Publications by authors named "Angelo Belotti"

20 Publications

  • Page 1 of 1

Development and Validation of a Simplified Score to Predict Early Relapse in Newly Diagnosed Multiple Myeloma (S-ERMM) in a Pooled Dataset of 2190 Patients.

Clin Cancer Res 2021 Apr 29. Epub 2021 Apr 29.

Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino

Background: Despite the improvement of therapeutic regimens, several multiple myeloma (MM) patients still experience early relapse (ER). This subset of patients currently represents an unmet medical need.

Methods: We pooled data from 7 European multicenter phase II/III clinical trials enrolling 2190 newly diagnosed (ND)MM patients from 2003 to 2017. Baseline patient evaluation included 14 clinically relevant features. Patients with complete data (n=1218) were split into training (n=844) and validation sets (n=374). In the training set, a univariate (UV) analysis and a multivariate (MV) logistic regression model on ER within 18 months (ER18) were made. The most accurate model was selected on the validation set. We also developed a dynamic version of the score by including response to treatment.

Results: The Simplified Early Relapse in MM (S-ERMM) score was modeled on 6 features weighted by a score: 5 points for high lactate dehydrogenase or t(4;14); 3 for del17p, abnormal albumin or bone marrow plasma cells >60%; and 2 for λ free-light chain. The S-ERMM identified 3 patient groups with different risks of ER18: Intermediate (Int) vs. Low (OR=2.39, p<0.001) and High vs. Low (OR=5.59, p<0.001). S-ERMM High/Int patients had significantly shorter OS (High vs. Low: HR=3.24, p<0.001; Int vs. Low: HR=1.86, p<0.001) and PFS2 (High vs. Low: HR=2.89, p<0.001; Int vs. Low: HR=1.76, p<0.001) than S-ERMM Low. The Dynamic (D)S-ERMM modulated the prognostic power of the S-ERMM.

Conclusion: Based on simple, widely available baseline features, the S-ERMM and DS-ERMM properly identified patients with different risks of ER and survival outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0134DOI Listing
April 2021

Clinical characteristics and risk factors for mortality in hematologic patients affected by COVID-19.

Cancer 2020 12 10;126(23):5069-5076. Epub 2020 Sep 10.

Hematology Department, ASST Spedali Civili, Brescia, Italy.

Background: Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID-19) pandemic. However, there are still few data on COVID-19 occurring in hematologic patients.

Methods: One hundred two patients with COVID-19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID-19 were analyzed by comparisons of patients with COVID-19 and the standard hematologic population managed at the same institutions in 2019. Thirty-day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID-19.

Results: Male sex was significantly more prevalent in patients with COVID-19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID-19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive-related treatments. The 30-day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID-19 (23.5%; P = .02) and uninfected hematologic controls (3%; P < .001). The severity of the respiratory syndrome at presentation and active hematologic treatment were independently associated with a worse prognosis. Neither diagnosis nor disease status affected the prognosis. The worst prognosis was demonstrated among patients on active hematologic treatment and those with more severe respiratory syndrome at COVID-19 presentation.

Conclusions: During the COVID-19 pandemic, patients should be advised to seek medical attention at the earliest signs of dyspnea and/or respiratory infection. Physicians should perform a risk-benefit analysis to determine the impact of temporarily deferring nonlifesaving treatments versus the risk of adverse outcomes associated with COVID-19.

Lay Summary: Coronavirus disease 2019 (COVID-19) infection occurs across all different types of hematologic disease; however, the risk of acquiring it is lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive treatment. The 30-day mortality rate is 39.2%, which is far higher than the rates for both uninfected hematologic controls (3%; P < .001) and nonhematologic patients with COVID-19 (23.5%; P = .02) despite matching for age, sex, comorbidities, and severity of disease. Variables independently associated with a worse prognosis are the severity of the respiratory syndrome at presentation and any type of active hematologic treatment. Neither diagnosis nor disease status influence the prognosis.
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http://dx.doi.org/10.1002/cncr.33160DOI Listing
December 2020

Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study.

Lancet Haematol 2020 Jun 30;7(6):e456-e468. Epub 2020 Apr 30.

Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.

Background: The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.

Methods: In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (ISS), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1·3 mg/m administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m administered orally on days 1-4) and prednisone (60 mg/m administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m), stratified by site and ISS disease stage. In centres with a double HSCT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1·3 mg/m either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.

