Publications by authors named "Andrea Bacigalupo"

260 Publications

Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes.

J Clin Oncol 2021 Feb 4:JCO2001659. Epub 2021 Feb 4.

Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy.

Purpose: Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication.

Methods: We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed.

Results: We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations (, , and ) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within - and -related MDS. MDS with complex karyotype and/or gene abnormalities and MDS with acute leukemia-like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features.

Conclusion: Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.
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http://dx.doi.org/10.1200/JCO.20.01659DOI Listing
February 2021

Coronavirus disease 2019 pandemic and allogeneic hematopoietic stem cell transplantation: a single center reappraisal.

Cytotherapy 2020 Dec 11. Epub 2020 Dec 11.

Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address:

Background: The coronavirus disease 2019 (COVID-19) pandemic has deeply modified the complex logistical process underlying allogeneic hematopoietic stem cell transplant practices.

Aim: In light of these changes, the authors compared data relative to allogeneic transplants carried out from 2018 at their center before (n = 167) and during the pandemic (n = 45).

Methods: The authors examined patient characteristics, donor and graft types, cell doses and main transplant outcomes. Moreover, the authors evaluated the rise of costs attributable to additional COVID-19-related procedures as well as the risk of adverse events these procedures conveyed to grafts or recipients.

Results: Overall, the number of transplants did not decrease during the pandemic, whereas patients at high relapse risk were prioritized. Transplants were mainly from matched unrelated donors, with a significant decrease in haploidentical related donors. Moreover, the use of bone marrow as a graft for haploidentical transplant was almost abandoned. Cryopreservation was introduced for all related and unrelated apheresis products, with a median storage time of 20 days. Notably, transplant outcomes (engraftment, acute graft-versus-host disease and non-relapse mortality) with cryopreserved products were comparable to those with fresh products.

Conclusions: Considering that the emergency situation may persist for months, cryopreserving allogeneic grafts can offer a lifesaving opportunity for patients whose allogeneic transplant cannot be postponed until after the end of the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.jcyt.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732233PMC
December 2020

Second haploidentical stem cell transplantation for primary graft failure.

Bone Marrow Transplant 2020 Dec 16. Epub 2020 Dec 16.

IRCCS Policlinico San Martino IST, Genova, Italy.

We report the outcome of 19 patients who experienced primary graft failure (PrGF) after a haploidentical (HAPLO), unmanipulated bone marrow transplant. The median age of patients was 52 years; the conditioning regimen of the first HAPLO transplant was either full dose total body irradiation (TBI) or fludarabine, busulfan, and thiotepa (TBF); PTCY was given to all patients together with cyclosporine and mycophenolate. All 19 patients with PrGF received a second HAPLO graft, at a median interval of 42 days (34-82) after HSCT, using the Baltimore protocol and G-CSF mobilized PB from the same (n = 13) or another HAPLO family donor (n = 6). GvHD prophylaxis was again PTCY-based; 14/19 patients had trilineage recovery (74%) and 1-year survival was 66%. Engraftment at second HAPLO was seen in 7/8 patient with, and in 5/7 patients without donor-specific antibodies (DSA). In a multivariate logistic regression analysis on the original group of 503 patients, there was a trend for a reduced dose of busulfan, to increase the risk of PrGF (p = 0.1). In conclusion, patients with PrGF following a HAPLO transplant, can be rescued with a second early HAPLO transplant, using the same or a different donor.
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http://dx.doi.org/10.1038/s41409-020-01183-9DOI Listing
December 2020

Haploidentical related donor compared to HLA-identical donor transplantation for chemosensitive Hodgkin lymphoma patients.

BMC Cancer 2020 Nov 24;20(1):1140. Epub 2020 Nov 24.

Hematology Department, Transplantation and Cellular Therapy Unit, Institut Paoli-Calmettes, Marseille, France.

Background: Allogeneic stem cell transplantation from haploidentical donor using an unmanipulated graft and post-transplantation cyclophosphamide (PT-Cy) is growing. Haploidentical transplantation with PT-Cy showed a major activity in Hodgkin lymphoma (HL), reducing the relapse incidence. The most important predictive factor of survival and toxicity was disease status before transplantation, which was better in patients with well controlled disease.

