Publications by authors named "Luisa Giaccone"

59 Publications

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

Evolving Therapeutic Approaches for Older Patients with Acute Myeloid Leukemia in 2021.

Cancers (Basel) 2021 Oct 11;13(20). Epub 2021 Oct 11.

Department of Oncology, Division of Hematology, Presidio Molinette, AOU Città della Salute e della Scienza di Torino, 10126 Turin, Italy.

Acute myeloid leukemia (AML) in older patients is characterized by unfavorable prognosis due to adverse disease features and a high rate of treatment-related complications. Classical therapeutic options range from intensive chemotherapy in fit patients, potentially followed by allogeneic hematopoietic cell transplantation (allo-HCT), to hypomethylating agents or palliative care alone for unfit/frail ones. In the era of precision medicine, the treatment paradigm of AML is rapidly changing. On the one hand, a plethora of new targeted drugs with good tolerability profiles are becoming available, offering the possibility to achieve a prolonged remission to many patients not otherwise eligible for more intensive therapies. On the other hand, better tools to assess patients' fitness and improvements in the selection and management of those undergoing allo-HCT will hopefully reduce treatment-related mortality and complications. Importantly, a detailed genetic characterization of AML has become of paramount importance to choose the best therapeutic option in both intensively treated and unfit patients. Finally, improving supportive care and quality of life is of major importance in this age group, especially for the minority of patients that are still candidates for palliative care because of very poor clinical conditions or unwillingness to receive active treatments. In the present review, we discuss the evolving approaches in the treatment of older AML patients, which is becoming increasingly challenging following the advent of new effective drugs for a very heterogeneous and complex population.
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http://dx.doi.org/10.3390/cancers13205075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534216PMC
October 2021

Letermovir Prophylaxis for Cytomegalovirus Infection in Allogeneic Stem Cell Transplantation: A Real-World Experience.

Front Oncol 2021 6;11:740079. Epub 2021 Sep 6.

UOC Ematologia con Trapianto CSE, AORN "Antonio Cardarelli", Napoli, Italy.

Despite effective treatments, cytomegalovirus (CMV) continues to have a significant impact on morbidity and mortality in allogeneic stem cell transplant (allo-SCT) recipients. This multicenter, retrospective, cohort study aimed to evaluate the reproducibility of the safety and efficacy of commercially available letermovir for CMV prophylaxis in a real-world setting. Endpoints were rates of clinically significant CMV infection (CSCI), defined as CMV disease or CMV viremia reactivation within day +100-+168. 204 adult CMV-seropositive allo-SCT recipients from 17 Italian centres (median age 52 years) were treated with LET 240 mg/day between day 0 and day +28. Overall, 28.9% of patients underwent a haploidentical, 32.4% a matched related, and 27.5% a matched unrelated donor (MUD) transplant. 65.7% were considered at high risk of CSCI and 65.2% had a CMV seropositive donor. Low to mild severe adverse events were observed in 40.7% of patients during treatment [gastrointestinal toxicity (36.3%) and skin rash (10.3%)]. Cumulative incidence of CSCI at day +100 and day +168 was 5.4% and 18.1%, respectively, whereas the Kaplan-Meier event rate was 5.8% (95% CI: 2.4-9.1) and 23.3% (95% CI: 16.3-29.7), respectively. Overall mortality was 6.4% at day +100 and 7.3% at day +168. This real-world experience confirms the efficacy and safety of CMV.
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http://dx.doi.org/10.3389/fonc.2021.740079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489185PMC
September 2021

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

Front Immunol 2021 19;12:641427. Epub 2021 May 19.

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

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-.-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.
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http://dx.doi.org/10.3389/fimmu.2021.641427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170404PMC
September 2021

Impact of anti-thymocyte globulin dose for graft-versus-host disease prophylaxis in allogeneic hematopoietic cell transplantation from matched unrelated donors: a multicenter experience.

Ann Hematol 2021 Jul 4;100(7):1837-1847. Epub 2021 May 4.

Department of Oncology, SSD Trapianto Allogenico di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Via Genova 3, 10126, Torino, Italy.

