospectively revised an Italian database of 263 very elderly CML patients receiving IM from the time of diagnosis. Median age at diagnosis was 78.5 years and 56% of patients had 2 or 3 comorbidities. A complete haematological and cytogenetic response were achieved in 244 (92.8%) and 184 (69.9%) patients, respectively. In 148 cases (56.2%), a major molecular response was observed, which was deep in 63 cases (24%). A blastic phase occurred in 11 patients (4.2%). After a median follow-up of 45.0 months, 93 patients have died (9 from disease progression) and 104 (39.5%) are still in treatment with IM. Incidence of grades 3-4 haematological and non-haematological toxicity was similar to those reported in younger patients. Five-year event-free survival was 54.5% and 45.2% in patients ≤ 80 years and > 80 years, respectively (p = 0.098). Five years OS was 75.7% and 61.6% in patients ≤80 years and > 80 years, respectively (p = 0.003). These findings show that IM plays an important role in frontline treatment of very elderly CML patients without increased toxicity and any effort to treat these patients with standard doses should be made in order to achieve responses as in younger subjects.
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http://dx.doi.org/10.1007/s00277-019-03767-yDOI Listing
October 2019

UGT1A1 genotype does not affect tyrosine kinase inhibitors efficacy and safety in chronic myeloid leukemia.

Am J Hematol 2019 11 9;94(11):E283-E285. Epub 2019 Aug 9.

Department of Clinical Sciences and Community Health, University of Milan, and Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1002/ajh.25596DOI Listing
November 2019

Integrating clinical, morphological, and molecular data to assess prognosis in patients with primary myelofibrosis at diagnosis: A practical approach.

Hematol Oncol 2019 Oct 22;37(4):424-433. Epub 2019 Aug 22.

Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, and Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on "other" mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I-IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I-IPSS-low risk (113 patients), I-IPSS-intermediate-1 risk (56 patients), I-IPSS-intermediate-2 risk (154 patients), and I-IPSS-high risk (78 patients). Median overall survival was 26.7 years in I-IPSS-intermediate-1, 10.8 in I-IPSS-intermediate-2, and 6.4 in I-IPSS-high-risk patients (log-rank test <0.0001); instead, it was not reached in the I-IPSS-low-risk cohort because of the extremely low number of registered deaths. The addition of GBMF and MS to IPSS improved the efficacy for predicting the risk of death. Indeed, the sensitivity of I-IPSS was significantly higher (P < .05) than that of IPSS, considering both total deaths and 5- and 10-year mortality. This comprehensive approach allows clinicians to evaluate mutual interactions between IPSS, GBMF, and MS and identify high-risk patients with poor prognosis who may benefit from aggressive treatments. More importantly, this integrated score can be easily applicable worldwide as it only required information that represent the good clinical practice in the management of PMF patients.
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http://dx.doi.org/10.1002/hon.2658DOI Listing
October 2019

Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment.

PLoS One 2019 18;14(7):e0218444. Epub 2019 Jul 18.

Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy.

Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218444PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638825PMC
February 2020

Osteolytic Lesions in Primary Myelofibrosis and Effect of Ruxolitinib Therapy: Report of a Case and Literature Review.

Chemotherapy 2018 9;63(6):340-344. Epub 2019 Apr 9.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy,

Here, we report the case of a young female affected by primary myelofibrosis (PMF) who developed an osteolytic lesion of the humerus during the follow-up, and the possible efficacy of ruxolitinib in controlling this rare event. After 26 years of follow-up, the patient reported onset of acute pain at the proximal region of the left upper limb. An X-ray revealed an osteolytic bone lesion in the proximal third of the humeral shaft, which was then confirmed by magnetic resonance imaging. A biopsy of the lytic lesion was done, revealing hypercellular bone marrow with hyperplastic granulopoiesis associated with megakaryocytic proliferation and atypia, accompanied by a diffuse and dense increase in reticulin fibrosis with extensive intersections and coarse bundles of thick fibers, consistent with a grade 3 collagen fibrosis. No new therapeutic intervention was initially required; however, 2 years later, the patient reported symptomatic splenomegaly and drenching night sweats, so ruxolitinib therapy was started. By week 8, the patient had near resolution of constitutional symptoms and a reduction of > 50% of the spleen size that normalized by 6 months; in addition, a repeat bone marrow biopsy showed a decrease in reticulin fibrosis grade. Interestingly, after 9 months of ruxolitinib therapy, further magnetic resonance imaging of the left upper limb showed the absence of bone lytic lesions and a substantial normalization of the bone tissue. In conclusion, with the present case report, we confirm ruxolitinib efficacy in reducing bone marrow fibrosis grade and assume its possible role in the resolution of osteolytic lesions in PMF. Obviously, further studies with a greater number of patients are needed to document the exact frequency of these unusual findings and the possible role of ruxolitinib in their treatment.
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http://dx.doi.org/10.1159/000497246DOI Listing
May 2019

