Publications by authors named "Marco Ladetto"

99 Publications

Outcomes following second allogeneic haematopoietic cell transplantation in patients with myelofibrosis: a retrospective study of the Chronic Malignancies Working Party of EBMT.

Bone Marrow Transplant 2021 Apr 6. Epub 2021 Apr 6.

CHU de Lille, univ Lille, INSERM U1286, INFINITE, 59000, Lille, France.

Therapeutic management of patients with primary or secondary myelofibrosis (MF) who experience relapse or graft failure following allogeneic haematopoietic cell transplantation (allo-HCT) remains heterogeneous. We retrospectively analyzed 216 patients undergoing a second allo-HCT for either relapse (56%) or graft failure (31%) between 2010 and 2017. Median age was 57.3 years (range 51-63). The same donor as for the first allo-HCT was chosen in 66 patients (31%) of whom 19 received an HLA-identical sibling donor, whereas a different donor was chosen for 116 patients (54%). Median follow-up was 40 months. Three-year overall survival (OS) and relapse-free survival (RFS) were 42% and 39%, respectively. Three-year non-relapse mortality (NRM) and relapse rates were 36% and 25%, respectively. Grade II-IV and III-IV acute GVHD occurred in 25% and 11% of patients, respectively, and the 3-year incidence of chronic GVHD was 33% including 14% for extensive grade. Graft-failure incidence at 1 year was 14%. In conclusion, our data suggest that a second allo-HCT is a potential option for patients failing first allo-HCT for MF albeit careful patient assessment is fundamental to identify individual patients who could benefit from this approach.
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http://dx.doi.org/10.1038/s41409-021-01271-4DOI Listing
April 2021

Outcomes of older patients with follicular lymphoma using individual data from 5922 patients in 18 randomized controlled trials.

Blood Adv 2021 Mar;5(6):1737-1745

University of Texas MD Anderson Cancer Center, Houston, TX.

Limited data exist to describe the clinical features and outcomes for elderly patients with follicular lymphoma (FL). The Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) group performed a prospectively planned pooled analysis of individual patient data from first-line randomized controlled trials (RCTs) and examined associations between age (≤70 vs >70 years), clinical characteristics, and FL outcomes. We identified 18 multicenter clinical RCTs in the FLASH database that enrolled elderly patients (>70 years). Primary end points were early disease outcomes, CR24 and CR30, and progression-free survival (PFS) at 24 months (PFS24). Secondary end points were PFS and overall survival (OS). We identified 5922 previously untreated FL patients from 18 RCTs. Patients age >70 years (vs ≤70 years) more commonly had elevated lactate dehydrogenase, hemoglobin <12 g/dL, ECOG PS ≥2, and elevated β2-microglobulin. Median follow-up was 5.6 years. Patients >70 years did not differ from patients ≤70 years in rates of CR24, CR30, or PFS24. With a median OS of 14.6 years for all patients, median OS was 7.4 and 15.7 years for patients >70 and ≤70 years of age, respectively (hazard ratio = 2.35; 95% confidence interval = 2.03-2.73; P < .001). Age >70 years was a significant predictor of OS and PFS due to higher rates of death without progression, but not PFS24, CR24, or CR30. FL patients >70 years treated on trials have similar early disease outcomes to younger patients. There is no disease-specific outcome difference between age groups. Age alone should not disqualify patients from standard treatments or RCTs.
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http://dx.doi.org/10.1182/bloodadvances.2020002724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993094PMC
March 2021

Targeted locus amplification to detect molecular markers in mantle cell and follicular lymphoma.

Hematol Oncol 2021 Mar 20. Epub 2021 Mar 20.

Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Torino, Torino, Italy.

Minimal residual disease (MRD) monitoring by PCR methods is a strong and standardized predictor of clinical outcome in mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, about 20% of MCL and 40% of FL patients lack a reliable molecular marker, being thus not eligible for MRD studies. Recently, targeted locus amplification (TLA), a next-generation sequencing (NGS) method based on the physical proximity of DNA sequences for target selection, identified novel gene rearrangements in leukemia. The aim of this study was to test TLA in MCL and FL diagnostic samples lacking a classical, PCR-detectable, t(11; 14) MTC (BCL1/IGH), or t(14; 18) major breakpoint region and minor cluster region (BCL2/IGH) rearrangements. Overall, TLA was performed on 20 MCL bone marrow (BM) or peripheral blood (PB) primary samples and on 20 FL BM, identifying a novel BCL1 or BCL2/IGH breakpoint in 16 MCL and 8 FL patients (80% and 40%, respectively). These new breakpoints (named BCL1-TLA and BCL2-TLA) were validated by ASO primers design and compared as MRD markers to classical IGH rearrangements in eight MCL: overall, MRD results by BCL1-TLA were superimposable (R Pearson = 0.76) to the standardized IGH-based approach. Moreover, MRD by BCL2-TLA reached good sensitivity levels also in FL and was predictive of a primary refractory case. In conclusion, this study offers the proof of principle that TLA is a promising and reliable NGS-based technology for the identification of novel molecular markers, suitable for further MRD analysis in previously not traceable MCL and FL patients.
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http://dx.doi.org/10.1002/hon.2864DOI Listing
March 2021

Addition of Rituximab in Reduced Intensity Conditioning Regimens for B-Cell Malignancies Does Not Influence Transplant Outcomes: EBMT Registry Analyses Following Allogeneic Stem Cell Transplantation for B-Cell Malignancies.