Despite the widespread use of rabbit anti-thymocyte globulin (ATG) to prevent acute and chronic graft-versus-host disease (aGVHD, cGVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), convincing evidence about an optimal dose is lacking. We retrospectively evaluated the clinical impact of two different ATG doses (5 vs 6-7.5 mg/kg) in 395 adult patients undergoing HSCT from matched unrelated donors (MUD) at 3 Italian centers. Cumulative incidence of aGVHD and moderate-severe cGVHD did not differ in the 2 groups. We observed a trend toward prolonged overall survival (OS) and disease-free survival (DFS) with lower ATG dose (5-year OS and DFS 56.6% vs. 46.3%, p=0.052, and 46.8% vs. 38.6%, p=0.051, respectively) and no differences in relapse incidence and non-relapse mortality. However, a significantly increased infection-related mortality (IRM) was observed in patients who received a higher ATG dose (16.7% vs. 8.8% in the lower ATG group, p=0.019). Besides, graft and relapse-free survival (GRFS) was superior in the lower ATG group (5-year GRFS 43.1% vs. 32.4%, p=0.014). The negative impact of higher ATG dose on IRM and GRFS was confirmed by multivariate analysis. Our results suggest that ATG doses higher than 5 mg/kg are not required for MUD allo-HCT and seem associated with worse outcomes.
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http://dx.doi.org/10.1007/s00277-021-04521-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195753PMC
July 2021

Impact of Allogeneic Stem Cell Transplantation on Testicular and Sexual Function.

Transplant Cell Ther 2021 02 14;27(2):182.e1-182.e8. Epub 2020 Dec 14.

Transition Unit for Childhood Cancer Survivors, Città della Salute e della Scienza Hospital, Turin, Italy. Electronic address:

High-dose chemotherapy and radiotherapy, administered as a conditioning regimen before stem cell transplantation, are known to negatively impact testicular function and sexuality. However, to date, only a few studies have simultaneously analyzed the real prevalence of these complications in this clinical setting. Therefore, this study aimed to assess the prevalence of testicular dysfunction and sexual impairment in a cohort of males who underwent allogeneic stem cell transplantation in adulthood. This observational, cross-sectional, single-center study consecutively enrolled 105 subjects on outpatient follow-up. Testicular function and sexuality were evaluated through a hormonal profile (testosterone, follicle-stimulating hormone, luteinizing hormone, and inhibin B) and the IIEF-15 questionnaire, respectively. We found a higher prevalence of hypogonadism (21%), impaired spermatogenesis (87%), and erectile dysfunction (72%) compared with the general population. Chronic graft-versus-host disease, especially of moderate/severe grade, was associated with an increased risk of developing erectile dysfunction (odds ratio, 6.338). Moreover, a high proportion of patients presented with alterations in all domains of sexual function, even after complete clinical remission of hematologic disease. Our data confirm both testicular function and sexuality alterations as frequent complications after allogeneic stem cell transplantation. A multidisciplinary approach is advisable for early diagnosis and adequate treatment.
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http://dx.doi.org/10.1016/j.jtct.2020.10.020DOI Listing
February 2021

Long-term Outcomes with Nonmyeloablative HLA-Identical Related Hematopoietic Cell Transplantation Using Tacrolimus and Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis.

Transplant Cell Ther 2021 02 11;27(2):163.e1-163.e7. Epub 2020 Dec 11.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, Washington.

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) from HLA-identical related donors using cyclosporine (CSP) and mycophenolate mofetil (MMF) for postgrafting immunosuppression is effective therapy for hematologic cancers. However, graft-versus-host-disease (GVHD) remains a major cause of morbidity and mortality. Pilot data suggested lower acute GVHD incidence with tacrolimus/MMF compared to historical experience using CSP/MMF after nonmyeloablative HCT. In a phase II multicenter trial, we evaluated the effect of tacrolimus/MMF for GVHD prophylaxis after HLA-identical related donor peripheral blood HCT in patients with hematologic malignancies (n = 150) using conditioning with 2 Gy total body irradiation (TBI) for patients with a preceding (within 6 months) planned autologous HCT (n = 50) or combined with 90 mg/m fludarabine for those without recent autologous HCT (n = 100). Oral tacrolimus was given from days -3 to 56 (tapered by day +180 if no GVHD). Oral MMF was given from days 0 to 27. Patient median age was 57 (range, 20 to 74) years. The cumulative incidences (CI) of day 100 grade II to IV and III to IV acute GVHD were 27% and 4%, respectively. With median follow-up of 10.3 (range, 3.1 to 14.5) years, the 5-year CI of chronic extensive GVHD was 48%. One-year and 5-year estimates of nonrelapse mortality, relapse/progression, survival, and progression-free survival were 9% and 13%, 35% and 50%, 73% and 53%, and 56% and 37%, respectively. GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute GVHD and compared favorably with results from a concurrent trial using CSP/MMF. A randomized phase III trial to investigate tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT is warranted.
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http://dx.doi.org/10.1016/j.jtct.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035484PMC
February 2021

European Myeloma Network perspective on CAR T-Cell therapies for multiple myeloma.