Methods: We included 198 HL in complete (CR) or partial remission (PR) before transplantation. Sixty-five patients were transplanted from haploidentical donor and 133 from a HLA identical donor (both sibling and unrelated donors). Survival analysis was defined according to the EBMT criteria. Survival curves were generated by using Kaplan-Meier method and differences between groups were compared by the log rank test or by the log rank test for trend when appropriated.

Results: The PFS, OS, and RI were significantly better in patients in CR compared to PR (55% vs 29% p = 0.001, 74% vs 55% p = 0.03, 27% vs 55% p <  0.001, respectively). The 2-year PFS was significantly better for HAPLO than HLA-id (63% vs 37%, p = 0.03), without difference in OS. The 1-year NRM was not different. The 2-year relapse incidence (RI) was lower in the HAPLO group (24% vs 44%, p = 0.008). Patients in CR receiving haplo HSCT showed higher 2-year PFS and lower 2-year RI than those allografted with HLA-id donor (75% vs 47%, p <  0.001 and 11% vs 34%, p < 0.001, respectively). In multivariate analysis, donor type and disease status before transplantation were independent predictors of PFS as well as they predict the risk of relapse. Disease status at transplantation and age were independently associated to OS.

Conclusions: Nonetheless this is a retrospective study, limiting the wide applicability of results, data from this analysis suggest that HLA mismatch can induce a strong graft versus lymphoma effect leading to an enhanced PFS.
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http://dx.doi.org/10.1186/s12885-020-07602-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685618PMC
November 2020

Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia of the Elderly: Review of Literature and New Perspectives.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020081. Epub 2020 Nov 1.

Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Roma.

Acute myeloid leukemia (AML) in patients over the age of 60 carries a poor prognosis, mainly due to unsatisfactory control of leukemia with chemotherapy alone. Allogeneic hemopoietic stem cell transplantation (HSCT) would provide significant anti-leukemic effect but is associated with morbidity and mortality, especially in older patients with comorbidities. Reduced-intensity conditioning (RIC) and non-myeloablative (NMA) conditioning regimens have been designed and have led to improved outcomes in this older patient population. New targeted agents, such as Flt3 inhibitors, are currently being used to improve the control of AML further and may be incorporated in a transplant approach. The increasing knowledge of AML in the elderly is currently being associated with a multidimensional approach to identify eligibility and design tailored transplant platforms.
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http://dx.doi.org/10.4084/MJHID.2020.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643805PMC
November 2020

Efficacy of ibrutinib in late relapse chronic lymphocytic leukemia after allogeneic hematopoietic stem cell transplantation.

Hematol Oncol 2020 Nov 5. Epub 2020 Nov 5.

Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.

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http://dx.doi.org/10.1002/hon.2826DOI Listing
November 2020

Full donor chimerism after allogeneic hematopoietic stem cells transplant for myelofibrosis: The role of the conditioning regimen.

Am J Hematol 2021 02 30;96(2):234-240. Epub 2020 Nov 30.

UO Ematologia e Trapianto di Midollo Osseo, IRCCS Ospedale Policlinico San Martino Genova, Genova, Italy.

The aim of this retrospective study was to assess the rate of full donor chimerism (F-DC) in patients with myelofibrosis, prepared for an allogeneic stem cell transplant, with one or two alkylating agents. We analyzed 120 patients with myelofibrosis, for whom chimerism data were available on day +30. There were two groups: 42 patients were conditioned with one alkylating agent (ONE-ALK), either thiotepa or busulfan or melphalan, in combination with fludarabine, whereas 78 patients were prepared with two alkylating agents, thiotepa busulfan and fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years), were less frequently splenectomized pre-HSCT (31% vs 59%), had more frequently intermediate-2/high DIPSS scores (90% vs 74%), were grafted more frequently from alternative donors (83% vs 33%) and received more frequently ruxolitinib pre-HSCT (26% vs 7%). The proportion of patients with F-DC on day +30, in the TBF vs the ONE-ALK group, was respectively 87% vs 45% (P < .001). The 5-year cumulative incidence of relapse was 9% in the TBF group, vs 43% for the ONE-ALK group (P < .001). The 5-year actuarial disease-free survival was 63% for TBF and 38% for the ONE-ALK group (P = .004). In conclusion, early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis, undergoing an allogeneic HSCT. The combination of two alkylating agents in the conditioning regimen, provides a higher chance of achieving full donor chimerism on day+30, and thus a higher chance of long term disease free survival.
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http://dx.doi.org/10.1002/ajh.26042DOI Listing
February 2021

Reducing infectious complications after allogeneic stem cell transplant.