Findings: Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60·3 months (IQR 52·2-67·6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56·7 months [95% CI 49·3-64·5] vs 41·9 months [37·5-46·9]; hazard ratio [HR] 0·73, 0·62-0·85; p=0·0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42·1 months (IQR 32·3-49·2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58·9 months [54·0-not estimable] vs 45·5 months [39·5-58·4]; HR 0·77, 0·63-0·95; p=0·014). The most common grade ≥3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).

Interpretation: This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone.

Funding: Janssen and Celgene.
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http://dx.doi.org/10.1016/S2352-3026(20)30099-5DOI Listing
June 2020

Transplant eligibility in elderly multiple myeloma patients: Prospective external validation of the international myeloma working group frailty score and comparison with clinical judgment and other comorbidity scores in unselected patients aged 65-75 years.

Am J Hematol 2020 07 23;95(7):759-765. Epub 2020 Apr 23.

Hematology Division, ASST Spedali Civili Brescia, Brescia, Italy.

Autologous stem cell transplantation (ASCT) is feasible and effective in selected older patients with Multiple Myeloma, but specific criteria for evaluating ASCT eligibility in elderly patients are lacking. We evaluated 131 patients aged 65-75 considered for ASCT at our center: The Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation comorbidity index (HCT-CI) and IMWG frailty score were obtained at diagnosis, but the intensity of treatment was left to physician's choice. The scores and age's impact on outcome was analyzed: 85 patients were judged transplant eligible, whereas 46 patients received a less intensive treatment (median follow up 27 months). No patients classified as frail had been considered eligible to ASCT with a worse outcome compared to fit and unfit patients (median PFS (progression free survival): 7.9 vs 32.9 and 29.6 months; P < .001). PFS was superior in the ASCT group (35.6 vs 19.9 months, P .013). In the ASCT group, PFS was better in patients aged 65-69 years than in patients ≥70 (51.5 vs 27.7 months, P.004). Indeed, in unfit patients aged ≥70 the PFS of the ASCT group was comparable to NO ASCT group (18 vs 27 months, P = .33) whereas in unfit patients aged 65-69 PFS was superior in the ASCT group: 43.3 vs 18.4 months, P .01. ISS III and impaired functional status independently affected PFS in a multivariate analysis (P .011 and P .006). While CCI and HCT-CI did not predict different outcome in ASCT patients, the IMWG frailty score would be of help in identifying unfit patients aged 70-75, whose outcome with ASCT selected by clinical judgment was no better than with less intensive treatments.
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http://dx.doi.org/10.1002/ajh.25797DOI Listing
July 2020

FGF Trapping Inhibits Multiple Myeloma Growth through c-Myc Degradation-Induced Mitochondrial Oxidative Stress.

Cancer Res 2020 06 24;80(11):2340-2354. Epub 2020 Feb 24.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Multiple myeloma, the second most common hematologic malignancy, frequently relapses because of chemotherapeutic resistance. Fibroblast growth factors (FGF) act as proangiogenic and mitogenic cytokines in multiple myeloma. Here, we demonstrate that the autocrine FGF/FGFR axis is essential for multiple myeloma cell survival and progression by protecting multiple myeloma cells from oxidative stress-induced apoptosis. In keeping with the hypothesis that the intracellular redox status can be a target for cancer therapy, FGF/FGFR blockade by FGF trapping or tyrosine kinase inhibitor impaired the growth and dissemination of multiple myeloma cells by inducing mitochondrial oxidative stress, DNA damage, and apoptotic cell death that were prevented by the antioxidant vitamin E or mitochondrial catalase overexpression. In addition, mitochondrial oxidative stress occurred as a consequence of proteasomal degradation of the c-Myc oncoprotein that led to glutathione depletion. Accordingly, expression of a proteasome-nondegradable c-Myc protein mutant was sufficient to avoid glutathione depletion and rescue the proapoptotic effects due to FGF blockade. These findings were confirmed on bortezomib-resistant multiple myeloma cells as well as on bone marrow-derived primary multiple myeloma cells from newly diagnosed and relapsed/refractory patients, including plasma cells bearing the t(4;14) translocation obtained from patients with high-risk multiple myeloma. Altogether, these findings dissect the mechanism by which the FGF/FGFR system plays a nonredundant role in multiple myeloma cell survival and disease progression, and indicate that FGF targeting may represent a therapeutic approach for patients with multiple myeloma with poor prognosis and advanced disease stage. SIGNIFICANCE: This study provides new insights into the mechanisms by which FGF antagonists promote multiple myeloma cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/11/2340/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2714DOI Listing
June 2020

Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis.