Haematologica 2021 08 1;106(8):2054-2065. Epub 2021 Aug 1.

Department of Molecular Biotechnology and Health Sciences, University of Torino and Department of Oncology, Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino.

Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.
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http://dx.doi.org/10.3324/haematol.2020.276402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327729PMC
August 2021

CMV retinitis in a stem cell transplant recipient treated with foscarnet intravitreal injection and CMV specific immunoglobulins.

Ther Adv Hematol 2020 10;11:2040620720975651. Epub 2020 Dec 10.

Stem Cell Transplant Center, AOU Citta' della Salute e della Scienza, Corso Bramante 88, Turin, 10126, Italy.

Cytomegalovirus (CMV) retinitis (CMVR) has been reported rarely in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In addition, little is known about strategies for ophthalmic surveillance and adequate antiviral treatment of CMVR. A case of CMVR in an allogeneic HSCT recipient is described, including clinical signs and therapy. An adult patient received HSCT from a matched unrelated donor for treatment of a Burkitt lymphoma. Donor and recipients were both CMV positive. Starting on day +40, the patient presented multiple CMV reactivation, treated with valganciclovir, foscarnet and a combination of both. On day +160, the patient started complaining of conjunctival hyperaemia and a decrease in visual acuity. Fundoscopy revealed retinal lesions consistent with CMVR, although whole blood CMV DNAemia was negative. Aqueous humor biopsy showed the presence of CMV infection (CMV DNA 230400 UI/ml). CMVR was treated with foscarnet (180 mg i.v. and 1.2 mg intravitreal injection) combined with anti CMV immunoglobulin at 0.5 ml/kg every 2 weeks. After 4 weeks of systemic therapy, 20 weekly doses of intravitreal foscarnet and six cycles of immunoglobulins, a significant improvement of visual acuity was observed. The treatment was well tolerated with no side effect. In conclusion, our case suggests that systemic and local antiviral treatment combined with CMV-specific-IVIG, may reduce CMV load in the eye of patients with CMVR, leading to a consistent improvement of visual acuity. Systematic ophthalmologic examination should be recommended in HSCT recipients with multiple CMV reactivations and high peak CMV DNA levels.
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http://dx.doi.org/10.1177/2040620720975651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734499PMC
December 2020

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

Expert Rev Hematol 2021 01 24;14(1):79-96. Epub 2020 Dec 24.

Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.

Introduction: 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: 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: 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 to 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.
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http://dx.doi.org/10.1080/17474086.2021.1860001DOI Listing
January 2021

Rescue treatment with eltrombopag in refractory cytopenias after allogeneic stem cell transplantation.

Ther Adv Hematol 2020 20;11:2040620720961910. Epub 2020 Oct 20.

A.O.U. Città della Salute e della Scienza, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Turin, Italy.

Background: Patients with post-transplant cytopenias due to poor graft function or primary engraftment failure show poor prognosis with a high mortality rate mainly because of graft host disease (GVHD), infection and/or bleeding. Treatment options are scarce and a CD34+ stem cell boost or a second bone marrow transplantation may be required to restore adequate haematopoiesis.

Methods: In the present study patients with primary engraftment failure ( = 1) and refractory poor graft function ( = 11) were treated with eltrombopag in a single centre. The reason for eltrombopag treatment was trilineage cytopenia in six patients, bilineage cytopenia in three patients and single lineage cytopenia in three patients. Eltrombopag was initiated at a median of 214 (range: 120-877) days after haematopoietic stem cell transplantation (HCST) and administered for a median time of 114 (range: 12 days to >490) days. In 8/12 patients eltrombopag was introduced at a dose of 75 mg/day and then increased to 150 mg/day after 1 week; 1 patient was given 50 mg eltrombopag per day, and 3 patients received 75 mg daily.