Front Immunol 2020 2;11:613954. Epub 2021 Feb 2.

Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001-2013) with either rituximab (R-RIC-9%) or non-rituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1-77.3) and 43.2 months (range 0.3-179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.
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http://dx.doi.org/10.3389/fimmu.2020.613954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884746PMC
February 2021

A brief rituximab, bendamustine, mitoxantrone (R-BM) induction followed by rituximab consolidation in elderly patients with advanced follicular lymphoma: a phase II study by the Fondazione Italiana Linfomi (FIL).

Br J Haematol 2021 Apr 21;193(2):280-289. Epub 2021 Jan 21.

SC Ematologia AOU Città della Salute e della Scienza di Torino, Torino, Italy.

Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R-BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy-six treatment-naive FL patients (aged 65-80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow-up was 44 months with 3-year progression-free-survival (PFS) and overall-survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl-2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R-BM was highly effective in clearing polymerase chain reaction-detectable disease: 29/31 (96%) evaluated patients converted to bcl-2/IGH negativity at the end of treatment. A brief R-BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment-naïve, FL patients, inducing high CR and molecular remission rates with prolonged PFS.
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http://dx.doi.org/10.1111/bjh.17283DOI Listing
April 2021

Allogeneic Stem Cell Transplantation in Mantle Cell Lymphoma in the Era of New Drugs and CAR-T Cell Therapy.

Cancers (Basel) 2021 Jan 14;13(2). Epub 2021 Jan 14.

SC Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy.

MCL is an uncommon lymphoproliferative disorder that has been regarded as incurable since its identification as a distinct entity. Allogeneic transplantation for two decades has represented the only option capable of ensuring prolonged remissions and possibly cure. Despite its efficacy, its application has been limited by feasibility limitations and substantial toxicity, particularly in elderly patients. Nevertheless, the experience accumulated over time has been wide though often scattered among retrospective and small prospective studies. In this review, we aimed at critically revise and discuss available evidence on allogeneic transplantation in MCL, trying to put available evidence into the 2020 perspective, characterized by unprecedented development of novel promising therapeutic agents and regimens.
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http://dx.doi.org/10.3390/cancers13020291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830938PMC
January 2021

Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial.

Lancet Haematol 2021 Jan 22;8(1):e34-e44. Epub 2020 Dec 22.

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

Background: Fit patients with mantle cell lymphoma aged 18-65 years are usually given cytarabine and rituximab-based induction regimens followed by autologous haematopoetic stem-cell transplantation (HSCT). We investigated whether post-autologous HSCT maintenance with lenalidomide improves progression-free survival in this population.

Methods: This open-label, randomised, multicentre, phase 3 trial was done at 49 haematology and oncology units in Italy and Portugal. Eligible patients had Ann Arbor stage III or IV treatment-naive mantle cell lymphoma (or stage II plus bulky disease [≥5 cm] or B symptoms), and had evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32). Patients were aged 18-59 years with Eastern Cooperative Oncology Group (ECOG) performance status 0-3, or aged 60-65 years with ECOG 0-2. After an optional prephase with vincristine and steroids (intravenous vincristine 1·4 mg/m on day 1, oral prednisone 100 mg [total dose] on days 1-5), patients were given three courses of R-CHOP (21-day cycle, intravenous rituximab 375 mg/m on day 1; intravenous doxorubicin 50 mg/m, vincristine 1·4 mg/m, and cyclophosphamide 750 mg/m on day 2; oral prednisone 100 mg/m on day 2-6). Patients then received one cycle of high-dose CTX (intravenous cyclophosphamide 4 g/m on day 1, intravenous rituximab 375 mg/m on day 4). After restaging, patients received two cycles of R-HD-cytarabine (high-dose intravenous cytarabine 2 g/m every 12 h on days 1-3, intravenous rituximab 375 mg/m on days 4 and 10). Patients with complete remission or partial remission proceeded to autologous HSCT and responding patients (complete remission or partial remission) with haematological recovery were randomly assigned (1:1) to receive 24 courses of oral lenalidomide maintenance (15 mg per day for patients with platelets >100 × 10 cells per L or 10 mg per day for platelets 60-100 × 10 cells per L, days 1-21 every 28 days) for 24 months, or observation. The primary endpoint was progression-free survival, measured in the randomised population. This study is registered with EudraCT (2009-012807-25) and ClinicalTrials.gov (NCT02354313).