Cancers (Basel) 2019 Nov 5;11(11). Epub 2019 Nov 5.

Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, via Genova 3, 10126 Torino, Italy.

We conducted a pooled analysis of two phase III trials, RV-MM-EMN-441 and EMN01, to compare maintenance with lenalidomide-prednisone vs. lenalidomide in newly diagnosed transplant-eligible and -ineligible myeloma patients. Primary endpoints were progression-free survival, progression-free survival 2 and overall survival with both regimens. A secondary aim was to evaluate the impact of duration of maintenance on overall survival and on outcome after relapse. A total of 625 patients (lenalidomide-prednisone arm, = 315; lenalidomide arm, = 310) were analyzed. The median follow-up was 58 months. Median progression-free survival (25 vs. 19 months; = 0.08), progression-free survival 2 (56 vs. 49 months; = 0.9) and overall survival (73 months vs. NR; = 0.08) were not significantly different between the two arms. Toxicity profiles of lenalidomide-prednisone and lenalidomide were similar, with the exception of neutropenia that was higher in the lenalidomide arm (grade ≥ 3: 9% vs. 19%, < 0.001), without an increase in the rate of infections. Overall survival (median NR vs. 49 months, < 0.001), progression-free survival from relapse (median 35 vs. 24 months, = 0.004) and overall survival from relapse (median not reached vs. 41 months, = 0.002) were significantly longer in patients continuing maintenance for ≥2 years. We showed that the addition of prednisone at 25 or 50 mg every other day (eod) to lenalidomide maintenance did not induce any significant advantage.
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http://dx.doi.org/10.3390/cancers11111735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896192PMC
November 2019

Circulating microRNAs and Their Role in Multiple Myeloma.

Noncoding RNA 2019 May 2;5(2). Epub 2019 May 2.

Clinical Research Development and Phase I Unit, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by bone marrow infiltration of clonal plasma cells. The recent literature has clearly demonstrated clonal heterogeneity in terms of both the genomic and transcriptomic signature of the tumor. Of note, novel studies have also highlighted the importance of the functional cross-talk between the tumor clone and the surrounding bone marrow milieu, as a relevant player of MM pathogenesis. These findings have certainly enhanced our understanding of the underlying mechanisms supporting MM pathogenesis and disease progression. Within the specific field of small non-coding RNA-research, recent studies have provided evidence for considering microRNAs as a crucial regulator of MM biology and, in this context, circulating microRNAs have been shown to potentially contribute to prognostic stratification of MM patients. The present review will summarize the most recent studies within the specific topic of microRNAs and circulating microRNAs in MM.
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http://dx.doi.org/10.3390/ncrna5020037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631121PMC
May 2019

Irreversible proteasome inhibition with carfilzomib as first line therapy in patients with newly diagnosed multiple myeloma: Early in vivo cardiovascular effects.

Eur J Pharmacol 2018 Nov 7;838:85-90. Epub 2018 Sep 7.

Cardiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University, Cardiothoracic Department, Spedali Civili of Brescia, Italy.

Patients who experienced cardiovascular side effects during cancer therapy with carfilzomib for multiple myeloma had relapsed multiple myeloma, so have be previously treated with other cancer therapies. The present is a single center cohort study to evaluate early cardiovascular effects of administration of irreversible proteasome inhibitor carfilzomib in naïve patients. We included 24 patients and collected cardiovascular side effects, echocardiographic parameters and endothelial function at baseline and after 4 cycles. At early follow up we observed increase in blood arterial pressure values (mean change in systolic pressure of 10 mmHg (P-value < 0.01; diastolic arterial pressure and mean arterial pressure of 3.3 mmHg and 5.4 mmHg, both P-value < 0.01). Reactive hyperemia PAT index was reduced in the whole cohort by a mean of 0.46 points (P-value < 0.01); diastolic function was changed: E-wave-deceleration-time (EDT) was reduced by 49,96 ± 31 ms, P-value < 0.05 and early diastolic tissue Doppler velocity (e') by a mean value of 1.46 cm/s, P - value 0.04. At early follow up we did not observe events of grade 3 or 4. We observe correlation between events and endothelial dysfunction at baseline and age (OR 1.9, CI 95% 0.05-5.804, P- value: 0.038 for RHI<1.67; OR 1,4, CI 95%0.99-2.56, P- value: 0.04 for age). Our results suggest that therapy with carfilzomib when used as first line therapy is responsible for increase in systemic blood pressure, alteration of endothelium-mediated vascular dilatation and early myocardial diastolic dysfunction.
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http://dx.doi.org/10.1016/j.ejphar.2018.09.014DOI Listing
November 2018

Mechanism of cardiovascular toxicity by proteasome inhibitors: New paradigm derived from clinical and pre-clinical evidence.