Results: In 10/12 patients eltrombopag significantly enhanced blood count values and patients became transfusion independent. Once stable haematological response was obtained, treatment was tapered until final discontinuation in 9/10 responding patients. No grade 3 or 4 toxicities were observed. At time of last follow up, 3/12 patients were dead, 2 due to disease relapse, 1 due to GVHD and pneumonia. All patients except one maintained their complete response and remain transfusion independent at a median of 858 (range: 429-1119) days.

Conclusion: These preliminary data confirm that eltrombopag is able to rescue multilineage haematopoiesis in patients with treatment-refractory cytopenias after allogeneic HSCT.
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http://dx.doi.org/10.1177/2040620720961910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594218PMC
October 2020

Impact of donor age and kinship on clinical outcomes after T-cell-replete haploidentical transplantation with PT-Cy.

Blood Adv 2020 08;4(16):3900-3912

Bone Marrow Transplant Unit, Humanitas Clinical and Research Center, Rozzano, Italy.

Donor selection contributes to improve clinical outcomes of T-cell-replete haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-Cy). The impact of donor age and other non-HLA donor characteristics remains a matter of debate. We performed a multicenter retrospective analysis on 990 haplo-SCTs with PT-Cy. By multivariable analysis, after adjusting for donor/recipient kinship, increasing donor age and peripheral blood stem cell graft were associated with a higher risk of grade 2 to 4 acute graft-versus-host-disease (aGVHD), whereas 2-year cumulative incidence of moderate-to-severe chronic GVHD was higher for transplants from female donors into male recipients and after myeloablative conditioning. Increasing donor age was associated with a trend for higher nonrelapse mortality (NRM) (hazard ratio [HR], 1.05; P = .057) but with a significant reduced risk of disease relapse (HR, 0.92; P = .001) and improved progression-free survival (PFS) (HR, 0.97; P = .036). Increasing recipient age was a predictor of worse overall survival (OS). Risk of relapse was higher (HR, 1.39; P < .001) in patients aged ≤40 years receiving a transplant from a parent as compared with a sibling. Moreover, OS and PFS were lower when the donor was the mother rather than the father. Pretransplant active disease status was an invariably independent predictor of worse clinical outcomes, while recipient positive cytomegalovirus serostatus and hematopoietic cell transplant comorbidity index >3 were associated with worse OS and PFS. Our results suggest that younger donors may reduce the incidence of aGVHD and NRM, though at higher risk of relapse. A parent donor, particularly the mother, is not recommended in recipients ≤40 years.
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http://dx.doi.org/10.1182/bloodadvances.2020001620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448598PMC
August 2020

Immunomodulatory and clinical effects of daratumumab in T-cell acute lymphoblastic leukaemia.

Br J Haematol 2020 10 19;191(1):e28-e32. Epub 2020 Jul 19.

Division of Haematology, Department of Oncology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino, Italy.

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http://dx.doi.org/10.1111/bjh.16960DOI Listing
October 2020

Optimal Delivery of Follow-Up Care After Allogeneic Hematopoietic Stem-Cell Transplant: Improving Patient Outcomes with a Multidisciplinary Approach.

J Blood Med 2020 15;11:141-162. Epub 2020 May 15.

Division of Hematology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.

The increasing indications for allogeneic stem-cell transplant in patients with hematologic malignancies and non-malignant diseases combined with improved clinical outcomes have contributed to increase the number of long-term survivors. However, survivors are at increased risk of developing a unique set of complications and late effects, besides graft-versus-host disease and disease relapse. In this setting, the management capacity of a single health-care provider can easily be overwhelmed. Thus, to provide appropriate survivorship care, a multidisciplinary approach for the long-term follow-up is essential. This review aims at summarizing the most relevant information that a health-care provider should know to establish a follow-up care plan, in the light of individual exposures and risk factors, that includes all organ systems and considers the psychological burden of these patients.
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http://dx.doi.org/10.2147/JBM.S206027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237112PMC
May 2020

The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice.

Front Immunol 2020 12;11:888. Epub 2020 May 12.

Department of Oncology/Hematology, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy.

Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products ( CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.
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http://dx.doi.org/10.3389/fimmu.2020.00888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235422PMC
April 2021

Long-term survival of 1338 MM patients treated with tandem autologous vs. autologous-allogeneic transplantation.

Bone Marrow Transplant 2020 09 14;55(9):1810-1816. Epub 2020 Apr 14.

University of Torino, Torino, Italy.