Expert Rev Hematol 2020 11 3;13(11):1235-1251. Epub 2020 Nov 3.

Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli- IRCCS , Rome, Italy.

Introduction: Infections remain a significant problem, in patients undergoing an allogeneic hematopoietic stem-cell transplant (HSCT) and efforts have been made over the years, to reduce the incidence, morbidity and mortality of infectious complications.

Areas Covered: This manuscript is focused on the epidemiology, risk factors and prevention of infections after allogeneic HSCT. A systematic literature review was performed using the PubMed database, between November 2019 and January 2020, with the following MeSH terms: stem-cell transplantation, infection, fungal, bacterial, viral, prophylaxis, vaccines, prevention. The authors reviewed all the publications, and following a common revision, a summary report was made and results were divided in three sections: bacterial, fungal and viral infections.

Expert Opinion: Different infections occur in the early, intermediate and late post-transplant period, due to distinct risk factors. Improved diagnostic techniques, pre-emtive therapy and better prophylaxis of immunologic complications, have reduced the morbidity and mortality of infections. The role of the gut microbiota is under careful scrutiny and may further help us to identify high-risk patients.
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http://dx.doi.org/10.1080/17474086.2020.1831382DOI Listing
November 2020

Impact of Educational Interventions on Psychological Distress During Allogeneic Hematopoietic Stem Cell Transplantation: A Randomised Study.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020067. Epub 2020 Sep 1.

Istituto di Sanità pubblica, Università Cattolica del Sacro Cuore, Roma, Italy.

Background: Physical and psychological factors, like wrong attitudes and behaviours, can negatively influence the health outcomes of the patients receiving allogeneic hematopoietic stem cell transplantation (AHSCT). Educational interventions aiming to improve knowledge on side effects, risks, complications and preventive behaviour can reduce psychological distress, and improve quality of life (QoL). We aimed to compare a standard approach with therapeutic patient education (TPE) to analyse the impact on AHSCT patients' QoL, psychological distress and knowledge of AHSCT side effects, risks complications and preventive behaviour.

Material And Methods: A prospective interventional study was conducted analysing data of 36 patients who received one of two different educational approaches, which were a standard approach (not-exposed) or TPE (exposed).

Results: In the exposed group QoL improved 14 days after transplantation (42.2 vs 25.6; p<0.03) and at time of discharge (36.6 vs 54.4; p<0.005). Anxiety and depression were better controlled in the exposed group, both at hospitalisation and discharge (anxiety: 48.1 vs 53.2; 46.4 vs 51.6. p<0.04; depression: 49 vs 55.3; 48 vs 54.3, p<0.03). Knowledge of AHSCT risks and complications improved in exposed patients, both at admission (10.1/15 vs 8/15 correct answers; p<0.01) and discharge (10.7/15 vs 8.8/15 correct answer; p<0.03).

Conclusions: The TPE for AHSCT patients improved knowledge, reduced anxiety and depression, which consequently increasing QoL. Therefore, we recommend our approach to further engage patients in the treatment plan, which should specifically take place prior to AHSCT initiation.
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http://dx.doi.org/10.4084/MJHID.2020.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485479PMC
September 2020

Days Alive Outside Hospital and Readmissions in Patients Undergoing Allogeneic Transplants from Identical Siblings or Alternative Donors.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020055. Epub 2020 Sep 1.

Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma.

We have studied the number of days alive outside the Hospital (DAOH) and the number of readmissions within the first 100 days after transplant in 185 patients who received an allogeneic hemopoietic stem cell transplant (HSCT). The donors were matched siblings (SIB; n=61), or alternative donors (ALT; n=124). The median number of DAOH for SIB transplants (78 days, range 21-84) was significantly greater than DAOH for ALT donor grafts (73 days, range 2-87) (p=0.0003). Other positive predictors of DAOH were the use of reduced-intensity regimens (p=0.01), grade 0-I acute graft versus host disease (GvHD) (p=0.0006), and a comorbidity index equal or less than two (p=0.04). Fifty-one patients required readmission (22%), which was predicted by grade II-IV acute GvHD (p=0.009), higher comorbidity index (p=0.06), and ALT donors as compared to SIBS (p=0.08). The CI of readmission was 18% (95%CI 10-31) for SIB and 30% (95%CI 23-39) for ALT donor grafts. The non relapse mortality (NRM) for patients re-admitted was 25% (95%CI 15-43%), compared to 5% (95%CI 2-12%) for patients not readmitted (p=0.0001). In a multivariate analysis, readmission was the strongest predictor of non-relapse mortality (NRM) (HR 2.0) (p=0.0006) and survival (HR 3.4) (p<0.0001).