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation.

Cancer Med 2019 05 4;8(5):2041-2055. Epub 2019 Apr 4.

Unit of Blood Diseases and Stem Cell Transplantation, DPT of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy.

Treatment-free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real-time quantitative PCR (RT-qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT-qPCR for BCR-ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected BCR-ABL1 transcripts in the RT-qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR and MR (P = 0.0104) or MR (P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR vs MR ) were superimposable. Conversely, patients with dPCR values <0.468 BCR-ABL1 copies/µL (as we previously described) showed a longer DMR duration (P = 0.0220) and mainly belonged to MR (P = 0.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR or MR . RT-qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation (P = 0.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR-ABL1 values ≥0.468 and 12/86 (14%) patients with BCR-ABL1 values <0.468 lost DMR in this cohort, respectively (P = 0.0003). Treatment-free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR ≥ 0.468 (TFR at 2 years 83% vs 52% P = 0.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation.
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http://dx.doi.org/10.1002/cam4.2087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536984PMC
May 2019

Excellent outcomes of 2G-TKI therapy after imatinib failure in chronic phase CML patients.

Oncotarget 2018 Mar 12;9(18):14219-14227. Epub 2018 Feb 12.

Division of Hematology and Bone Marrow Transplantation, Department of Medical Area, ASUI Udine, Udine, Italy.

Second-generation tyrosine kinase inhibitors (2G-TKIs) dasatinib and nilotinib produced historical rates of about 50% complete cytogenetic response (CCyR) and about 40% major molecular response (MMR) in chronic myeloid leukaemia (CML) patients failing imatinib. Direct comparisons between dasatinib and nilotinib are lacking, and few studies addressed the dynamics of deep molecular response (DMR) in a "real-life" setting. We retrospectively analyzed 163 patients receiving dasatinib ( = 95) or nilotinib ( = 68) as second-line therapy after imatinib. The two cohorts were comparable for disease's characteristics, although there was a higher rate of dasatinib use in imatinib-resistant and of nilotinib in intolerant patients. Overall, 75% patients not in CCyR and 60% patients not in MMR at 2G-TKI start attained this response. DMR was achieved by 61 patients (37.4%), with estimated rate of stable DMR at 5 years of 24%. After a median follow-up of 48 months, 60% of patients persisted on their second-line treatment. Rates and kinetics of cytogenetic and molecular responses, progression-free and overall survival were similar for dasatinib and nilotinib. In a "real-life" setting, dasatinib and nilotinib resulted equally effective and safe after imatinib failure, determining high rates of CCyR and MMR, and a significant chance of stable DMR, a prerequisite for treatment discontinuation.
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http://dx.doi.org/10.18632/oncotarget.24478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865665PMC
March 2018

Low-Dose Ponatinib in Intolerant Chronic Myeloid Leukemia Patients: A Safe and Effective Option.

Clin Drug Investig 2018 05;38(5):475-476

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

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http://dx.doi.org/10.1007/s40261-018-0623-7DOI Listing
May 2018

The and polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia.

Oncotarget 2017 Oct 30;8(50):88021-88033. Epub 2017 Sep 30.

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

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of (rs683369 [c.480C>G]) and (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, and polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, n contrast to data obtained in patients treated with imatinib, and polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.
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http://dx.doi.org/10.18632/oncotarget.21406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675690PMC
October 2017

Pleural effusion and molecular response in dasatinib-treated chronic myeloid leukemia patients in a real-life Italian multicenter series.

Ann Hematol 2018 Jan 2;97(1):95-100. Epub 2017 Oct 2.