Contrary to tandem autologous transplant (auto-auto), autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers graft-versus-myeloma (GVM) effect but with higher toxicity. Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological randomization) and yielded conflicting results. A pooled analysis of multiple trials with extended follow up provides an opportunity to compare these strategies. We obtained individual patient data from participants of four trials comparing auto-auto vs. auto-allo after induction therapy. There were 899 patients in auto-auto and 439 in auto-allo. Median follow up of survivors was 118.5 months. Median overall survival (OS) was 78.0 months in auto-auto and 98.3 months in auto-allo (HR = 0.84, P = 0.02). OS was 36.4% vs. 44.1% at 10 years (P = 0.01) for auto-auto and auto-allo, respectively. Progression-free survival was also improved in auto-allo (HR = 0.84, P = 0.004). Risk of non-relapse mortality was higher in auto-allo (10 year 8.3% vs. 19.7%, P < 0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P < 0.001). Median post relapse survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR = 0.71, P < 0.001). This supports the existence of durable GVM effect enhancing myeloma control with subsequent therapies.
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http://dx.doi.org/10.1038/s41409-020-0887-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483973PMC
September 2020

Extracellular Vesicles After Allogeneic Hematopoietic Cell Transplantation: Emerging Role in Post-Transplant Complications.

Front Immunol 2020 20;11:422. Epub 2020 Mar 20.

Stem Cell Transplant Program, Department of Oncology, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy.

Extracellular vesicles (EVs) play an important role in the cellular crosstalk by transferring bioactive molecules through biological barriers from a cell to another, thus influencing recipient cell functions and phenotype. Therefore, EVs are increasingly being explored as biomarkers of disease progression or response to therapy and as potential therapeutic agents in different contexts including in hematological malignancies. Recently, an EV role has emerged in allogeneic hematopoietic cell transplantation (allo-HCT) as well. Allogeneic hematopoietic cell transplantation often represents the only curative option in several hematological disorders, but it is associated with potentially life-threatening complications that can have a significant impact on clinical outcomes. The most common complications have been well-established and include graft-versus-host disease and infections. Furthermore, relapse remains an important cause of treatment failure. The aim of this review is to summarize the current knowledge, the potential applications, and clinical relevance of EVs in allo-HCT. Herein, we will mainly focus on the immune-modulating properties of EVs, in particular those derived from mesenchymal stromal cells, as potential therapeutic strategy to improve allo-HCT outcome. Moreover, we will briefly describe the main findings on EVs as biomarkers to monitor graft-versus-host disease onset and tumor relapse.
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http://dx.doi.org/10.3389/fimmu.2020.00422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100658PMC
March 2021

An update on the treatment of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Expert Rev Hematol 2019 11 25;12(11):937-945. Epub 2019 Aug 25.

Department of Oncology, SSCVD Trapianto di Cellule Staminali, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.

: Human Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Standard treatment options have for long been limited to a small number of effective drugs with significant toxicities.: In this manuscript, the authors update a previous review summarizing recent developments in the virology lab and their possible implications for treatment strategies at bedside. In particular, the authors focused on new antiviral drugs already available and under investigation in clinical trials and innovative immunotherapeutic approaches, including adoptive T-cell therapy and vaccines.: Broader knowledge of CMV biology and its relationship with the host immune system is greatly contributing to the development of novel therapeutic approaches. The availability of new drugs, the improved techniques for virological testing and the more accurate patient risk stratification allow to better individualize treatment, limiting toxicity while sparing antiviral effects. The role of immunotherapy is clearly emerging and will further expand our treatment armamentarium.
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http://dx.doi.org/10.1080/17474086.2019.1657399DOI Listing
November 2019

Adoptive immunotherapy with CAR modified T cells in cancer: current landscape and future perspectives.

Front Biosci (Landmark Ed) 2019 06 1;24:1284-1315. Epub 2019 Jun 1.

SSD Trapianto allogenico di cellule staminali, Department of Oncology, A.O.U. Citta della Salute e della Scienza di Torino, via Genova 3, 10126 Torino, Italy.

Cellular therapies are a rapidly evolving approach to treat cancer in the light of their unique mechanism of action that potentially overcomes drug resistance and induces durable remissions. Modalities of adoptive cell therapy include gene-modified T cells expressing novel T cell receptors or chimeric antigen receptors (CAR) that modify the immune system to recognize tumor cells and carry out potent anti-tumor effector functions. CAR T cells have shown very promising clinical results and several trials are being conducted worldwide to establish their role in cancer treatment. Most successful results have been observed in lymphoproliferative disorders with the use of CD19-directed CAR T cells, which led to their commercial approval by FDA. In this review, we provide a comprehensive overview of the current role of CAR T cell therapies in hematological malignancies and solid tumors, their associated toxicities and potential future developments in the armamentarium for cancer treatment.
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http://dx.doi.org/10.2741/4780DOI Listing
June 2019

Haplo-identical allografting with post-transplant cyclophosphamide in high-risk patients.

