Publications by authors named "Giovanni Grillo"

30 Publications

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GITMO REGISTRY STUDY ON ALLOGENEIC TRANSPLANTATION IN PATIENTS AGED OVER 60 FROM 2000 TO 2017. IMPROVEMENTS AND CRITICISMS.

Transplant Cell Ther 2021 Nov 21. Epub 2021 Nov 21.

Unit of Haematology and Stem Cell Transplant Centre, "San Camillo" Hospital, Rome, Italy.

Background: Nowadays, allogeneic stem cell transplantation (Allo-SCT) can be offered to patients up to the age of 70-72 years and represents one of the most effective curative treatments for many hematological malignancies.

Objectives: The primary objective of the study is to collect data from the allo-SCTs performed in Italy from 2000 to 2017 in patients over 60 years of age to evaluate the changes in safety and efficacy outcomes as well as their distribution and characteristics over time.

Study Design: The GITMO AlloEld study (ClinicalTrials.gov: NCT04469985) is a retrospective, analysis of the allo-SCTs performed 30 Italian transplant Centers on older patients (≥ 60 years) from 2000 to 2017 (n=1,996).

Results: For the purpose of analysis, patients were grouped into three time periods: time A: 2000-2005, n=256 (12%); time B: 2006-2011, n=584 (29%); and time C: 2012-2017, n=1156 (59%). After a median follow-up of 5.6 years, the 5-year Non Relapse Mortality (NRM) remained stable (time A: 32.8%; time B: 36.2%; and time C: 35.0%, p = 0.5); the Overall Survival (OS) improved (time A: 28.4%; time B: 31.8%; and time C: 37.3%, p = 0.012); and the Cumulative Incidence of Relapse (CIR) reduced (time A: 45.3%; time B: 38.2%; time C: 30.0%, p < 0.0001). The 2-year incidence of extensive cGVHD reduced significantly (time A: 17.2%; time B: 15.8%; and time C: 12.2%, p = 0.004). Considering times A and B together (2000-2011), the 2-year NRM was positively correlated to the HCT-CI score; patients with HCT-CI of 0, 1 or 2, or ≥3 had rates of NRM of 25.2%, 33.9%, and 36.1%, respectively, (p < 0.001). Meanwhile, after 2012, the HCT-CI score was not significantlly predictive of NRM.

Conclusions: The study shows that the transplant procedure in elderly patients became more effective over time. Relapse incidence remains the major problem and strategies to prevent it are under investigation (e.g. post-transplant maintenance). Today, the selection of patients aged over 60 could be improved by combining HCT-CI and frailty assessments to better predict NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.11.006DOI Listing
November 2021

Epidemiology, diagnosis and management of Baastrup's diseases: a systematic review.

J Neurosurg Sci 2021 Aug 3. Epub 2021 Aug 3.

Department of Aging, Neurological, Orthopaedic and Head-Neck Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.

Introduction: Baastrup disease (BD) is a common cause of low back pain which is often underdiagnosed. It is characterized by adjacent interspinous processes contact and it can be associated with cystic lesions. The aim of this review is to evaluate the epidemiology, diagnosis, and treatment options of patients with BD.

Evidence Acquisition: The present study is performed according to PRISMA statement. MEDLINE via PubMed and Embase, Scopus, Cochrane Library database were searched using the keywords: "Baastrup", "Kissing Spines", "Syndrome", "Disease". A total of 35 papers met our inclusion criteria. Full text were reviewed for demographic, clinical data and treatment.

Evidence Synthesis: 1308 patients were included in the studies. The mean age of the enrolled patients was 59.6 years. The M:F ratio was 1.3:1. Population-based studies demonstrated a decade on decade increase in the incidence. Standard and dynamic flexion-extension radiographs of the lumbar spine were performed in 213 (16.2%) of cases. MRI was performed in 735 patients (56,2%) whereas FDG PET/CT was used to demonstrate BD in 77 included cases (5.9%). CT scan was performed in 574 cases (43.9%). 26 studies reported the treatment choice for a total of 277 patients. Anti-inflammatory drugs and physical therapy were chosen in 99 cases (35.7%). Percutaneous infiltrations and surgical decompression in 80 (28.9%) and 196 (70.7%) patients respectively.

Conclusions: Baastrup disease is a common cause of low back pain. Proper diagnosis needs for imaging investigations and dynamic flexion-extension radiographs. Conservative and surgical therapies are available but there is a need for randomized clinical trials.
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http://dx.doi.org/10.23736/S0390-5616.21.05428-XDOI Listing
August 2021

Complete resolution of a cutaneous grade 2 graft-versus-host disease after liver transplantation using ruxolitinib.

Clin Transplant 2021 08 6;35(8):e14366. Epub 2021 Jun 6.

Division of General Surgery and Transplantation, Department of Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

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http://dx.doi.org/10.1111/ctr.14366DOI Listing
August 2021

Correlation analysis between virtual and Complement-Dependent-Cytotoxicity crossmatch in a monocenter retrospective series of 118 allografted patients.

Curr Res Transl Med 2021 05 23;69(2):103287. Epub 2021 Mar 23.

SIMT, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy.