Eur J Pharmacol 2018 Jun 15;828:80-88. Epub 2018 Mar 15.

Cardiology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University, Cardiothoracic Department, Spedali Civili of Brescia, Italy.

Proteasome Inhibitors (PI) have now become the cornerstone of treatment of multiple myeloma (MM). Carfilzomib has been demonstrated to cause more frequent cardiovascular side effects such as dyspnea, hypertension, and heart failure. Recent pre-clinical studies have investigated the effects of proteasome on myocardial and vascular cells, but the pathogenic mechanism underlying the effects of proteasome inhibition on these cells is poorly understood. We reviewed the evidence from clinical trials, post-hoc analysis and small observational studies currently available and summarized the data from experimental, focusing on the pathogenic mechanisms potentially implicated in the cardiovascular toxicity of proteasome inhibitor, particularly of carfilzomib that is most responsible for cardiovascular side effects. Finally, we tried to suggest future perspectives for diagnostic and therapeutic approach to this type of cardiovascular damage.
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http://dx.doi.org/10.1016/j.ejphar.2018.03.022DOI Listing
June 2018

Bone Marrow Stroma and Vascular Contributions to Myeloma Bone Homing.

Curr Osteoporos Rep 2017 10;15(5):499-506

Clinical Research Development and Phase I Unit, ASST Spedali Civili di Brescia, P.le Spedali Civili, n.1, 25123, Brescia, Italy.

Purpose Of The Review: Herein we dissect mechanisms behind the dissemination of cancer cells from primary tumor site to the bone marrow, which are necessary for metastasis development, with a specific focus on multiple myeloma.

Recent Findings: The ability of tumor cells to invade vessels and reach the systemic circulation is a fundamental process for metastasis development; however, the interaction between clonal cells and the surrounding microenvironment is equally important for supporting colonization, survival, and growth in the secondary sites of dissemination. The intrinsic propensity of tumor cells to recognize a favorable milieu where to establish secondary growth is the basis of the "seed and soil" theory. This theory assumes that certain tumor cells (the "seeds") have a specific affinity for the milieu of certain organs (the "soil"). Recent literature has highlighted the important contributions of the vascular niche to the hospitable "soil" within the bone marrow. In this review, we discuss the crucial role of stromal cells and endothelial cells in supporting primary growth, homing, and metastasis to the bone marrow, in the context of multiple myeloma, a plasma cell malignancy with the unique propensity to primarily grow and metastasize to the bone marrow.
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http://dx.doi.org/10.1007/s11914-017-0399-3DOI Listing
October 2017

Good Outcome for Very High Risk Adult B-cell Acute Lymphoblastic Leukaemia Carrying Genetic Abnormalities t(4;11)(q21;q23) or t(9;22)(q34;q11), if Promptly Submitted to Allogeneic Transplantation, after Obtaining a Good Molecular Remission.

Mediterr J Hematol Infect Dis 2015 1;7(1):e2015041. Epub 2015 Jun 1.

Haematology Division and BMT Unit, Ospedale San Gerardo, Monza, Italy.

Background And Objectives: Acute lymphoblastic leukaemia (ALL) carrying t(9;22) or t(4;11) genetic abnormalities represents a very high risk subtype of disease (VHR-ALL). Hematopoietic stem cell transplantation (HSCT) remains the best curative option not only for t(4;11) ALL, but also for t(9;22) ALL in the tyrosin-kinase inhibitors era. In the last years, low molecular level of minimal residual disease (MRD) before HSCT was reported as one of the best favourable indexes for survival in ALL. Here we observed that even these patients can show a favourable outcome if submitted to HSCT with very low MRD.

Methods: We considered 18 consecutive VHR-ALL patients eligible to HSCT. 16 of them were transplanted in first remission, as soon as possible, employing myelo-ablative conditioning regimens. Molecular MRD has been evaluated before and after HSCT.