Hematology and Transplants Unit, University of Bari, Bari, Italy.

Pleural effusion (PE) represents the leading cause of dasatinib (DAS) discontinuation. However, the pathogenic mechanism of this adverse event (AE) is unknown and its management unclear. We investigated if a DAS dose reduction after the first PE would prevent the recurrence of this AE. We retrospectively collected data on all the cases of PE in CML-chronic phase (CP) DAS-treated patients from November 2005 to February 2017 in 21 Italian hematological centers. We identified 196 cases of PE in a series of 853 CML-CP DAS-treated patients (incidence 23.0%). DAS starting dose was 100 mg/day in 70.4% of patients, less than 100 mg/day in 14.3%, and more than 100 mg/day in the remaining cases. Median time from DAS start to PE was 16.6 months. At first PE development, 28.6% of patients were in MMR, and 37.8% in deep molecular response (DMR). DAS was temporary interrupted in 71.9% of cases, with a dose reduction in 59.2%. Recurrence was observed in 59.4% of the cases. Treatment was definitively discontinued due to PE in 29.1% of the cases. Interestingly, among patients whose DAS dosage was reduced, 59.5% experienced PE recurrence. DAS dose reduction after the first episode of PE did not prevent recurrence of this AE. Therefore, once a MMR or a DMR is achieved, different strategies of DAS dose management can be proposed prior to the development of PE, such as daily dose reduction or, as an alternative option, an on/off treatment with a weekend drug holiday.
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http://dx.doi.org/10.1007/s00277-017-3144-1DOI Listing
January 2018

Ponatinib as a Valid Alternative Strategy in Patients with Blast Crisis-Chronic Myeloid Leukemia Not Eligible for Allogeneic Stem Cells Transplantation and/or Conventional Chemotherapy: Report of a Case.

Case Rep Hematol 2017 14;2017:6167345. Epub 2017 Aug 14.

Hematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation and University of Milan, Milan, Italy.

Currently, imatinib and dasatinib are the only tyrosine-kinase inhibitors approved in the US and Europe for the treatment of blast crisis of chronic myeloid leukemia (BC-CML) at diagnosis, while ponatinib is the only inhibitor used in patients bearing T315I mutation. Here we report the case of a 61-year-old man diagnosed with B-cell lymphoid BC-CML, initially treated with imatinib 800 mg day and then with dasatinib 140 mg day because of intolerance. A complete cytogenetic response (CCyR) was achieved at three months; however, three months later a relapse was observed, and the T315I mutation was detected. Ponatinib 45 mg once daily was then started together with a short course of chemotherapy. Bone marrow evaluation after six months of therapy showed the regaining of CCyR, together with the achievement of a deep molecular response. However, one year from ponatinib start the patient experienced a new disease relapse; he was effectively treated with ponatinib and chemotherapy once again, but in the meanwhile an ischemic stroke was detected. This case report confirms the high efficacy of ponatinib monotherapy in BC-CML patients, representing a valid option for non-allogeneic stem cells transplantation eligible cases and the only one available for those carrying the T315I mutation.
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http://dx.doi.org/10.1155/2017/6167345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584354PMC
August 2017

Reactive follicular hyperplasia on dasatinib treatment for chronic myeloid leukemia.

Ann Hematol 2017 Nov 19;96(11):1953-1954. Epub 2017 Aug 19.

Hematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Via Francesco Sforza 35, 20122, Milan, Italy.

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http://dx.doi.org/10.1007/s00277-017-3105-8DOI Listing
November 2017

An unusual type of myeloid sarcoma localization following myelofibrosis: A case report and literature review.

Leuk Res Rep 2017 27;8:7-10. Epub 2017 Jul 27.

Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, Milan, Italy.

Myeloid Sarcoma (MS) is a rare malignancy that can present as an isolated disease or more frequently in association with or following acute myeloid leukemia or other myeloid neoplasms and rarely following myelofibrosis. Since molecular pathogenesis and prognostic factors of MS are not well understood, its prognosis remains poor even in the era of novel agents and target therapies. We report the case of a patient with MS following myelofibrosis with multiple subcutaneous, cutaneous and muscle localizations; the latter has been reported in the literature as anecdotal. In this way we aimed to enhance the understanding of this disease.
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http://dx.doi.org/10.1016/j.lrr.2017.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536879PMC
July 2017

Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients.