Purpose Of The Study: The detection of patients' anti-HLA antibodies before allogeneic hematopoietic stem cell transplantation (HSCT) may affect post-transplant outcome, due to a potential detrimental impact on engraftment or toxicity-related issues. Crossmatch (XM) techniques provide support to physicians during the pre-transplant phase but the role of Complement-Dependent Cytotoxicity XM (CDC-XM) is not well-defined when performed routinely and in parallel with the virtual XM.

Patients And Methods: We report here our experience with both virtual and CDC-XM tests on n = 118 patients undergoing search for a donor other than HLA-identical sibling from July 2013 to June 2018 at our Institution. When anti-HLA antibodies (Abs) were present, they were classified as donor-specific Abs (DSA) or non-DSA.

Results: On the n = 118 patients, n = 35 (29.7 %) had a positive virtual XM test (of which one of more DSA were found in n = 8; 6.8 %) and n = 5 had a positive CDC-XM test. These latter, positive for HLA class II only, were interpreted as false-positive results due to prior administration of anti-CD20 to the patients, all affected by lymphoma; none of them had a positive virtual XM for anti-HLA Abs of class II. Importantly, all these patients successfully engrafted, further supporting the lack of significant impact of CDC-XM positive results in this series.

Conclusions: According to our data on more than a hundred patients, routinely performed CDC-XM does not seem to add significant information with respect to virtual XM. We cannot exclude the usefulness of CDC-XM in specific situations, although a positive CDC-XM result was an unfrequent event.
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http://dx.doi.org/10.1016/j.retram.2021.103287DOI Listing
May 2021

Correction to: Tregs and GvHD prevention by extracorporeal photopheresis: observations from a clinical trial.

Exp Hematol Oncol 2021 Mar 17;10(1):22. Epub 2021 Mar 17.

Servizio Di Immunoematologia E Medicina Trasfusionale, ASST Grande Ospedale Metropolitano Niguarda, Piazza Dell'Ospedale Maggiore, 3, 20162, Milano, Italy.

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http://dx.doi.org/10.1186/s40164-021-00216-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972182PMC
March 2021

Tregs and GvHD prevention by extracorporeal photopheresis: observations from a clinical trial.

Exp Hematol Oncol 2021 Feb 16;10(1):14. Epub 2021 Feb 16.

Ematologia, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy.

The aim of the present study was to evaluate the circulating T regulatory cells (Tregs) in patients undergoing extracorporeal photopheresis (ECP) for the prevention of chronic graft-versus-host disease (GvHD) and to search for any correlation between Tregs counts and chronic GvHD occurrence. Among n = 12 patients with complete longitudinal data, the median cumulative values of absolute peripheral Tregs counts were 21.64 and 63.49 cells/µL for patients who developed chronic GvHD and those who did not develop it, respectively (p = 0.05). The analysis of the median absolute counts of peripheral HLA-DR + Tregs provided similar results, showing that 20% (1 out of 5) and 100% (7 out of 7) of patients with HLA-DR + Tregs values of > 5 cells/µL were in the GvHD and non-GvHD groups, respectively (p = 0.01). In conclusion, the present results support the involvement of Tregs in the prevention of chronic GvHD in patients receiving ECP and suggest Tregs count as a potential biomarker of ECP effectiveness. Future strategies are needed to enhance Tregs expansion and/or activity in conjunction with ECP for an effective chronic GvHD prevention.
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http://dx.doi.org/10.1186/s40164-021-00210-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887801PMC
February 2021

FZD6 triggers Wnt-signalling driven by WNT10B expression and highlights new targets in T-cell acute lymphoblastic leukemia.

Hematol Oncol 2021 Aug 16;39(3):364-379. Epub 2021 Feb 16.

Department of Health Sciences, University of Milan, Milan, Italy.

Wnt/Fzd signaling has been implicated in hematopoietic stem cell maintenance and in acute leukemia establishment. In our previous work, we described a recurrent rearrangement involving the WNT10B locus (WNT10B ), characterized by the expression of WNT10B transcript variant, in acute myeloid leukemia. To determine the occurrence of WNT10B in T-cell acute lymphoblastic leukemia (T-ALL), we retrospectively analyzed an Italian cohort of patients (n = 20) and detected a high incidence (13/20) of WNT10B expression. To address genes involved in WNT10B molecular response, we have designed a Wnt-targeted RNA sequencing panel. Identifying Wnt agonists and antagonists, it results that the expression of FZD6, LRP5, and PROM1 genes stands out in WNT10B positive patients compared to negative ones. Using MOLT4 and MUTZ-2 as leukemic cell models, which are characterized by the expression of WNT10B , we have observed that WNT10B drives major Wnt activation to the FZD6 receptor complex through receipt of ligand. Additionally, short hairpin RNAs (shRNAs)-mediated gene silencing and small molecule-mediated inhibition of WNTs secretion have been observed to interfere with the WNT10B/FZD6 interaction. We have therefore identified that WNT10B knockdown, or pharmacological interference by the LGK974 porcupine (PORCN) inhibitor, reduces WNT10B/FZD6 protein complex formation and significantly impairs intracellular effectors and leukemic expansion. These results describe the molecular circuit induced by WNT10B and suggest WNT10B/FZD6 as a new target in the T-ALL treatment strategy.
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http://dx.doi.org/10.1002/hon.2840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451758PMC
August 2021

Hematopoietic stem cell transplantation for adults with relapsed acute promyelocytic leukemia in second complete remission.

