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Identifying and managing CAR T-cell-mediated toxicities: on behalf of an Italian CAR-T multidisciplinary team

Martino, Massimo; Macheda, Sebastiano; Aguglia, Umberto; Arcudi, Luciano; Pucci, Giulia; Martino, Bruno; Altomonte, Maria; Rossetti, Antonio Maria; Cusumano, Giuseppa; Russo, Letteria; Imbalzano, Lucrezia; Stelitano, Caterina; Alati, Caterina; Germano', Jessyca; Labate, Demetrio; Amalfi, Vincenzo; Florenzano, Maria Teresa; Morabito, Antonella; Borzumati, Vittoria; Dattola, Vincenzo; Gattuso, Caterina; Moschella, Antonio; Quattrone, Domenico; Curmaci, Francesco; Franzutti, Claudio; Scappatura, Giuseppe; Rao, Carmelo Massimiliano; Loddo, Viviana; Pontari, Antonella; Pellicano', Maria; Surace, Rosangela; Sanguedolce, Cristina; Naso, Virginia; Ferreri, Anna; Irrera, Giuseppe; Console, Giuseppe; Moscato, Tiziana; Loteta, Barbara; Canale, Filippo Antonio; Trimarchi, Alfonso; Monteleone, Renza; Al Sayyad, Said; Cirrone, Frank; Bruno, Benedetto
INTRODUCTION/UNASSIGNED:Chimeric antigen receptor (CAR)-T-cell therapy is a new treatment for patients with hematologic malignancies in which other therapies have failed. AREAS COVERED/UNASSIGNED:The review provides an overview for recognizing and managing the most acute toxicities related to CAR-T cells. EXPERT OPINION/UNASSIGNED:The development of immune-mediated toxicities is a common challenge of CAR-T therapy. The mechanism that determines this toxicity is still unclear, although an unfavorable tumor microenvironment and a pro-inflammatory state put patients at risk. The monitoring, diagnosis, and treatment of post-CAR-T toxicities must be determined and based on international guidelines and internal clinical practice. It is urgent to identify biomarkers that can identify patients at greater risk of developing complications. The adoption of consistent grading criteria is necessary to improve toxicity management strategies continually. The first-line therapy consists of supportive care and treatment with tocilizumab or corticosteroids. An early start of cytokine blockade therapies could mitigate toxicity. The plan will include cytokine release prophylaxis, a risk-adapted treatment, prevention of on-target/off-tumor effect, and a switch on/off CAR-T approach.
PMID: 34463175
ISSN: 1744-7682
CID: 5011682

Improving prognostic assignment in older adults with multiple myeloma using acquired genetic features, clonal hemopoiesis and telomere length

Boyle, Eileen M; Williams, Louis; Blaney, Patrick; Ashby, Cody; Bauer, Michael; Walker, Brian A; Ghamlouch, Hussein; Choi, Jinyoung; Perrial, Emeline; Wang, Yubao; Caro, Jessica; Stoeckle, James H; Arbini, Arnaldo; Kaminetzky, David; Braunstein, Marc; Bruno, Benedetto; Razzo, Beatrice; Diamond, Benjamin; Maclachlan, Kylee; Maura, Francesco; Landgren, Ola; Litke, Rachel; Fegan, Christopher D; Keats, Johnathan; Auclair, Daniel; Davies, Faith E; Morgan, Gareth J
PMID: 34148053
ISSN: 1476-5551
CID: 4918002

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades

Cooper, Jason P; Storer, Barry E; Granot, Noa; Gyurkocza, Boglark; Sorror, Mohamed L; Chauncey, Thomas R; Shizuru, Judith; Franke, Georg-Nikolaus; Maris, Michael B; Boyer, Michael; Bruno, Benedetto; Sahebi, Firoozeh; Langston, Amelia A; Hari, Parameswaran; Agura, Edward D; Petersen, Søren Lykke; Maziarz, Richard T; Bethge, Wolfgang; Asch, Julie; Gutman, Jonathan A; Olesen, Gitte; Yeager, Andrew M; Hübel, Kai; Hogan, William J; Maloney, David G; Mielcarek, Marco; Martin, Paul J; Flowers, Mary E D; Georges, George E; Woolfrey, Ann E; Deeg, H Joachim; Scott, Bart L; McDonald, George B; Storb, Rainer; Sandmaier, Brenda M
We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.
PMID: 32499241
ISSN: 1592-8721
CID: 4600702

Comparison between Primary Prophylaxis and Pre-Emptive Therapy for Citomegalovirus after Hematopoietic Stem-Cell Transplantation [Meeting Abstract]