Ann Hematol 2018 Nov 9;97(11):2205-2215. Epub 2018 Jul 9.

Department of Oncology, SSD Trapianto Allogenico, Presidio Molinette, AOU Città della Salute e della Scienza di Torino, Via Genova 3, 10126, Torino, Italy.

Haplo-identical transplants (Haplo-Tx) are an important alternative for patients with hematological malignancies who lack a HLA-identical donor. Seventy-one T-replete Haplo-Tx were performed in 70 high-risk patients at our center; 22/70 (31%) patients with refractory/relapsed leukemia received sequential salvage therapy (SeqTh) with high-dose chemotherapy followed by Haplo-Tx during the chemotherapy-induced neutropenia. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide (days + 3 and + 4) with tacrolimus and mycophenolic acid. After a median follow-up of 29.2 months, 3-year overall survival (OS) and event-free survival (EFS) were 43.8 and 40.2%, while 3-year cumulative incidences (CIs) of non-relapse mortality (NRM) and relapse (RI) were 27 and 33%. Day 100 and day 400 CI of grade III-IV acute and moderate-severe chronic GVHD were 11 and 15%. Three-year RI was significantly lower in patients in complete remission (CR) versus those not in CR at the time of transplant (21.5 vs. 48%, p = 0.009) and in patients who received PBSC as compared to BM (22 vs. 45%, p = 0.009). In patients treated with SeqTh, 3-year OS was 19%, while 3-year RI and NRM were 52 and 28% at a median follow-up of 50 months. Overall, Haplo-Tx was feasible in heavily pretreated high-risk patients without a suitable HLA-identical donor.
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http://dx.doi.org/10.1007/s00277-018-3433-3DOI Listing
November 2018

Eltrombopag for the Treatment of Refractory Pure RBC Aplasia after Major ABO Incompatible Hematopoietic Stem Cell Transplantation.

Biol Blood Marrow Transplant 2018 08 21;24(8):1765-1770. Epub 2018 Apr 21.

A.O.U. Città della Salute e della Scienza, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Turin, Italy.

Pure RBC aplasia (PRCS) is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many therapeutic options are available to treat this condition, including erythropoietin, rituximab, bortezomib, plasma exchange, immunoadsorption, donor lymphocyte infusion, mesenchymal stem cells, antithymocyte globulin, and high-dose steroids; however, treatment outcomes are often variable and can sometimes lead to disappointing results. In this brief article we report our experience with 2 patients with PRCA after major ABO-incompatible HSCT who were resistant to multiple therapeutic interventions and who eventually benefited from treatment with eltrombopag, a thrombopoietin mimetic approved by the US Food and Drug Administration for the treatment of patients with immune thrombocytopenic purpura or severe aplastic anemia refractory to immunosuppressive agents or not eligible for HSCT. Data from these 2 patients show that eltrombopag was effective in treating erythroid aplasia and transfusion dependence after HSCT in patients who did not benefit from multiple previous treatments. Moreover, eltrombopag was well tolerated, with only a transient thrombocytosis requiring dose adjustment and no evidence of clonal evolution. Based on the positive results obtained in these 2 patients, we suggest that eltrombopag may have a favorable effect on unilineage cytopenias such as PRCA. Further studies in a large proportion of patients are mandatory to confirm these preliminary results.
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http://dx.doi.org/10.1016/j.bbmt.2018.04.022DOI Listing
August 2018

Hematopoietic cell transplantation comorbidity index and risk of developing invasive fungal infections after allografting.

Bone Marrow Transplant 2018 10 13;53(10):1304-1310. Epub 2018 Apr 13.

Department of Oncology, Stem Cell Transplant Center, AOU Città della Salute e della Scienza, Turin, Italy.