Bone Marrow Transplant 2021 06 15;56(6):1272-1280. Epub 2020 Dec 15.

Hôpital Saint Antoine, Sorbonne University, Department of Hematology, Paris, France.

We retrospectively compared outcomes of a large series of adult patients with APL in CR2 receiving alloHSCT (n = 228) or autoHSCT (n = 341) reported to the European Society for Blood and Marrow Transplantation from January 2004 to December 2018. The 2-year cumulative incidence of non-relapse mortality was significantly higher for alloHSCT 17.3% (95% CI 12.5-22.8) compared with autoHSCT 2.7% (95% CI 1.2-5) (p = 0.001), while differences in relapse rate were not significant (28% versus 22.9%; p = 0.28). Leukemia-free survival (LFS) and overall survival (OS) favored autoHSCT with 74.5% (95% CI 69-79.2) and 82.4% (95% CI 77.3-86.5) compared with alloHSCT with 54.7% (95% CI 47.5-61.3) (p = 0.001) and 64.3% (95% CI 57.2-70.6), respectively (p = 0.001 and p = 0.001). Multivariable analysis showed significantly worse LFS after alloHSCT (HR 0.49; 95% CI 0.37-0.67; p < 0.0001), older age (p = 0.001), and shorter time from diagnosis to transplant (p = 0.00015). Similar results were obtained for OS. The study shows that autoHSCT resulted in better survival outcomes (LFS and OS) for APL in CR2. These results were mainly due to reduced NRM in the autoHSCT as compared to alloHSCT.
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http://dx.doi.org/10.1038/s41409-020-01162-0DOI Listing
June 2021

I stay at home with headache. A survey to investigate how the lockdown for COVID-19 impacted on headache in Italian children.

Cephalalgia 2020 11;40(13):1459-1473

Headache Center, Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.

Objective: The present Italian multicenter study aimed at investigating whether the course of primary headache disorders in children and adolescents was changed during the lockdown necessary to contain the COVID-19 emergency in Italy.

Methods: During the lockdown, we submitted an online questionnaire to patients already diagnosed with primary headache disorders. Questions explored the course of headache, daily habits, psychological factors related to COVID-19, general mood and school stress. Answers were transformed into data for statistical analysis. Through a bivariate analysis, the main variables affecting the subjective trend of headache, and intensity and frequency of the attacks were selected. The significant variables were then used for the multivariate analysis.

Results: We collected the answers of 707 patients. In the multivariate analysis, we found that reduction of school effort and anxiety was the main factor explaining the improvement in the subjective trend of headache and the intensity and frequency of the attacks ( < 0.001). The greater the severity of headache, the larger was the clinical improvement ( < 0.001). Disease duration was negatively associated with the improvement ( < 0.001). It is noteworthy that clinical improvement was independent of prophylaxis ( > 0.05), presence of chronic headache disorders ( > 0.05) and geographical area ( > 0.05).

Conclusions: Our study showed that lifestyle modification represents the main factor impacting the course of primary headache disorders in children and adolescents. In particular, reduction in school-related stress during the lockdown was the main factor explaining the general headache improvement in our population.
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http://dx.doi.org/10.1177/0333102420965139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684684PMC
November 2020

Persistent post-traumatic headache: a migrainous loop or not? The clinical evidence.

J Headache Pain 2020 May 24;21(1):55. Epub 2020 May 24.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Background: Headache is a common complication of traumatic brain injury. The International Headache Society defines post-traumatic headache as a secondary headache attributed to trauma or injury to the head that develops within seven days following trauma. Acute post-traumatic headache resolves after 3 months, but persistent post-traumatic headache usually lasts much longer and accounts for 4% of all secondary headache disorders.

Main Body: The clinical features of post-traumatic headache after traumatic brain injury resemble various types of primary headaches and the most frequent are migraine-like or tension-type-like phenotypes. The neuroimaging studies that have compared persistent post-traumatic headache and migraine found different structural and functional brain changes, although migraine and post-traumatic headache may be clinically similar. Therapy of various clinical phenotypes of post-traumatic headache almost entirely mirrors the therapy of the corresponding primary headache and are currently based on expert opinion rather than scientific evidence. Pharmacologic therapies include both abortive and prophylactic agents with prophylaxis targeting comorbidities, especially impaired sleep and post-traumatic disorder. There are also effective options for non-pharmacologic therapy of post-traumatic headache, including cognitive-behavioral approaches, onabotulinum toxin injections, life-style considerations, etc. CONCLUSION: Notwithstanding some phenotypic similarities, persistent post-traumatic headache after traumatic brain injury, is considered a separate phenomenon from migraine but available data is inconclusive. High-quality studies are further required to investigate the pathophysiological mechanisms of this secondary headache, in order to identify new targets for treatment and to prevent disability.
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http://dx.doi.org/10.1186/s10194-020-01122-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245945PMC
May 2020

Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma.