Findings: Between May 4, 2010, and Aug 24, 2015, 303 patients were screened for inclusion and 300 patients were enrolled (median age 57 years, IQR 51-62; 235 [78%] male). 95 patients were excluded before randomisation, mostly due to disease progression, adverse events, and inadequate recovery. 104 patients were randomly assigned to the lenalidomide maintenance group and 101 patients to the observation group. 11 (11%) of 104 patients assigned to lenalidomide did not start treatment (3 withdrew, 6 adverse events or protocol breach, 2 lost to follow-up). At a median follow-up of 38 months after randomisation (IQR 24-50), 3-year progression-free survival was 80% (95% CI 70-87) in the lenalidomide group versus 64% (53-73) in the observation group (log-rank test p=0·012; hazard ratio 0·51, 95% CI 0·30-0·87). 41 (39%) of 104 patients discontinued lenalidomide for reasons including death or progression. Treatment-related deaths were recorded in two (2%) of 93 patients in the lenalidomide group (1 pneumonia, 1 thrombotic thrombocytopenic purpura), and one (1%) of 101 in the observation group (pneumonia). 59 (63%) of 93 patients in the lenalidomide group had grade 3-4 haematological adverse events versus 12 (12%) of 101 patients in the observation group (p<0·0001). 29 (31%) of 93 patients in the lenalidomide group and eight (8%) of 101 patients in the observation group had grade 3-4 non-haematological adverse events (p<0·0001), of which infections were the most common.Serious adverse events were reported in 22 (24%) of 93 patients in the lenalidomide group and five (5%) of 101 patients in the observation group. Pneumonia and other infections were the most common serious adverse events.

Interpretation: Despite non-negligibile toxicity, lenalidomide after autologous HSCT improved progression-free survival in patients with mantle cell lymphoma, highlighting the role of maintenance in mantle cell lymphoma.

Funding: Fondazione Italiana Linfomi and Celgene.
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http://dx.doi.org/10.1016/S2352-3026(20)30358-6DOI Listing
January 2021

A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma.

Future Oncol 2021 Jan 28;17(3):255-262. Epub 2020 Sep 28.

Centre Hospitalier Universitaire de Nantes, 44093 Nantes, France.

Mantle cell lymphoma is an aggressive B-cell malignancy. Current frontline chemoimmunotherapies produce high response rates but relapse is inevitable. Furthermore, the elderly and those with comorbidities are precluded from standard regimens and stem cell transplant, leaving them with limited options. Targeted therapies, including Bruton tyrosine kinase inhibitors, are an effective treatment strategy in mantle cell lymphoma. Zanubrutinib is a potent next-generation Bruton tyrosine kinase inhibitor that has demonstrated complete and sustained Bruton tyrosine kinase occupancy, minimal off-target effects and favorable pharmacokinetic/pharmacodynamic properties. Described herein is an ongoing Phase III study comparing the efficacy and safety of zanubrutinib plus rituximab followed by zanubrutinib monotherapy versus bendamustine plus rituximab followed by observation in transplant-ineligible patients with previously untreated mantle cell lymphoma. Clinical Trial Registration: NCT04002297 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0794DOI Listing
January 2021

Minimal Residual Disease in Mantle Cell Lymphoma: Methods and Clinical Significance.

Hematol Oncol Clin North Am 2020 10 5;34(5):887-901. Epub 2020 Aug 5.

Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, Kiel 24105, Germany.

Several biological and clinical features have been recognized in mantle cell lymphoma (MCL). In recent years, the minimal residual disease (MRD) has been extensively investigated and is now considered as one of the strongest clinical predictors in this lymphoma. This article reviews methods used for the assessment of MRD in MCL and discusses their strengths and weaknesses. In addition, it examines the MRD contribution to the biology knowledge of MCL and the development of effective strategies for its management, including the possibility of personalized treatment based on MRD response.
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http://dx.doi.org/10.1016/j.hoc.2020.06.006DOI Listing
October 2020

Immunoglobulin kappa deleting element rearrangements are candidate targets for minimal residual disease evaluation in mantle cell lymphoma.

Hematol Oncol 2020 Dec 28;38(5):698-704. Epub 2020 Aug 28.