Results: Immediately before HSCT, MRD revealed: complete molecular remission (MRD(neg)) for five patients, and a level <1×10(-3) for seven patients. 100 days after HSCT we had: MRD(neg) for seven patients and a decrease for all the others after HSCT. After the tapering of immunosuppressive drugs, 13 patients reached the MRD(neg) in a median time of 8 months (range 3-16). In the intention to treat analysis, 14/18 patients are alive and disease free at the date of analysis. Overall survival and event free survival is of 78% and 66% respectively, with an average follow-up of 45 months (range 6-84) since HSCT.

Conclusion: Early transplantation with low MRD level seems to be correlated with a favourable outcome also in VHR-ALL.
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http://dx.doi.org/10.4084/MJHID.2015.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450652PMC
June 2015

Peripheral blood lymphocyte/monocyte ratio predicts outcome in follicular lymphoma and in diffuse large B-cell lymphoma patients in the rituximab era.

Clin Lymphoma Myeloma Leuk 2015 Apr 23;15(4):208-13. Epub 2014 Oct 23.

Division of Hematology, Ospedale San Gerardo - Università degli Studi Milano Bicocca, Monza, Italy.

Background: Diffuse large B-cell lymphoma is an aggressive lymphoma and a large number of studies have therefore focused on the search for prognostic factors. The same interest concerns FL, for which identification of patients candidates for watch and wait (W&W) strategy is still an option. Studies about the number and type of lymphocytes and monocytes detectable in patients with Hodgkin and non-Hodgkin lymphomas indicate they might affect the pathogenesis and prognosis of these diseases. LMR is recently under investigation as a new prognostic parameter in DLBCL; the role of this ratio in FL in the rituximab era is unknown.

Patients And Methods: We retrospectively analyzed 137 DLBCL and 132 FL patients referred to our institution; among FL pts, a W&W approach was performed at diagnosis for 42 patients. The remaining patients were treated with rituximab-containing therapy. We analyzed different LMR cutoff values at diagnosis and we wanted to investigate the prognostic effect among DLBCL and FL.

Results: We found that the most discriminative LMR was 2.4 for DLBCL and 2 for FL. Among DLBCL patients, an LMR value < 2.4 was associated with a worse 2-year progression-free survival (PFS), and we observed no difference in overall survival and complete response rate. Considering FL patients, LMR > 2 was associated with a longer time to treatment start compared with the LMR < 2 group (P = .0096). Among the 92 patients treated with rituximab chemotherapy, 2-year PFS was superior in the LMR > 2 group.

Conclusion: LMR at diagnosis is a simple tool to better define long-term outcome of DLBCL and FL patients. The use of this tool might better define selection in FL of ideal candidates for W&W strategy.
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http://dx.doi.org/10.1016/j.clml.2014.10.001DOI Listing
April 2015

Non transferrin bound iron (NTBI) in acute leukemias throughout conventional intensive chemotherapy: kinetics of its appearance and potential predictive role in infectious complications.

Leuk Res 2015 Jan 15;39(1):88-91. Epub 2014 Nov 15.

Department of Medicine and Medical Specialities, "Ca' Granda" Foundation IRCCS, University of Milan, Via F. Sforza 35, 20122 Milano, Italy. Electronic address:

We analyzed appearance of non transferrin bound iron (NTBI) in 30 transplant eligible patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) during conventional chemotherapy treatment program and evaluated possible relationship with transfusional body iron intake, iron parameters and clinical complications. For each course, serum samples for NTBI detection were taken prior to chemotherapy, during treatment and during subsequent bone marrow myelosuppression: NTBI was assessed by HPLC. Appearance of NTBI was observed from the start of induction treatment and was still detectable during bone marrow myelosuppression; the recovery of the bone marrow function coincided with the disappearance of NTBI. This kinetic was observed in all subsequent high doses chemotherapy courses, independently from confounding variables such as transfusional iron intake and transferrin saturation. NTBI seems to be a consequence of chemotherapy induced lysis of bone marrow cells and, partly, of hepatocytes after cytotoxic injury. The subsequent persistence of NTBI throughout bone marrow myelosuppression is related to the transient suspension of erythropoietic activity. Moreover, NTBI levels >2μM at the beginning of iatrogenic myelosuppression were associated with higher risk of sepsis caused by Gram negative Bacilli (RR 2.571), also compared with other infectious complications (RR 1.954).
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http://dx.doi.org/10.1016/j.leukres.2014.11.003DOI Listing
January 2015

Iron chelation therapy with deferasirox in the management of iron overload in primary myelofibrosis.

Mediterr J Hematol Infect Dis 2014 1;6(1):e2014042. Epub 2014 Jun 1.

Hematology Division, San Gerardo Hospital, Monza, Italy.