Haematologica 2021 04 1;106(4):978-986. Epub 2021 Apr 1.

Dept. of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, USA.

CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with >= grade 3 neutropenia seen in 21/70 (30-0%) patients at day 30 and persisting in 3/31 (9-7%) patients at 1 year. B cells were undetectable in 30/34 (88-2%) patients at day 30, but were detected in 11/19 (57-9%) at 1 year. Median IgG levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/μl at 1 year after axi-cel (n=19, range 33 - 269). In total, 23/85 (27-1%) patients received IVIG after axi-cel, and 34/85 (40-0%) received G-CSF. Infections in the first 30 days occurred in 31/85 (36-5%) patients, of which 11/85 (12-9%) required intravenous antibiotics or hospitalization ("severe") and were associated with cytokine release syndrome (CRS), neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, 7 severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T cell immunosuppression without severe infection.
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http://dx.doi.org/10.3324/haematol.2019.238634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017820PMC
April 2021

The number of HLA confirmatory tests during unrelated donor search as a driver for the evaluation of back-up haploidentical donor(s).

Transfus Apher Sci 2020 Aug 31;59(4):102766. Epub 2020 Mar 31.

ASST Grande Ospedale Metropolitano Niguarda, Milano. Piazza Dell'Ospedale Maggiore 3, 20162, Milano, Italy.

Introduction: the identification of a suitable donor in an appropriate timing represents a crucial step in the preparation of allogeneic stem cell transplantation (HSCT). At our Institution, for patients lacking an HLA-identical sibling, a haploidentical donor is considered in the absence of a 10/10-matched or a one-locus HLA-mismatched unrelated donor (UD), but the optimal timing of work-up of potential familiar haploidentical donor(s) by the Apheresis Team is actually unknown.

Patients & Methods: we analyzed here n = 167 UD searches launched at our Hospital between July 2013 and July 2018 and looked for any correlation between the number of HLA confirmatory tests received and the final type of donor selected for HSCT, in an attempt to identify those situations where prompt evaluation of haploidentical donor(s) is warranted.

Results: a total of n = 117 transplants were performed and haploidentical HSCTs were n = 16 (14 %). In n = 93 cases (56 %) the number of HLA confirmatory tests received were two; they were one, zero and three for n = 52, n = 14 and n = 8 patients, respectively. Only 5 % of haploidentical donors were used when two confirmation test samples were received whereas this percentage rises to 17 % when only one sample reached the HLA lab. When no confirmation tests were available, haploidentical transplant occurred in 100 % of cases.

Conclusions: besides the situations with no HLA confirmation tests, the evaluation of any haploidentical donor(s) should be promptly started also when only one HLA confirmatory test is received, in order to optimise the potential work-up process and avoid delay in transplantation.
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http://dx.doi.org/10.1016/j.transci.2020.102766DOI Listing
August 2020

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia in the Era of Tyrosine Kinase Inhibitors: A Registry-Based Study of the Italian Blood and Marrow Transplantation Society (GITMO).

Biol Blood Marrow Transplant 2019 12 7;25(12):2388-2397. Epub 2019 Aug 7.

Centro Unico Regionale Trapianto Cellule Staminali e Terapie Cellulari A. Neri, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.

We performed a nationwide registry-based analysis to describe the clinical outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ALL) who underwent an allogeneic hematopoietic stem cell transplantation (HSCT) after a tyrosine kinase inhibitor (TKI)-based treatment A total of 441 patients were included in the study. The median age at HSCT was 44 years (range, 18 to 70 years). All 441 patients (100%) received TKI before HSCT (performed between 2005 and 2016). Of these 441 patients, 404 (92%) were in cytologic complete remission (CR), whereas the remaining 37 (8%) had active disease at the time of HSCT. Molecular minimal residual disease (MRD) was negative in 147 patients (36%) at the time of HSCT. The donor was unrelated in 46% of patients. The most prevalent source of stem cells was peripheral blood (70%). The conditioning regimen was myeloablative in 82% of cases (total body irradiation-based in 50%) and included antithymocyte globulin in 51% of patients. With a median follow-up after HSCT of 39.4 months (range, 1 to 145 months), the probability of overall survival (OS) at 1, 2, and 5 years was 69.6%, 61.1% and 50.3%, respectively, with a median OS of 62 months. Progression-free survival (PFS) at 1, 2, and 5 years was 60.2%, 52.1% and 43.7%, respectively. OS and PFS were significantly better in patients who were in CR and MRD-negative at the time of HSCT compared with patients who were in CR but MRD-positive (50% OS not reached versus 36 months; P = .015; 50% PFS not reached versus 26 months, P = .003). The subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT had a better outcome (5-year OS, 70%). Conversely, the 37 patients who underwent a HSCT with active Ph ALL had a median OS of 7 months and a median PFS of 5 months. The 5-year cumulative incidence of relapse was significantly lower in MRD-negative patients (19.5% versus 35.4%; P = .001). Nonrelapse mortality (NRM) after 1, 2, and 5 years was 19.1% (95% confidence interval [CI], 15.5% to 22.9%), 20.7% (95% CI, 17% to 24.7%), and 24.1% (95% CI, 20% to 28.5%), respectively. NRM was significantly lower with a modified European Society for Blood and Marrow Transplantation (mEBMT) risk score of 0 to 2 compared with ≥3 (15% versus 25%; P = .016). The median OS for Ph ALL patients who underwent a TKI-based treatment followed by an allogeneic HSCT, in recent years at the GITMO centers, was 62 months. Evaluation of the mEBMT risk score can be useful to predict NRM. Our data confirm that HSCT is a potentially curative treatment for Ph ALL with an excellent outcome for the subgroup of MRD-negative patients both at HSCT and at 3 months after HSCT (5-year OS, 70%).
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http://dx.doi.org/10.1016/j.bbmt.2019.07.037DOI Listing
December 2019