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

Minimal residual disease (MRD) assessment is of high clinical relevance in patients with mantle cell lymphoma (MCL). In mature B-cell malignancies, the presence of somatic hypermutations (SHM) in Variable-Diversity-Joining Heavy chain (VDJH) rearrangements leads to frequent mismatches between primers, probes, and the target, thus impairing tumor cells quantification. Alternative targets, such as immunoglobulin kappa-deleting-element (IGK-Kde) rearrangements, might be suitable for MRD detection. We aimed at evaluating the applicability of IGK-Kde rearrangements for MRD quantification in MCL patients by real-time quantitative polymerase chain reaction (RQ-PCR)/digital-droplet-PCR (ddPCR). IGK screening was performed on bone marrow samples from two cohorts: the first from Turin (22 patients enrolled in the FIL-MCL0208 trial, NCT02354313) and the second from Rome (15 patients). IGK-Kde rearrangements were found in 76% (28/37) of cases, representing the sole molecular marker in 73% (8/11) of IGH-BCL1/IGH negative cases. MRD RQ-PCR monitoring was possible in 57% (16/28) of cases, showing a 100% concordance with the conventional targets. However, the frequent background amplification affected the sensitivity of the assay, that was lower in MCL compared to acute lymphoblastic leukemia and in line with multiple myeloma published results. ddPCR had a good concordance with RQ-PCR and it might help to identify false positive/negative results. From a clinical perspective, we suggest that IGK-Kde can be a candidate target for MRD monitoring and deserves a validation of its predictive value in prospective MCL series.
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http://dx.doi.org/10.1002/hon.2792DOI Listing
December 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, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milano.

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

Controversies in the Treatment of Follicular Lymphoma.

Hemasphere 2020 Feb 10;4(1):e317. Epub 2020 Jan 10.

University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA.

The overall prognosis of patients with follicular lymphoma has substantially improved over the last decades with a 10-year overall survival of around 80% for the majority of patients. However, for most patients follicular lymphoma it is still a relapsing and remitting disease. Furthermore, certain subsets of patients still have much shorter survival. Currently, there is no established standard how to treat high-risk follicular lymphoma. With advances in the understanding of the biology and pathogenesis of B cell malignancies, a plethora of new compounds have been investigated in FL. These compounds have the potential to increase efficacy if added to current regimens or even replace them. The implementation of these compounds in treatment algorithms is another unsolved issue. This overview highlights major controversies in the treatment of follicular lymphoma and discusses the most recent and relevant clinical trials.
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http://dx.doi.org/10.1097/HS9.0000000000000317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000465PMC
February 2020

EHA Endorsement of ESMO Clinical Practice Guidelines for Marginal Zone Lymphomas.

Hemasphere 2020 Apr 11;4(2):e351. Epub 2020 Mar 11.

Department of Medicine III, University Hospital, LMU, Munich, Germany.

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http://dx.doi.org/10.1097/HS9.0000000000000351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162085PMC
April 2020

Droplet Digital PCR Quantification of Mantle Cell Lymphoma Follow-up Samples From Four Prospective Trials of the European MCL Network.

Hemasphere 2020 Apr 3;4(2):e347. Epub 2020 Apr 3.

Biological Hematology, Université de Paris (Descartes), Assistance Publique - Hôpitaux de Paris and Institut Necker Enfants Malades (INEM), Paris, France.

Minimal residual disease (MRD) has been increasingly investigated in mantle cell lymphoma (MCL), including for individual therapeutic stratification and pre-emptive treatment in clinical trials. Although patient/allele specific real-time quantitative polymerase chain reaction (qPCR) of IGH or BCL1-IGH clonal markers is the gold-standard method, its reliance on a standard curve for relative quantification limits quantification of low-level positivity within the 1E-4 to 1E-5 range; over half of positive MRD samples after treatment fall below the quantitative range (BQR) of the standard curve. Droplet digital PCR (ddPCR), in contrast, allows absolute quantification, including for samples with no baseline determination of tumor infiltration by multicolor flow cytometry (MFC), avoiding the need for a reference standard curve. Using updated, optimized, ddPCR criteria we compared it with qPCR in 416 MRD samples (and with MFC in 63), with over-representation (61%) of BQR results by qPCR, from a total of 166 patients from four prospective MCL clinical trials. ddPCR, qPCR and MFC gave comparable results in MRD samples with at least 0.01% (1E-4) positivity. ddPCR was preferable to qPCR since it provided more robust quantification at positivity between 1E-4 and 1E-5. Amongst 240 BQR samples with duplicate or triplicate analysis, 39% were positive by ddPCR, 49% negative and only 12% remained positive below quantifiable ddPCR limits. The prognostic relevance of ddPCR is currently under assessment in the context of prospective trials within the European MCL Network.
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http://dx.doi.org/10.1097/HS9.0000000000000347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162081PMC
April 2020

Organizational determinants of hospital stay: establishing the basis of a widespread action on more efficient pathways in medical units.

Intern Emerg Med 2020 09 7;15(6):1011-1019. Epub 2020 Jan 7.

General and Medical Direction, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.