Faraci, D G; Lia, G; Butera, S; Cerrano, M; Ciccone, G; Castiglione, A; Zanotto, E; Cavallo, R; Dellacasa, C M; Busca, A; Bruno, B; Giaccone, L
Background: Cytomegalovirus (CMV) infection is one of the most common complication after allogeneic hematopoietic stem-cell transplantation (HSCT) and remains associated with significant morbidity. Letermovir is an antiviral drug approved for prevention of CMV infection in seropositive HSCT recipients (R+), inhibiting the CMVterminase complex and thus acting in a different way than other standard approved antiviral drugs. In Italy, Letermovir has been available since 2019.
Method(s):We conducted a single-center cohort observational retrospective study, analysing 107 patients at highest risk of CMV infection according to recipient positive/donor negative (R+/D-) CMV serostatus, transplanted between January 2015 and April 2020 at our Center. Patients unable to take oral therapy at day +7 from HSCT or assuming drugs for concomitant clinical conditions bringing about major pharmacokinetic interaction were excluded. Nineteen of them received primary Letermovir prophylaxis (starting within day +28, up to day +100), whereas 74 patients did not (historical control group). In both groups, patients underwent pre-emptive therapy (PET) strategy according to twice weekly monitoring of blood CMV-DNA levels through PCR analysis. We compared cumulative incidence of clinically significant CMV infection (CS-CMVi), defined as CMV reactivation (CMV-DNAemia leading to PET) or CMV tissue invasive disease at day +100 and day +200. Patients who discontinued drug assumption before day +100 or had missing endpoint data at day +100 were imputed as having a primary endpoint event, according to the drug registration trial. Survival functions were estimated by the Kaplan-Meier method and compared using log-rank test.
Result(s): Letermovir prophylaxis started at a median of 11 days (range, 5-27) after HSCT. The median duration of Letermovir administration was 89 days (range, 40-113). The only early stop was due to patient death, not related to CMV or drug toxicity. None of the 19 patients in Letermovir group experienced CMV reactivation at day +100, compared to 51 in the historical group. Of note, 83% of patients receiving prophylaxes developed graft-versus-host disease (GVHD) before CS-CMVi. Overall, at day +100 CS-CMVi occurred in 5.3% and 71.6% of patients in Letermovir group and historical control group, respectively (p <.001). A trend toward lower CS-CMVi was also observed in the Letermovir group at day +200 (63,2% vs 81,1%, p=.0956). Median time to CSCMVi was +147 and +44 days after HSCT in Letermovir group and historical control group, respectively. One patient in Letermovir group and 4 in the historical one developed CMV tissue invasive disease. No difference in mortality was observed between the two groups, even if a longer follow-up period is needed.
Conclusion(s): Our experience demonstrated the efficacy of Letermovir in a real-world setting for CMV prevention in the first 14 weeks after HSCT. Further studies are needed to establish the cost-effectiveness of Letermovir primary prophylaxis compared to PET approach, and the role of extension of Letermovir beyond day +100 in high-risk subgroup
EMBASE:635560932
ISSN: 1476-5365
CID: 4992212

Chromothripsis as a pathogenic driver of multiple myeloma

Maura, Francesco; Boyle, Eileen M; Rustad, Even H; Ashby, Cody; Kaminetzky, David; Bruno, Benedetto; Braunstein, Marc; Bauer, Michael; Blaney, Patrick; Wang, Yubao; Ghamlouch, Hussein; Williams, Louis; Stoeckle, James; Davies, Faith E; Walker, Brian A; Maclachlan, Kylee; Diamond, Ben; Landgren, Ola; Morgan, Gareth J
Analysis of the genetic basis for multiple myeloma (MM) has informed many of our current concepts of the biology that underlies disease initiation and progression. Studying these events in further detail is predicted to deliver important insights into its pathogenesis, prognosis and treatment. Information from whole genome sequencing of structural variation is revealing the role of these events as drivers of MM. In particular, we discuss how the insights we have gained from studying chromothripsis suggest that it can be used to provide information on disease initiation and that, as a consequence, it can be used for the clinical classification of myeloma precursor diseases allowing for early intervention and prognostic determination. For newly diagnosed MM, the integration of information on the presence of chromothripsis has the potential to significantly enhance current risk prediction strategies and to better characterize patients with high-risk disease biology. In this article we summarize the genetic basis for MM and the role played by chromothripsis as a critical pathogenic factor active at early disease phases.
PMID: 33958284
ISSN: 1096-3634
CID: 4866742

COVID-19 in a post-transplant heart recipient who developed aggressive lymphoma: A biphasic course during rituximab treatment

Clerico, Michele; Dogliotti, Irene; Calcagno, Andrea; Grimaldi, Daniele; Leone, Sarah; Ragaini, Simone; Boffini, Massimo; Caracciolo, Daniele; Ferrero, Simone; Barbero, Cristina; Zanotto, Elisa; Stroffolini, Giacomo; Cavallo, Rossana; Rinaldi, Mauro; Bruno, Benedetto; Cavallo, Federica
SCOPUS:85109685911
ISSN: 2572-9241
CID: 4963702

The outcome of two or more HLA loci mismatched unrelated donor hematopoietic cell transplantation for acute leukemia: an ALWP of the EBMT study