A double-hit High-grade B-cell lymphoma with three-way translocation t(3;8;14)(q27;q24;q32) involving BCL6, MYC, and IGH.

Clin Case Rep 2018 Dec 26;6(12):2411-2415. Epub 2018 Oct 26.

Department of Laboratory Medicine ASST Grande Ospedale Metropolitano Niguarda Milan Italy.

We describe an High-grade B-cell lymphoma case, in which a complex translocation t(3;8;14) with effects on the genes BCL6, MYC, and IGH, was detected. This case could be the first double-hit lymphoma with a single chromosome rearrangement causing the double effect with three genes involved.
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http://dx.doi.org/10.1002/ccr3.1871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293148PMC
December 2018

Feasibility of all-oral anti-HCV treatment during DHAP chemotherapy and autologous stem cell transplantation for T-cell lymphoma.

New Microbiol 2018 07 5;41(3):242-245. Epub 2018 Apr 5.

Niguarda Hepatitis Center, Division of Infectious Diseases, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

The role of anti-HCV direct-acting agents (DAAs) is well described in HCV-related lymphoproliferative disorders, whereas few data are available on their use in other malignancies, such as aggressive T-cell lymphomas requiring autologous stem cell transplantation (ASCT). We describe two oncologic cirrhotic patients treated with DAAs who underwent ASCT achieving cure for both diseases. Co-administration of sofosbuvir with cisplatin led an unexpected severe kidney impairment that did not resolve 30 weeks after drug exposure. The optimal timing of DAA administration in the ASCT setting has yet to be defined: our experience shows that co-administration is feasible, but requires close monitoring for adverse events.
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July 2018

Clofarabine-based chemotherapy as a bridge to transplant in the setting of refractory or relapsed acute myeloid leukemia, after at least one previous unsuccessful salvage treatment containing fludarabine: a single institution experience.

Int J Hematol 2017 Jun 20;105(6):769-776. Epub 2017 Feb 20.

Hematology, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, 20162, Milan, Italy.

For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. "Salvage" therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30-50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based "salvage" attempt in a "real life" (outside a clinical trial) context. No death related to the clofarabine-based treatment was observed. Four of the 14 patients (29%) reached complete remission and one (7%) achieved a reduction of marrow blasts to fewer than 10%. Three of these five patients were successfully transplanted and have shown a long-term survival. The small number of this group of patients does not permit the identification of clinical features clearly related to a favorable outcome, but we note that all the three long-term survivals were FLT3 wild type. Clofarabine-based "salvage therapy" in patients with very poor expectancy is feasible even after a fludarabine-based salvage attempt, albeit with success only in a small percentage of cases (3/14 = 21%).
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http://dx.doi.org/10.1007/s12185-017-2198-0DOI Listing
June 2017

Allogeneic peripheral blood stem cell transplantation and accelerated atherosclerosis: An intriguing association needing targeted surveillance. Lessons from a rare case of acute anterior myocardial infarction.

Eur Heart J Acute Cardiovasc Care 2020 Oct 24;9(7):NP3-NP7. Epub 2016 May 24.

De Gasperis Cardio Centre, Niguarda Ca' Granda Hospital, Milan, Italy.

We report the case of a 23-year-old man who developed an acute ST-elevation myocardial infarction secondary to acute thrombotic occlusion of the proximal left anterior descending coronary artery five years after undergoing chemotherapy, radiotherapy, haematopoietic stem cell transplantation for acute lymphoblastic leukaemia and bulky mediastinal mass involving the pleura and pericardium. His medical history also included Graft versus Host Disease developed 13 months after transplantation and acute myocarditis three months before the actual hospital admission. To the best of our knowledge, coronary artery disease as a complication of haematopoietic stem cell transplantation and low-dose mediastinal radiation therapy in young patients has been rarely reported in the medical literature. Clinicians should have a high degree of suspicion of coronary artery disease in patients treated with allogeneic haematopoietic stem cell transplantation, especially in patients previously treated with target mediastinal radiotherapy, as a group at risk of premature and significantly accelerated atherosclerosis, in order to make a timely and correct diagnosis.
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http://dx.doi.org/10.1177/2048872616652311DOI Listing
October 2020

Response of steroid-refractory chronic graft-versus-host disease to extracorporeal photopheresis correlates with the dose of CD3+ lymphocytes harvested during early treatment cycles.