Given the high hospital costs, the increasing clinical complexity and the overcrowding of emergency departments, it is crucial to improve the efficiency of medical admissions. We aimed at isolating organizational drivers potentially targetable through a widespread improvement action. We studied all medical admissions in a large tertiary referral hospital from January 1st to December 31st, 2018. Data were retrieved from the administrative database. Available information included age, sex, type (urgent or elective) and Unit of admission, number of internal transfers, main ICD-9 diagnosis, presence of cancer among diagnoses, surgical or medical code, type of discharge, month, day and hour of admission and discharge. National Ministry of Health database was used for comparisons. 8099 admissions were analyzed. Urgent admissions (80.5% of the total) were responsible for longer stays and were the object of the multivariate analysis. The variables most influencing length-of-stay (LOS) were internal transfers and assisted discharge: they contributed, respectively, to 62% and 40% prolongation of LOS. Also, the daily and weekly kinetics of admission accounted for a significant amount of variation in LOS. Long admissions (≥ 30 days) accounted for the 15.5% of total bed availability. Type of discharge and internal transfers were again among the major determinants. A few factors involved in LOS strictly depend on the organizational environment and are potentially modifiable. Re-engineering should be focused on making more efficient internal and external transitions and at ensuring continuity of the clinical process throughout the day and the week.
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http://dx.doi.org/10.1007/s11739-019-02267-1DOI Listing
September 2020

Prolonged survival in the absence of disease-recurrence in advanced-stage follicular lymphoma following chemo-immunotherapy: 13-year update of the prospective, multicenter randomized GITMO-IIL trial.

Haematologica 2019 11 11;104(11):2241-2248. Epub 2019 Apr 11.

Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milano

A prospective trial conducted in the period 2000-2005 showed no survival advantage for high-dose chemotherapy with rituximab and autograft (R-HDS) conventional chemotherapy with rituximab (CHOP-R) as first-line therapy in 134 high-risk follicular lymphoma patients aged <60 years. The study has been updated at the 13-year median follow up. As of February 2017, 88 (66%) patients were alive, with overall survival of 66.4% at 13 years, without a significant difference between R-HDS (64.5%) and CHOP-R (68.5%). To date, 46 patients have died, mainly because of disease progression (47.8% of all deaths), secondary malignancies (3 solid tumor, 9 myelodysplasia/acute leukemia; 26.1% of all deaths), and other toxicities (21.7% of all deaths). Complete remission was documented in 98 (73.1%) patients and associated with overall survival, with 13-year estimates of 77.0% and 36.8% for complete remission no-complete remission, respectively. Molecular remission was documented in 39 (65%) out of 60 evaluable patients and associated with improved survival. In multivariate analysis, complete remission achievement had the strongest effect on survival (<0.001), along with younger age (=0.002) and female sex (=0.013). Overall, 50 patients (37.3%) survived with no disease recurrence (18 CHOP-R, 32 R-HDS). This follow up is the longest reported on follicular lymphoma treated upfront with rituximab-chemotherapy and demonstrates an unprecedented improvement in survival compared to the pre-rituximab era, regardless of the use of intensified or conventional treatment. Complete remission was the most important factor for prolonged survival and a high proportion of patients had prolonged survival in their first remission, raising the issue of curability in follicular lymphoma. (Registered at clinicaltrials.gov identifier: 00435955).
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http://dx.doi.org/10.3324/haematol.2018.209932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821615PMC
November 2019

Applying Data Warehousing to a Phase III Clinical Trial From the Fondazione Italiana Linfomi Ensures Superior Data Quality and Improved Assessment of Clinical Outcomes.

JCO Clin Cancer Inform 2019 10;3:1-15

Division of Hematology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.

Purpose: Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points.

Methods: Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact.

Results: The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index.

Conclusion: The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.
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http://dx.doi.org/10.1200/CCI.19.00049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873907PMC
October 2019

mutations and disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study.

Haematologica 2020 06 19;105(6):1604-1612. Epub 2019 Sep 19.

Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.

In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of and disruption of by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding mutations and disruption to the MIPI-c backbone, we derived a new prognostic index, the "MIPI-genetic" ("MIPI- g"). The "MIPI-g" improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring mutations share the same poor outcome as patients harboring disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. ().
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http://dx.doi.org/10.3324/haematol.2018.214056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271566PMC
June 2020

Incidence and outcome of Kaposi sarcoma after hematopoietic stem cell transplantation: a retrospective analysis and a review of the literature, on behalf of infectious diseases working party of EBMT.

Bone Marrow Transplant 2020 01 21;55(1):110-116. Epub 2019 Aug 21.

Department of Pediatric Hematology Oncology, University Hospital, Collegium Medicum UMK, Bydgoszcz, Poland.