Histopathology 2017 Dec 28;71(6):897-908. Epub 2017 Sep 28.

Hematology Division, IRCCS Ca' Granda, Maggiore Policlinico Hospital Foundation, Milan, Italy.

Aims: To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications.

Methods And Results: Reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (log-rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients.

Conclusion: The comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high-risk patients and improved PPV when applied in addition to IPSS.
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http://dx.doi.org/10.1111/his.13309DOI Listing
December 2017

CD18 promoter methylation is associated with a higher risk of thrombotic complications in primary myelofibrosis.

Ann Hematol 2016 Dec 5;95(12):1965-1969. Epub 2016 Sep 5.

Hematopathology Section, Pathology Unit, Department of Pathophysiology and Transplantation, University of Milan, and IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, Milan, Italy.

Morbidity and mortality of BCR-ABL1-negative myeloproliferative neoplasm (MPN) patients are influenced by disease-related hemostatic complications, mostly of thrombotic nature. The pathogenesis of thrombosis is multifactorial: in particular, it has been demonstrated that a deregulated expression of Mac1 (also known as surface receptor integrin CD18/CD11b) by leukocytes has a role in favoring platelets' activation in MPN patients. Based on these data, we investigated the epigenetic status of CD18/CD11b in 78 primary myelofibrosis (PMF) patients to explore any possible association between the epigenetic profiles of these two genes and thrombotic risk. The percentage of CD18 methylation in the PMF samples ranged from hypomethylated to hypermethylated (range: 11-90 %, mean: 64 %), whereas in controls CD18 methylation status clustered in a more restricted interval (range: 24-68 %, mean: 45 %; cases vs.

Controls: p = 0.006). Furthermore, the results showed that CD18 hypermethylation (>76 % methylation) was correlated with thrombotic complications. On the contrary, CD11b promoter resulted unmethylated (1-5 %) in both cases and controls. Previous studies showed that older age, JAK2V617F mutation, and thrombophilia might play a role in MPN patients' thrombotic risk. In our cases, the prognostic value of these variables was coherent, being thrombotic events significantly associated with age >65 years (p = 0.001), JAK2 mutation (p = 0.01), and positive thrombophilia tests (p = 0.04). However, multivariate analysis showed that only CD18 methylation and age >65 years were independent prognostic factors of thrombosis (p = 0.02 and p = 0.04, respectively). Taken together, our findings suggest a possible role of CD18 epigenetic regulation in the pathogenesis of the thrombotic complications in PMF patients.
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http://dx.doi.org/10.1007/s00277-016-2812-xDOI Listing
December 2016

Imatinib and polypharmacy in very old patients with chronic myeloid leukemia: effects on response rate, toxicity and outcome.

Oncotarget 2016 Nov;7(48):80083-80090

Hematology and Transplants Unit, University of Bari, Bari, Italy.

Background: About 40% of all patients with chronic myeloid leukemia are currently old or very old. They are effectively treated with imatinib, even though underrepresented in clinical studies. Furthermore, as it happens in the general population, they often receive multiple drugs for associated chronic illnesses. Aim of this study was to assess whether or not in imatinib-treated patients aged >75 years the exposure to polypharmacy (5 drugs or more) had an impact on cytogenetic and molecular response rates, event-free and overall survival, as well as on hematological or extra-hematological toxicity.

Methods: 296 patients at 35 Italian hematological institutions were evaluated.

Results: Polypharmacy was reported in 107 patients (36.1%), and drugs more frequently used were antiplatelets, diuretics, proton pump inhibitors, ACE-inhibitors, beta-blockers, calcium channel blockers, angiotensin II receptors blockers, statins, oral hypoglycemic drugs and alpha blockers. Complete cytogenetic response was obtained in 174 patients (58.8%), 78 (26.4%) within 6 month, 63 (21.3%) between 7 and 12 months. Major molecular response was obtained in 153 patients (51.7%), 64 (21.6%) within the 12 month. One hundred and twenty-eight cases (43.2%) of hematological toxicity were recorded, together with 167 cases (56.4%) of extra-hematological toxicity. Comparing patients exposed to polypharmacy to those without, no difference was observed pertaining to the dosage of imatinib, cytogenetic and molecular responses and hematological and extra-hematological toxicity.