Transfusion 2016 Feb 10;56(2):505-10. Epub 2015 Oct 10.

Transfusion Medicine Department, Ospedale Niguarda Ca' Granda, Milan, Italy.

Background: Extracorporeal photopheresis (ECP) is a recognized second-line treatment for steroid-refractory chronic graft-versus-host disease (cGVHD). Treatment course is usually long, expensive, and demanding for patients, so predictors for response are needed. We carried out a retrospective study on cGVHD patients treated at our institution with the aim to identify a possible correlation between apheretic yields composition and probability of response.

Study Design: Patients treated for at least 6 months were eligible for the study. Flow cytometry data, including absolute counts of lymphocytes and their subpopulations in ECP products from cGVHD patients, were collected. For each cell population 1) the median dose per procedure harvested during the first 3 months of treatment and 2) the cumulative dose collected in the same period were compared with clinical response.

Results: A total of 726 ECP procedures were performed in 15 patients. Overall response, defined as either a complete response (CR) or a partial response according to National Institutes of Health criteria, was obtained in 10 of 15 patients (66.7%), and CR, in eight of 15 (53.3%). According to Cox regression analysis, the probability of achieving an overall response is significantly correlated with the median number of CD3+, CD3+CD4+, and CD3+CD8+ lymphocytes collected during the early treatment phase (first 3 months).

Conclusion: Our data suggest that CD3+ cell evaluation in ECP during the early phase of treatment course could predict response and help identify patients who deserve further treatment.
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http://dx.doi.org/10.1111/trf.13369DOI Listing
February 2016

Identification of hematopoietic progenitor cell donor characteristics predicting successful mobilization: results of an Italian multicenter study.

Transfusion 2014 Aug 3;54(8):2028-33. Epub 2014 Mar 3.

Transfusion Medicine Department, Ospedale Niguarda Ca' Granda, Milan, Italy.

Background: Peripheral blood (PB) hematopoietic progenitor cells (HPC) collected by apheresis are the first-choice source for allogeneic stem cell transplantation. The target HPC dose is usually considered to be 4 × 10(6) CD34+ cells/kg of the recipient, but higher doses are required in reduced-intensity conditioning and haploidentical transplants. Thus, prolonged stimulation and repeated collections or failure to reach HPC target may occur, increasing risks for donors and recipients. We carried out a retrospective multicenter study on healthy donors, to identify donor variables which may correlate with HPC mobilization.

Study Design And Methods: HPC allogeneic donations from sibling and unrelated donors performed in two centers from 1995 to 2012 were analyzed. We defined a mobilization cutoff of 50 × 10(6) CD34+ cells/L and tested somatic variables, blood counts, and granulocyte-colony-stimulating factor (G-CSF) dose and molecular form.

Results: A total of 360 donors were analyzed (male, 201; female, 159; sibling, 348; unrelated, 12; median [range] age, 44.8 [13-80] years). Median peak CD34+ in PB was 54.4 × 10(6) /L (range, 5 × 10(6) -299 × 10(6) ). By multivariate analysis, we identified the following variables to correlate with good mobilization: 1) male sex (p<0.0005); 2) younger age (p=0.007); 3) higher baseline (premobilization) white blood cell (WBC) count (p<0.0005); 4) higher G-CSF dosage (p<0.0005); and 5) use of lenograstim rather than filgrastim (p<0.002).

Conclusion: In healthy donors it is possible to predict successful HPC mobilization by donor sex, age, WBC count, and G-CSF form and dose. Furthermore, based on these data, it may be possible, at least in parental setting, to modulate G-CSF dosage on the basis of donor characteristics.
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http://dx.doi.org/10.1111/trf.12612DOI Listing
August 2014

Flow cytometry and cytomorphology evaluation of hematologic malignancy in cerebrospinal fluids: comparison with retrospective clinical outcome.

Ann Hematol 2011 Jul 7;90(7):827-35. Epub 2011 Jan 7.

Department of Transfusion Medicine and Division of Hematology, Niguarda Ca' Granda Hospital, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy,

An independent clinical assessment was compared with flow cytometry (FCM) and cytomorphology results obtained on 227 cerebrospinal fluids investigated for hematologic malignancy, in a retrospective longitudinal study with a median observation time of 11 months. A combined method assessment (CMA), defining "positive" a sample if at least one method gave "positive" results, was also tested. Eleven out of 55 screening samples and 53 out of 166 follow-up samples resulted positive at clinical evaluation. FCM and CM were concordant with positive clinical assessment in 68.5% and 51.5% of cases, respectively. According to CMA, 10.5% of samples (resulting false negative by either FCM or cytomorphology) were rescued as true positive. FCM retained significantly higher accuracy than cytomorphology (p=0.0065) and 100% sensitivity when at least 220 leukocytes were acquired. CMA accuracy was higher than FCM accuracy and significantly higher than cytomorphology accuracy in the analysis of all samples (p<0.0001), samples from mature B/T cell neoplasms (p=0.0021), and samples drawn after intrathecal treatment (p=0.0001). When acquiring ≤220 leukocytes, FCM accuracy was poor, and combining cytomorphology added statistically significant diagnostic advantage (p=0.0043). Although FCM is the best diagnostic tool for evaluating CSF, morphology seems helpful especially when clinically positive follow-up samples are nearly acellular.
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http://dx.doi.org/10.1007/s00277-010-1145-4DOI Listing
July 2011

Bortezomib plus dexamethasone can improve stem cell collection and overcome the need for additional chemotherapy before autologous transplant in patients with myeloma.