The incidence, the clinical characteristics, and the outcome of Kaposi sarcoma (KS) in patients after hematopoietic stem cell transplantation (HSCT) were assessed. During the period 1987-2018, 13 cases of KS were diagnosed, 3 females and 10 males, median age of 50 years, median time from HSCT of 7 months. KS had an incidence of 0.17% in allogeneic and 0.05% in autologous HSCT. HHV-8 was documented in eight of nine tumor tissue samples assessed. The organ involvement was: skin in nine, lymph nodes in six, oral cavity in four, and visceral in three patients, respectively; seven patients had >1 organ involved. Five patients had immunosuppression withdrawn, whereas four and three patients received radiotherapy and chemotherapy, respectively. Eight patients are alive (median follow-up 48 months, range 5-128), whereas five patients died after a median time of 8 months from the diagnosis of KS. However, no death was caused by KS. We conclude that the incidence of KS after HSCT is very low. Although KS can be managed with the reduction of immunosuppression, visceral forms may require chemotherapy and/or radiotherapy. The low prevalence of KS indicates that screening for HHV-8 serology and surveillance for HHV-8 viremia are not indicated in HSCT patients.
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http://dx.doi.org/10.1038/s41409-019-0644-8DOI Listing
January 2020

Minimal residual disease (MRD) in non-Hodgkin lymphomas: Interlaboratory reproducibility on marrow samples with very low levels of disease within the FIL (Fondazione Italiana Linfomi) MRD Network.

Hematol Oncol 2019 Oct 16;37(4):368-374. Epub 2019 Aug 16.

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

In 2009, the four laboratories of the Fondazione Italiana Linfomi (FIL) minimal residual disease (MRD) Network started a collaborative effort to harmonize and standardize their methodologies at the national level, performing quality control (QC) rounds for follicular lymphoma (FL) and mantle cell lymphoma (MCL) MRD assessment. In 16 QC rounds between 2010 and 2017, the four laboratories received 208 bone marrow (BM) samples (126 FL; 82 MCL); 187 were analyzed, according to the EuroMRD Consortium guidelines, by both nested (NEST) polymerase chain reaction (PCR) and real-time quantitative (RQ) PCR for BCL2/IGH MBR or IGHV rearrangements. Here, we aimed at analyzing the samples that challenged the interlaboratory reproducibility and data interpretation. Overall, 156/187 BM samples (83%) were concordantly classified as NEST+/RQ+ or NEST-/RQ- by all the four laboratories. The remaining 31 samples (17%) resulted alternatively positive and negative in the interlaboratory evaluations, independently of the method and the type of rearrangement, and were defined "borderline" (brd) samples: 12 proved NEST brd/RQ brd, 7 NEST-/RQ brd, 10 NEST brd/RQ positive not quantifiable (PNQ), and 2 NEST brd/RQ-. Results did not change even increasing the number of replicates/sample. In 6/31 brd samples, droplet digital PCR (ddPCR) was tested and showed no interlaboratory discordance. Despite the high interlaboratory reproducibility in the MRD analysis obtained and maintained by the QC round strategy, samples with the lowest MRD levels can still represent a challenge: 17% (31/187) of our samples showed discordant results in interlaboratory assessments, with 6.4% (12/187) remained brd even applying the two methods. Thus, although representing a minority, brd samples are still problematic, especially when a clinically oriented interpretation of MRD results is required. Alternative, novel methods such as ddPCR and next-generation sequencing have the potential to overcome the current limitations.
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http://dx.doi.org/10.1002/hon.2652DOI Listing
October 2019

Bleomycin, vinblastine and dacarbazine combined with nonpegylated liposomal doxorubicin (MBVD) in elderly (≥70 years) or cardiopathic patients with Hodgkin lymphoma: a phase-II study from Fondazione Italiana Linfomi (FIL).

Leuk Lymphoma 2019 12 8;60(12):2890-2898. Epub 2019 Jul 8.

Hematology Unit, Azienda Unità Sanitaria Locale IRCCS, Reggio Emilia, Italy.

This phase-II study assessed activity and toxicity of substituting conventional doxorubicin with nonpegylated liposomal doxorubicin in the conventional ABVD regimen for the treatment of elderly or cardiopathic patients with HL. Stage I-IIA and IIB-IV patients were treated with three courses of MBVD plus radiotherapy, or six courses of MBVD, respectively, plus radiotherapy limited to bulky or residual disease areas. The primary endpoints were CR rate and the rate of cardiac events. Forty-seven patients were enrolled. Median age was 75 years, 13 had stage I-II disease. Overall, CR was achieved by 36 patients (77%, 95% CI: 62-88), 100% and 68% in stage I-II and III-IV, respectively. With a median follow-up of 40 months (IQR: 36-45). Three-year overall survival (OS) and progression-free survival (PFS) were 70% and 43%, respectively. Cardiac events grades 3-5 were reported in two patients. In conclusion, MBVD's activity and safety profile was comparable to historical ABVD data.
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http://dx.doi.org/10.1080/10428194.2019.1608529DOI Listing
December 2019

Minimal Residual Disease in Indolent Lymphomas: A Critical Assessment.