We evaluated the potential correlation of the hematopoietic cell transplantation comorbidity index (HCT-CI) with the risk of developing post-transplant invasive fungal infections (IFIs). Between January 2009 and March 2015, 312 consecutive patients who received a first allograft entered the study. Low/intermediate HCT-CI risk score (0-2) was observed in 172/312 (55%), whereas high HCT-CI score (≥3) was seen in 140/312 (45%). Overall, 51/312 (16%) patients experienced IFI, defined as possible in 19 (6%), probable in 27 (9%), and proven in 5 (2%). Cumulative incidence of probable-proven IFI at 1 year was 8.5% with a significant higher incidence in patients with high HCT-CI (12%) vs. those with low-intermediate HCT-CI (5%; p = 0.006). There was a strong trend for a higher incidence of baseline severe pulmonary comorbidity in patients who developed probable-proven IFI (p = 0.051). One-year cumulative incidence of non-relapse mortality was higher in patients with IFI vs. those without, 49 and 16% (p < 0.001). By multivariate analysis, disease status at transplant and high HCT-CI, when combined with acute GVHD, were independently associated with the risk of post-transplant IFI. This study shows that a high HCT-CI predicts the risk of developing IFI and may indicate the need of mold-active antifungal prophylaxis in high-risk patients.
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http://dx.doi.org/10.1038/s41409-018-0161-1DOI Listing
October 2018

Late-Onset Hepatic Veno-Occlusive Disease after Allografting: Report of Two Cases with Atypical Clinical Features Successfully Treated with Defibrotide.

Mediterr J Hematol Infect Dis 2018 1;10(1):e2018001. Epub 2018 Jan 1.

A.O.U. Città della Salute e della Scienza di Torino, Dipartimento di Oncologia, SSD Trapianto allogenico di cellule staminali, Torino, Italy.

Hepatic Veno-Occlusive Disease (VOD) is a potentially severe complication of hematopoietic stem cell transplantation (HSCT). Here we report two patients receiving an allogeneic HSCT who developed late onset VOD with atypical clinical features. The two patients presented with only few risk factors, namely, advanced acute leukemia, a myeloablative busulphan-containing regimen and received grafts from an unrelated donor. The first patient did not experience painful hepatomegaly and weight gain and both patients showed only a mild elevation in total serum bilirubin level. Most importantly, the two patients developed clinical signs beyond day 21 post-HSCT. Hepatic transjugular biopsy confirmed the diagnosis of VOD. Intravenous defibrotide was promptly started leading to a marked clinical improvement. Based on our experience, liver biopsy may represent a useful diagnostic tool when the clinical features of VOD are ambiguous. Early therapeutic intervention with defibrotide represents a crucial issue for the successful outcome of patients with VOD.
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http://dx.doi.org/10.4084/MJHID.2018.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760078PMC
January 2018

From transplant to novel cellular therapies in multiple myeloma: European Myeloma Network guidelines and future perspectives.

Haematologica 2018 02 7;103(2):197-211. Epub 2017 Dec 7.

Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands.

Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival, although an overall survival benefit was not observed in all trials. Moreover, follow up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens such as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant has not been extensively evaluated. In the case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that, in young and fit patients, may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets, and chimeric antigen receptor-T cells. Despite encouraging preliminary results, longer follow up and larger patient numbers are needed before the clinical use of these novel therapies can be widely recommended.
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http://dx.doi.org/10.3324/haematol.2017.174573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792264PMC
February 2018

Restoring Natural Killer Cell Immunity against Multiple Myeloma in the Era of New Drugs.

Front Immunol 2017 7;8:1444. Epub 2017 Nov 7.

Department of Oncology/Hematology, A.O.U. Città della Salute e della Scienza di Torino, Presidio Molinette, Torino, Italy.

Transformed plasma cells in multiple myeloma (MM) are susceptible to natural killer (NK) cell-mediated killing engagement of tumor ligands for NK activating receptors or "missing-self" recognition. Similar to other cancers, MM targets may elude NK cell immunosurveillance by reprogramming tumor microenvironment and editing cell surface antigen repertoire. Along disease continuum, these effects collectively result in a progressive decline of NK cell immunity, a phenomenon increasingly recognized as a critical determinant of MM progression. In recent years, unprecedented efforts in drug development and experimental research have brought about emergence of novel therapeutic interventions with the potential to override MM-induced NK cell immunosuppression. These NK-cell enhancing treatment strategies may be identified in two major groups: (1) immunomodulatory biologics and small molecules, namely, immune checkpoint inhibitors, therapeutic antibodies, lenalidomide, and indoleamine 2,3-dioxygenase inhibitors and (2) NK cell therapy, namely, adoptive transfer of unmanipulated and chimeric antigen receptor-engineered NK cells. Here, we summarize the mechanisms responsible for NK cell functional suppression in the context of cancer and, specifically, myeloma. Subsequently, contemporary strategies potentially able to reverse NK dysfunction in MM are discussed.
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http://dx.doi.org/10.3389/fimmu.2017.01444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682004PMC
November 2017

Long-Term Follow-Up of a Donor versus No-Donor Comparison in Patients with Multiple Myeloma in First Relapse after Failing Autologous Transplantation.