Nagler, Arnon; Dholaria, Bhagirathbhai; Labopin, Myriam; Bruno, Benedetto; Rambaldi, Alessandro; Pioltelli, Pietro; La Nasa, Giorgio; Socié, Gerard; Mielke, Stephan; Ruggeri, Marco; Saccardi, Riccardo; Franke, Georg-Nikolaus; Finke, Jürgen; Savani, Bipin N; Ruggeri, Annalisa; Mohty, Mohamad
A mismatched unrelated (MMUD) donor represents an alternative therapeutic option for patients who need allogeneic hematopoietic cell transplantation (allo-HCT) and do not have a human leukocyte antigen (HLA) matched donor. We studied outcomes of patients with acute leukemia transplanted from ≥2 HLA allele MMUD. The study population consisted of 465 patients. The median follow-up period was 63 and 75 months in the AML and ALL groups, respectively. The incidence of grade II-IV and grade III-IV acute (a) graft-versus-host disease (GVHD) during the first 100 days was 37% and 16%, respectively. Total and extensive chronic (c) GVHD rates at 2 years were 38% and 17%, respectively. In the entire population, the 5-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival and refined GVHD-free, relapse-free survival (GRFS) was 33%, 31%, 37%, 41%, and 27%, respectively. In the multivariate analysis, HLA-DR mismatch was a poor prognostic factor, giving a significantly higher NRM [hazard ratio (HR), 1.67, p = 0.02]; poorer LFS (HR, 1.42, p = 0.03); OS (HR, 1.46, p = 0.03) and higher aGVHD grade II-IV (HR, 1.46, p = 0.05). In this study, allo-HCT from ≤6/8 HLA allele MMUD in acute leukemia patients resulted in acceptable LFS and refined GRFS. HLA-DR mismatch was a poor prognostic factor.
PMID: 32561816
ISSN: 1476-5365
CID: 4600722

Biomarkers for Early Complications of Endothelial Origin After Allogeneic Hematopoietic Stem Cell Transplantation: Do They Have a Potential Clinical Role?

Lia, Giuseppe; Giaccone, Luisa; Leone, Sarah; Bruno, Benedetto
Endothelial cell (EC) dysfunction causes a number of early and life-threatening post hematopoietic stem cell transplant (HCT) complications that result in a rapid clinical decline. The main early complications are graft-vs.-host disease (GVHD), transplant associated thrombotic microangiopathy (TA-TMA), and sinusoidal obstruction syndrome (SOS). Post-HCT endothelial dysfunction occurs as a result of chemotherapy, infections, and allogeneic reactivity. Despite major advances in transplant immunology and improvements in supportive care medicine, these complications represent a major obstacle for successful HCT. In recent years, different biomarkers have been investigated for early detection of post-transplant endothelial cell dysfunction, but few have been validated. In this review we will define GVHD, TA-TMA and SOS, summarize the current data available in HCT biomarker research and identify promising biomarkers for detection and diagnosis of early HCT complications.
PMCID:8170404
PMID: 34093530
ISSN: 1664-3224
CID: 4905992

Biomarkers for acute and chronic graft versus host disease: state of the art

Giaccone, Luisa; Faraci, Danilo Giuseppe; Butera, Sara; Lia, Giuseppe; Di Vito, Clara; Gabrielli, Giulia; Cerrano, Marco; Mariotti, Jacopo; Dellacasa, Chiara; Felicetti, Francesco; Brignardello, Enrico; Mavilio, Domenico; Bruno, Benedetto
INTRODUCTION/BACKGROUND:Despite significant advances in treatment and prevention, graft-versus-host disease (GVHD) still represents the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Thus, considerable research efforts have been made to find and validate reliable biomarkers for diagnosis, prognosis and risk stratification of GVHD. AREAS COVERED/UNASSIGNED:In this review the most recent evidences on different types of biomarkers studied for GVHD, such as genetic, plasmatic, cellular markers and those associated with microbiome, were summarized. A comprehensive search of peer-review literature was performed in PubMed including meta-analysis, preclinical and clinical trials, using the terms: cellular and plasma biomarkers, graft-versus-host disease, cytokines, and allogeneic hematopoietic stem cell transplantation. EXPERT OPINION/UNASSIGNED:In the near future, several validated biomarkers will be available to help clinicians in the diagnosis of GVHD, the identification of patients at high risk of GVHD development and in patients' stratification according to its severity. Then, immunosuppressive treatment could be tailored on each patient's real needs. However, more efforts are needed to achieve this goal. Although most of the proposed biomarkers currently lack validation with large scale clinical data, their study led to improved knowledge of the biological basis of GVHD, and ultimately to implementation of GHVD treatment.
PMID: 33297779
ISSN: 1747-4094
CID: 4727612

Response assessment to venetoclax in relapsed/refractory chronic lymphocytic leukemia by ultrasonography [Letter]

Benedetti, Edoardo; Baratè, Claudia; Bruno, Benedetto; Bramanti, Emilia; Ghia, Paolo; Scarfò, Lydia; Morganti, Riccardo; Ricchiuto, Vittorio; Galimberti, Sara
PMID: 33316660
ISSN: 1873-5835
CID: 4727532