Curr Treat Options Oncol 2018 11 6;19(12):71. Epub 2018 Nov 6.

A.O. SS Antonio e Biagio and Cesare Arrigo, Alessandria, Italy.

Opinion Statement: Indolent non-Hodgkin lymphomas (iNHL) are a heterogeneous group of pathologies characterized by a prolonged natural history and good response to treatment. They also have a tendency to relapse, in some cases with a worse prognosis. One of the main objectives in the newest clinical trials is to identify patients at high risk of relapse. This cannot be accomplished using only clinical prognostic scores. Detection of minimal residual disease (MRD) is effective in evaluating long-term disease response, with a strong and independent predictive value that was demonstrated in large cohorts of patients. Analysis of MRD allows patient stratification based on the risk for relapse; therefore, different therapeutic programs can be designed based on the response characteristics. This tailored therapy is already happening in current clinical trials. Limits imposed by traditional PCR-based tools are being overcome due to new molecular biology techniques like droplet digital PCR and next generation sequencing. Although these techniques are not yet standardized, they will likely increase the reliability and ensure broad applicability of MRD detection in future years.
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http://dx.doi.org/10.1007/s11864-018-0594-1DOI Listing
November 2018

Methods and role of minimal residual disease after stem cell transplantation.

Bone Marrow Transplant 2019 05 16;54(5):681-690. Epub 2018 Aug 16.

Medical Center of the Johann-Wolfgang Goethe University, Frankfurt am Main, Germany.

Relapse is the major cause of treatment failure after stem cell transplantation. Despite the fact that relapses occurred even if transplantation was performed in complete remission, it is obvious that minimal residual disease is present though not morphologically evident. Since adaptive immunotherapy by donor lymphocyte infusion or other novel cell therapies as well as less toxic drugs, which can be used after transplantation, the detection of minimal residual disease (MRD) has become a clinical important variable for outcome. Besides the increasing options to treat MRD, the most advanced technologies currently allow to detect residual malignant cells with a sensitivity of 10 to 10.Under the patronage of the European Society for Blood and Marrow Transplantation (EBMT) and the American Society for Blood and Marrow Transplantation (ASBMT) the 3rd workshop was held on 4/5 November 2016 in Hamburg/Germany, with the aim to present an up-to-date status of epidemiology and biology of relapse and to summarize the currently available options to prevent and treat post-transplant relapse. Here the current methods and role of minimal residual disease for myeloid and lymphoid malignancies are summarized.
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http://dx.doi.org/10.1038/s41409-018-0307-1DOI Listing
May 2019

STAble: a novel approach to de novo assembly of RNA-seq data and its application in a metabolic model network based metatranscriptomic workflow.

BMC Bioinformatics 2018 07 9;19(Suppl 7):184. Epub 2018 Jul 9.

Dipartimento di Scienze e Innovazione Tecnologica, Università degli Studi del Piemonte Orientale, 15121, Alessandria, Italy.

Background: De novo assembly of RNA-seq data allows the study of transcriptome in absence of a reference genome either if data is obtained from a single organism or from a mixed sample as in metatranscriptomics studies. Given the high number of sequences obtained from NGS approaches, a critical step in any analysis workflow is the assembly of reads to reconstruct transcripts thus reducing the complexity of the analysis. Despite many available tools show a good sensitivity, there is a high percentage of false positives due to the high number of assemblies considered and it is likely that the high frequency of false positive is underestimated by currently used benchmarks. The reconstruction of not existing transcripts may false the biological interpretation of results as - for example - may overestimate the identification of "novel" transcripts. Moreover, benchmarks performed are usually based on RNA-seq data from annotated genomes and assembled transcripts are compared to annotations and genomes to identify putative good and wrong reconstructions, but these tests alone may lead to accept a particular type of false positive as true, as better described below.

Results: Here we present a novel methodology of de novo assembly, implemented in a software named STAble (Short-reads Transcriptome Assembler). The novel concept of this assembler is that the whole reads are used to determine possible alignments instead of using smaller k-mers, with the aim of reducing the number of chimeras produced. Furthermore, we applied a new set of benchmarks based on simulated data to better define the performance of assembly method and carefully identifying true reconstructions. STAble was also used to build a prototype workflow to analyse metatranscriptomics data in connection to a steady state metabolic modelling algorithm. This algorithm was used to produce high quality metabolic interpretations of small gene expression sets obtained from already published RNA-seq data that we assembled with STAble.

Conclusions: The presented results, albeit preliminary, clearly suggest that with this approach is possible to identify informative reactions not directly revealed by raw transcriptomic data.
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http://dx.doi.org/10.1186/s12859-018-2174-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069750PMC
July 2018

Droplet Digital PCR for Minimal Residual Disease Detection in Mature Lymphoproliferative Disorders.

Methods Mol Biol 2018 ;1768:229-256

Division of Hematology, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.