Conclusion: Notwithstanding the several interactions reported in the literature between imatinib and some of the medications considered herewith, this fact does not seem to have a clinical impact on response rate and outcome.
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http://dx.doi.org/10.18632/oncotarget.11657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346773PMC
November 2016

Anagrelide and Mutational Status in Essential Thrombocythemia.

BioDrugs 2016 Jun;30(3):219-23

Oncohematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation and University of Milan, Via Francesco Sforza 35, 20122, Milan, Italy.

Background: Anagrelide is an orally active, quinazolone-derived, platelet-lowering agent that acts by blocking megakaryocyte maturation and polyploidization as well as proplatelet formation, and is currently indicated for second-line treatment of high-risk patients with essential thrombocythemia (ET) in Europe. In recent years various clinical trials have confirmed the safety and efficacy of this drug in ET, with some also considering Janus kinase 2 (JAK2) mutational status, but have not confirmed the impact that the other driver mutations, i.e., calreticulin (CALR) and myeloproliferative leukemia virus (MPL), may have on the response to this therapy.

Objective: To assess the impact of JAK2, MPL, CALR gene mutational status on response to anagrelide therapy in patients with ET treated at the Oncohematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Milan between 2004 and 2015.

Methods: Among 213 ET patients who were diagnosed between January 1983 to November 2014, 21 consecutive cases who were started on anagrelide as a second-line therapy and received at least 1-year of treatment were included. Inclusion criteria were the availability of demographic, clinical, histological, and hematologic data at diagnosis, and at least one granulocyte DNA sample to assess the mutational status of the JAK2, MPL, and CALR genes.

Results: The JAK2V617F mutation was detected in seven patients (33.3 %), CALR mutations were identified in another seven cases, and the remaining seven patients were defined as "triple-negative" (i.e., no JAK2, CALR, or MPL mutation). After a median anagrelide treatment duration of 4.6 years, 16 of 21 patients (76.2 %) achieved at least a partial platelet response: in particular, the hematological response rate was substantially comparable between JAK2-positive and "triple-negative" patients, whereas the five patients who did not achieve any platelet response all had CALR mutations.

Conclusion: Although it needs to be confirmed with a larger number of ET patients treated with anagrelide, we suggest that mutational status should be considered carefully when deciding on the most appropriate therapy for each patient, mainly because anagrelide alone was not able to achieve an appropriate hematological response in CALR-mutated ET cases.
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http://dx.doi.org/10.1007/s40259-016-0170-9DOI Listing
June 2016

Comprehensive Molecular Analyses in a Case of Masked Philadelphia Chronic Myeloid Leukemia.

Cytogenet Genome Res 2015 5;147(1):35-40. Epub 2015 Dec 5.

Oncohematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, Milan, Italy.

Here, we report the case of an 80-year-old woman with masked Philadelphia chronic myeloid leukemia (Ph CML). At diagnosis, qualitative PCR demonstrated the presence of a typical e14a2 configuration, and chromosome analysis showed an apparently normal female karyotype. However, FISH with BCR-ABL1 dual fusion probes gave a positive signal in 152/200 analyzed nuclei, with the fusion signal detected on the long arm of a cytogenetically normal chromosome 9. Using locus-specific probes for chromosome 9 and 22 telomeres, a third chromosome involvement was excluded. Furthermore, microarray analysis from the same specimens showed a normal result. Due to a high Charlson Comorbidity Index, the patient was treated with a reduced dose of imatinib, achieving a rapid hematological response after 1 month. However, after 6 months of imatinib therapy, she had to be considered as warning (Ph+ 26.5%, BCR-ABL1 >1%) according to the European LeukemiaNet 2013 recommendations. In conclusion, we confirmed the importance of a combination of cytogenetic and molecular techniques for the diagnosis and therapy monitoring of masked Ph CML, but, different from what has been reported in the literature so far, we cannot completely exclude the fact that the unusual cytogenetic pattern of this patient may have negatively influenced her response to tyrosine kinase inhibitor therapy.
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http://dx.doi.org/10.1159/000442039DOI Listing
June 2016