Leuk Lymphoma 2010 Feb;51(2):236-42

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

The aim of this phase II trial was to investigate the efficacy of bortezomib plus dexamethasone (Vel-Dex) as induction therapy in patients with multiple myeloma (MM) and to define the role of intensification before transplantation. Fifty-seven patients were treated with four courses of Vel-Dex, two cycles of dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP), and a single autologous transplant. Fourteen patients (25%) went off-study: seven after Vel-Dex, seven after DCEP. All patients yielded high numbers of stem cells (median CD34+ cells 7.5 x 106/kg); 54 of the 57 patients (94%) collected > or =4 x 106/kg CD34+ cells, 60% with a single leukapheresis. The overall response rate (ORR) after Vel-Dex was 86% (70% had a very good partial response [VGPR] or better) regardless of cytogenetic abnormalities and International Staging System stage (ISS). The response at the end of the two DCEP cycles remained unchanged in 35 patients (70%), worsened in 15 (20%), and improved in 5 (10%). Because of the consistent drop-out, the ORR in intention-to-treat analysis decreased significantly from 86% after Vel-Dex to 76% after DCEP, and 73% after transplantation. However, when considering the subset of 43 patients who completed the program, the ORR was 96% (complete response 39%, VGPR 41%, partial response 16%). In conclusion, Vel-Dex produces high response rates, improves stem cell collection, and overcomes the need for intensification before autologous transplantation.
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http://dx.doi.org/10.3109/10428190903452826DOI Listing
February 2010

Total serum tryptase: a predictive marker for KIT mutation in acute myeloid leukemia.

Leuk Res 2009 Sep 29;33(9):1282-4. Epub 2009 Apr 29.

Department of Oncology, Niguarda Hospital, Piazza Ospedale Maggiore, 3-20162 Milan, Italy.

Human tryptase is a serine protease expressed in mast-cells. We previously observed that AML blast cells, cultured in vitro from a KIT D816Y patient, give rise to adherent cells with mast-cell like phenotype and tryptase was released in the serum-free medium. To correlate total serum tryptase (ts-try) levels with cytogenetic features and KIT mutational status, we analyzed serum samples from AML patients at diagnosis. In 70 out of 155 patients (45%) we detected elevated ts-try (>15 ng/mL), significantly linked to t(8;21) (P < .001) and inv(16) (P = .007). In patients that achieved complete remission the ts-try decreased to normal values. In 75 patients screened for KIT mutation, we found a clear relationship between elevated ts-try and mutated patients with t(8;21) (P < .001). In conclusion, we propose that checking for ts-try at diagnosis of AML may be a simple tool to select patients to be addressed to KIT mutation screening.
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http://dx.doi.org/10.1016/j.leukres.2009.03.043DOI Listing
September 2009

Molecular analysis of PDGFRA and PDGFRB genes by rapid single-strand conformation polymorphism (SSCP) in patients with core-binding factor leukaemias with KIT or FLT3 mutation.

Anticancer Res 2008 Sep-Oct;28(5A):2745-51

Division of Hematology, Niguarda Hospital, Milan, Italy.

Background: Mutations involving KIT and FLT3 genes, encoding tyrosine kinase (TK) membrane receptors, are detected in core-binding factor leukaemia (CBFL) patients. PDFGRA and PDGFRB encode class III TK receptors and are involved both in physiological processes and in the pathogenesis of haematological and solid tumours. The aim of this study was to investigate if PDGFR mutations are involved in CBFL.

Patients And Methods: In order to detect PDGFR mutations in CBFL, 35 patients without KIT or FLT3 mutations patients were screened by rapid and sensitive single-strand conformation polymorphism (SSCP) analysis. Sequence analysis was performed in polymerase chain reaction (PCR) products showing altered mobility in SSCP analysis in order to determine the nucleotide changes.

Results: Three types of single-nucleotide polymorphism (SNP) were detected in the PDGFRA gene (exon 12, exon 13 and exon 18) while no mutation of PDGFRB was detected in the tested CBFLs.

Conclusion: These data showed that no pathogenic mutations in PDGFRA and PDGFRB were detected in the context of CBFL without KIT and FLT3 mutations. Thus, PDGFR genes do not seem to be involved in CBFL and future studies are needed to establish the genetic causes of the disease in these particular patients.
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December 2008

Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study.

Blood 2006 May 29;107(9):3463-8. Epub 2005 Dec 29.

Division of Hematology, Ospedale Niguarda, Piazza Ospedale Maggiore 3, 20162-Milano, Italy.

Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KIT mutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KIT TKD mutation at codon 816 (TKD(816)) was associated with a high white blood cell count at diagnosis (median, 29.60 x 10(9)/L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD(816) mutated patients (n = 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KIT unmutated (c-KIT(-)) patients (90% vs 35.3%, P = .002; 25% vs 76.5%, P = .006, respectively). No difference in relapse incidence (P = .126) and OS (P = .474) was observed between the c-KIT mutated other than TKD(816) (n = 7) and the c-KIT(-) patients. These findings indicate that c-KIT TKD(816) mutation has a negative impact on the outcome of AML with t(8;21).
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http://dx.doi.org/10.1182/blood-2005-09-3640DOI Listing
May 2006

Imatinib mesylate in the treatment of Core Binding Factor leukemias with KIT mutations. A report of three cases.

Leuk Res 2005 Apr 12;29(4):397-400. Epub 2005 Jan 12.

Division of Haematology, Niguarda Hospital, Piazza Ospedale Maggiore 3, 20162 Milan, Italy.

Aim of this study is to investigate the capability of Imatinib to induce an anti-leukemic effect in Core Binding Factor (CBF)-leukemia patients presenting either with extracellular juxtamembrane or kinase KIT mutations. On the basis of a screening analysis for KIT mutations, two patients with a kinase mutation and one with extracellular juxtamembrane mutation, in first or subsequent leukemic relapse, received 400mg Imatinib twice daily for 30 days. After Imatinib discontinuation, bone marrow cells were re-tested to assess the KIT mutational status and the chromosomal set. In our experience, none of the treated patients had a response by standard criteria; in particular, we did not observe any activity against acute myeloid leukemia (AML) associated with KIT kinase mutations. However, in the patient with extracellular juxtamembrane mutation, Imatinib seems to have some clinical beneficial effect and, most important, is able to abrogate the leukemic subclone carrying the mutation. Whether Imatinib, in combination with other agents, may play a role in the treatment of AML with more sensitive extracellular juxtamembrane KIT mutation remains to be determined.
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http://dx.doi.org/10.1016/j.leukres.2004.10.005DOI Listing
April 2005

KIT activating mutations: incidence in adult and pediatric acute myeloid leukemia, and identification of an internal tandem duplication.

Haematologica 2004 Aug;89(8):920-5

Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Italy.

Background And Objectives: Mutations of KIT receptor tyrosine kinase are involved in the constitutive activation and development of human hematologic malignancies. Gain-of-function mutations in the second intracellular kinase domain (TK2) and in the juxtamembrane domain are described in patients with core binding factor acute myeloid leukemia (CBFL) and are associated with leukocytosis. We evaluated the incidence of KIT mutation in 52 adult patients with de novo CBFL and in 49 FLT3/ITD-negative childhood patients with de novo acute myeloid leukemia (AML), excluding cases of acute promyelocytic leukemia.

Design And Methods: In order to analyze the role of KIT in CBFL we examined the KIT mutations in 52 adult CBFL, including 15 previously reported patients, and in 49 non-APL childhood AML patients using sensitive detection methods. We correlated our findings with the presence of trisomy 4 and investigated the relationship of the extra chromosome 4 with KIT mutations.

Results: Several kinds of gain-of-function KIT mutations were found in 24 of the 52 (46.1%) adult CBFL cases and 6 of the 49 (12.2%) non-APL childhood AML patients. KIT mutations were detected in 4 of the 8 adult patients and one childhood AML case bearing trisomy of chromosome 4 as either the sole cytogenetic aberration or a karyotypic aberration additional to t(8;21). In three of the trisomy 4 cases we demonstrated that trisomy 4 leads to duplication of the KIT mutated allele.

Interpretation And Conclusions: These results underline that the KIT gene is activated in AML characterized by distinct cytogenetic and molecular genetic patterns and represents the most frequently mutated target in adult CBFL.
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August 2004

Chronic myelogenous leukemia with acquired c-kit activating mutation and transient bone marrow mastocytosis.

Hematol J 2004 ;5(3):273-5

Division of Hematology, Niguarda Hospital, Milan, Italy.

Mutations of the c-kit gene have been reported in myeloproliferative disorders. We describe here a case of Ph+ (b2a2) chronic myelogenous leukemia that, during the course of disease, showed an unusual bone marrow mast-cell infiltration. A mutational screening for the c-kit gene, performed on DNA routinely cryopreserved during the follow-up, evidenced the D816Y-activating mutation as an additional genetic abnormality. Treatment with imatinib mesylate resulted in a substantial decrease of the BCR-ABL/ABL ratio and in the absence of c-kit mutation. It is likely that the superimposed c-kit mutation, in this case, may account for the transient bone marrow mastocytosis.
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http://dx.doi.org/10.1038/sj.thj.6200348DOI Listing
September 2004

High incidence of neutropenia in patients treated with rituximab after autologous stem cell transplantation.

Haematologica 2004 Mar;89(3):361-3

We report a high incidence of neutropenia in patients treated with rituximab prior to and following autologous stem cell transplantation (ASCT). Fourteen patients with follicular or mantle-cell lymphoma were treated with high dose (HD) therapy followed by an in vivo-purged autologous graft.
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March 2004
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