Minimal residual disease (MRD) detection has a powerful prognostic relevance for response evaluation and prediction of relapse in hematological malignancies. Real-time quantitative PCR (qPCR) has become the settled and standardized method for MRD assessment in lymphoid disorders. However, qPCR is a relative quantification approach, since it requires a reference standard curve. Droplet digital PCR (ddPCR) allows a reliable absolute tumor burden quantification withdrawing the need for preparing, for each experiment, a tumor-specific standard curve. We have recently shown that ddPCR has a good concordance with qPCR and could be a feasible and reliable tool for MRD monitoring in mature lymphoproliferative disorders. In this chapter we describe the experimental workflow, from the detection of the clonal molecular marker to the MRD monitoring by ddPCR, in patients affected by multiple myeloma, mantle cell lymphoma and follicular lymphoma. However, standardization programs among different laboratories are needed in order to ensure the reliability and reproducibility of ddPCR-based MRD results.
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http://dx.doi.org/10.1007/978-1-4939-7778-9_14DOI Listing
February 2019

Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma: clinical outcome and correlation with genomic data. A phase 2 study of the Fondazione Italiana Linfomi.

Leuk Lymphoma 2018 12 4;59(12):2904-2910. Epub 2018 Apr 4.

n Fondazione Italiana Linfomi , Alessandria , Italy.

We investigated panobinostat 40 mg three times weekly in 35 adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Overall response rate and complete response were 17.1% and 11.4%, respectively. Median progression-free survival (PFS) and overall survival were 2.4 and 7.6 months, respectively. Calculated 12, 24 and 36 months PFS were 26%, 11% and 11%, respectively. Four patients who achieved a sustained CR, continued receiving panobinostat for an overall period of 44, 48, 50, 62 months. Thrombocytopenia grade 3 (5 patients) and 4 (24 patients) represented the main toxic effect, causing dose reduction or treatment suspension in 19 patients. Genomic analysis was unable to identify any relationship between mutations and response; TP53 mutation appeared not to impact the clinical outcome. Overall, panobinostat has a modest activity in R/R DLBCL patients, however it can induce very long lasting responses in some cases. Thrombocytopenia frequently limits the use of this agent.
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http://dx.doi.org/10.1080/10428194.2018.1452208DOI Listing
December 2018

Highly sensitive mutation detection by droplet digital polymerase chain reaction in Waldenström macroglobulinemia.

Haematologica 2018 06 22;103(6):1029-1037. Epub 2018 Mar 22.

Department of Molecular Biotechnologies and Health Sciences, Hematology Division, University of Torino, Italy.

We here describe a novel method for mutation detection and minimal residual disease monitoring in Waldenström macroglobulinemia, by droplet digital polymerase chain reaction, in bone marrow and peripheral blood cells, as well as in circulating cell-free DNA. Our method shows a sensitivity of 5.00×10, which is far superior to the widely used allele-specific polymerase chain reaction (1.00×10). Overall, 291 unsorted samples from 148 patients (133 with Waldenström macroglobulinemia, 11 with IgG lymphoplasmacytic lymphoma and 4 with IgM monoclonal gammopathy of undetermined significance) were analyzed: 194 were baseline samples and 97 were followup samples. One hundred and twenty-two of 128 (95.3%) bone marrow and 47/66 (71.2%) baseline peripheral blood samples scored positive for To investigate whether detection by droplet digital polymerase chain reaction could be used for minimal residual disease monitoring, mutation levels were compared with -based minimal residual disease analysis in 10 patients, and was found to be as informative as the classical, standardized, but not yet validated in Waldenström macroglobulinemia, -based minimal residual disease assay (r=0.64). Finally, detection by droplet digital polymerase chain reaction on plasma circulating tumor DNA from 60 patients showed a good correlation with bone marrow findings (bone marrow median mutational value 1.92×10, plasma circulating tumor DNA value: 1.4×10, peripheral blood value: 1.03×10). This study indicates that droplet digital polymerase chain reaction assay of is a feasible and sensitive tool for mutation screening and minimal residual disease monitoring in Waldenström macroglobulinemia. Both unsorted bone marrow and peripheral blood samples can be reliably tested, as can circulating tumor DNA, which represents an attractive, less invasive alternative to bone marrow for detection.
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http://dx.doi.org/10.3324/haematol.2017.186528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058774PMC
June 2018

A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial.

Haematologica 2018 05 22;103(5):849-856. Epub 2018 Feb 22.

Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy.

Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptor and B-cell receptor) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes (, and ), was used to classify the 83 cases (43 B-cell receptor and 40 B-cell receptor). The B-cell receptor signature associated with shorter progression-free survival (=0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival (=0.0014 and =0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homogenously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL- 0208 clinical trial. ().
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http://dx.doi.org/10.3324/haematol.2017.184325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927985PMC
May 2018