Biol Blood Marrow Transplant 2018 02 12;24(2):406-409. Epub 2017 Oct 12.

Department of Hematology, DAME, University of Udine, Udine, Italy.

We report the long-term clinical outcomes of a retrospective multicenter study that enrolled 169 patients with multiple myeloma (MM) in first relapse after failing autologous stem cell transplantation (SCT). After HLA typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT (allo-SCT), were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. At a median follow-up of 30 months (range, 2-180 months) for all patients and 110 months (range, 38-180 months) for surviving patients, 7-year progression-free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR], 2.495; 95% confidence interval [CI], 1.770-3.517; P < .0001). Seven-year overall survival (OS) was 31% in the donor group and 9% in the no-donor group (HR, 1.835; 95% CI, 1.306-2.577; P < .0001). By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS. The long-term follow-up of this study confirms the significant PFS benefit and provides new evidence of an OS advantage for patients with MM who have a suitable donor and undergo allo-SCT. Allo-SCT should be considered as a treatment option in young relapsed patients with high-risk disease features after first-line treatment.
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http://dx.doi.org/10.1016/j.bbmt.2017.10.014DOI Listing
February 2018

Impact of New Drugs on the Long-Term Follow-Up of Upfront Tandem Autograft-Allograft in Multiple Myeloma.

Biol Blood Marrow Transplant 2018 01 4;24(1):189-193. Epub 2017 Oct 4.

Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy; Department of Oncology, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.

Before the introduction of "new drugs," we designed a trial in which 162 newly diagnosed myeloma patients were biologically randomized to receive either an autologous stem cell transplant (auto-SCT) followed by a nonmyeloablative allogeneic stem cell transplant (allo-SCT) or a double auto-SCT. Fifty-eight patients in the allo-SCT arm and 46 in the double auto-SCT arm completed the assigned treatment. At a median follow-up of 12.3 years from allo-SCT and 12.1 years from second auto-SCT, median overall survival (OS) was 11.4 in the allo-SCT arm and 3.9 years in the auto-SCT -arm (P = .007), whereas event-free survival was 3.6 and 1.5 years (P < .001), respectively. A subset of allo-SCT patients showed persistent molecular remission. Two-year cumulative incidence of chronic graft-versus-host disease was 67.2%. At 5 years, 39% of these patients were alive, disease-free, and off immunosuppression; 36.6% had relapsed and 12.2% were still on immunosuppression. Thirty-three of 58 patients (allo-SCT arm) and 39 of 46 (auto-SCT arm) relapsed at least once and were rescued with new drugs. In the allo-SCT arm, 2 patients in biochemical relapse did not reach clinical criteria for treatment. Overall 28 (90%) were treated with new drugs and 14 (45%) received donor lymphocyte infusions (DLIs). In 28 of 31 patients (90%) DLIs were given with new drugs. Median OS from first relapse was 7.5 years in the allo-SCT arm and 2 years in the auto-SCT arm (P = .01). Patients who received DLI showed significantly longer OS (hazard ratio, .38; P = .042) as compared with auto-SCT patients. This difference was slightly lower when only allo-SCT patients who did not receive DLIs were considered (hazard ratio, .56; P = .154). In summary, long-term disease-free survival and survival outcomes after treating relapse with new drugs with or without DLIs were better in allo-SCT patients.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.017DOI Listing
January 2018

Immuno-oncologic Approaches: CAR-T Cells and Checkpoint Inhibitors.

Clin Lymphoma Myeloma Leuk 2017 08 17;17(8):471-478. Epub 2017 Jun 17.

Department of Molecular Biotechnology and Health Sciences, University of Turin, Struttura Semplice Dipartimentale Allogeneic Stem Cell Transplant, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.

Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti-PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach.
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http://dx.doi.org/10.1016/j.clml.2017.06.014DOI Listing
August 2017
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