Deferasirox (DSX) is the principal option currently available for iron-chelation-therapy (ICT), principally in the management of myelodysplastic syndromes (MDS), while in primary myelofibrosis (PMF) the expertise is limited. We analyzed our experience in 10 PMF with transfusion-dependent anemia, treated with DSX from September 2010 to December 2013. The median dose tolerated of DSX was 750 mg/day (10 mg/kg/day), with 3 transient interruption of treatment for drug-related adverse events (AEs) and 3 definitive discontinuation for grade 3/4 AEs. According to IWG 2006 criteria, erythroid responses with DSX were observed in 4/10 patients (40%), 2 of them (20%) obtaining transfusion independence. Absolute changes in median serum ferritin levels (Delta ferritin) were greater in hematologic responder (HR) compared with non-responder (NR) patients, already at 6 months of ICT respect to baseline. Our preliminary data open new insights regarding the benefit of ICT not only in MDS, but also in PMF with the possibility to obtain an erythroid response, overall in 40 % of patients. HR patients receiving DSX seem to have a better survival and a lower incidence of leukemic transformation (PMF-BP). Delta ferritin evaluation at 6 months could represent a significant predictor for a different survival and PMF-BP. However, the tolerability of the drug seems to be lower compared to MDS, both in terms of lower median tolerated dose and for higher frequency of discontinuation for AEs. The biological mechanism of action of DSX in chronic myeloproliferative setting through an independent NF-κB inhibition could be involved, but further investigations are required.
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http://dx.doi.org/10.4084/MJHID.2014.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063602PMC
June 2014

A Case of Atypical Delayed and Prolonged Hematologic Toxicity With Azacitidine in Chronic Myelomonocytic Leukemia (CMML) and Review of Literature.

Mediterr J Hematol Infect Dis 2012 13;4(1):e2012017. Epub 2012 Mar 13.

Divisione di Ematologia, Ospedale San Gerardo - Università degli studi Milano Bicocca, Monza, Italia.

Hypomethylating drugs are useful and have been approved for the treatment of myelodysplastic syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS, have included only a small number of patients with CMML, and there are just a few specific reports on CMML patients. The Azacitidine is actually authorised for the treatment of CMML patients with 10-29% marrow blasts without myeloproliferative disorder, who are not eligible for haematopoietic stem cell transplantation. This hypomethylating agent in MDS is known for causing transient cytopenias, most often occurring during the first 2 cycles. Here we report a case of an atypical delayed and prolonged hematologic toxicity during Azacitidine treatment in a CMML patient; furthermore we also reviewed the literature regarding the efficacy of the drug and the management of hematologic adverse effects, in term of dose adjustments or alternative schedule of administration, in specific CMML setting.
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http://dx.doi.org/10.4084/MJHID.2012.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340986PMC
October 2012

Circulating endothelial cells and endothelial activation in essential thrombocythemia: results from CD146+ immunomagnetic enrichment--flow cytometry and soluble E-selectin detection.

Am J Hematol 2012 Mar 21;87(3):319-20. Epub 2011 Dec 21.

Ospedale San Gerardo-Universita' Milano Bicocca, Clinica Ematologica, Monza, Italy.

Circulating endothelial cells (CECs) have been studied in cardiovascular disorders and as a marker of angiogenetic activity; clinical applications are limited by a lack of consensus on their phenotypic identification and quantification. We determined CECs in essential thrombocythemia (ET) patients, to investigate their possible pathogenetic role. We considered CECs as CD146⁺/CD45⁻ nucleated cells, detected in peripheral blood from 21 healthy controls and 39 ET patients, performing a combination of pre-enrichment of CD146⁺ circulating cells and multiparametric flow cytometry measurement (FCM). Levels of CECs in ET patients were higher with respect to controls (median 2844 CECs/mL vs. 121.3 CECs/mL, P < 0.0001). Apparently hydroxyurea treatment did not influence the levels of CECs. As another established marker of endothelial activation, we also assessed soluble E-selectin (sE-selectin) levels in 31 of the ET patients and compared with 39 healthy volunteers: median sE-selectin level in ET patients was 35.3 ng/mL, higher with respect to controls (24.48 ng/mL), P = 0.0369. Our data suggest that endothelium in ET is activated, reflecting a significant role of angiogenesis in this disorder and suggesting an important endothelial contribution in the hypercoagulable state of ET patients.
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http://dx.doi.org/10.1002/ajh.22264DOI Listing
March 2012