In Conclusion: ALT donor transplants have lower numbers of DAOH, as compared to SIB grafts, which implies longer stay in hospital and higher costs. Readmission to hospital within 100 days, is predicted by acute GvHD, comorbidity index, donor type, and has a significant strong impact on non-relapse mortality and survival.
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http://dx.doi.org/10.4084/MJHID.2020.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485463PMC
September 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

Department of Oncology/Hematology, Azienda Ospedaliera Universitaria (AOU) Città della Salute e della Scienza di Torino, Presidio Molinette, Turin, 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

A 30-month-old boy with aplastic anemia caused by electrocution.

Ann Hematol 2020 Oct 24;99(10):2439-2440. Epub 2020 Jul 24.

Instituto di Ematologia, Fondazione Policlinico Universitario Gemelli IRCSS, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1007/s00277-020-04189-xDOI Listing
October 2020

Timing of Post-Transplantation Cyclophosphamide Administration in Haploidentical Transplantation: A Comparative Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2020 10 6;26(10):1915-1922. Epub 2020 Jul 6.

Hematology Department, Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, Paris, France; Sorbonne Universités, INSERM, Centre de Recherche Saint-Antoine, UPMC Univ Paris 06, Paris, France; European Society for Blood and Marrow Transplantation, Paris, France.

The timing of immunosuppressive therapy used in combination with post-transplantation cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (haplo-HSCT) is not standardized. We evaluated the schedules of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on days +3 and +4 along with tacrolimus (group 1; n = 215), with cyclosporine A (CSA) and mycophenolate mofetil (MMF) from day +5 (group 2; n = 170), or CSA + MMF from day 0 or 1 with PTCY on days +3 and +5 (group 3; n = 124). Compared with the other 2 groups, patients in group 3 were younger (median age, 46 years; P = .02) and more often received bone marrow (77%; P < .01) and a regimen containing thiotepa, fludarabine, and busulfan (84%; P< .01). At 2 years, overall survival was 44% was in group 1, 48% in group 2, and 59% in group 3 (P= .15); leukemia-free survival (LFS) was 43%, 46%, and 53% (P= .05); and refined graft-versus-host disease-free, relapse-free survival (rGRFS) was 33%, 39%, and 36% (P = .02). The incidence of grade II-IV acute GVHD was 25% in group 1, 39% in group 2, and 18% in group 3 (P< .01); incidence of chronic GVHD was 25%, 21%, and 24% (P= .50); relapse incidence was 36%, 37%, and 26% (P= .02); and nonrelapse mortality was 26%, 20%, and 21% (P= .35). On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCY was associated with a better LFS (hazard ratio [HR], .58; P= .02) and improved rGRFS (HR, .62; P = .02). In this study, the timing of immunosuppression influenced the outcomes of haplo-HSCT with PTCY. An early start of CSA + MMF with PTCY administered on days +3 and +5 improves LFS and rGRFS.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.026DOI Listing
October 2020

Haploidentical hematopoietic stem cell transplantation in aplastic anemia: a systematic review and meta-analysis of clinical outcome on behalf of the severe aplastic anemia working party of the European group for blood and marrow transplantation (SAAWP of EBMT).

Bone Marrow Transplant 2020 10 28;55(10):1906-1917. Epub 2020 Apr 28.

King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Aplastic anemia (AA) is a serious hematological disorder, which is solely cured by hematopoietic stem cell transplantation (HSCT). Haploidentical HSCT is an emerging modality with encouraging outcomes in several blood conditions. The present study aims to comprehensively assess the feasibility and safety of haploidentical HSCT in patients with severe and very severe AA. It is a systematic review and meta-analysis of studies related to haploidentical stem cell transplantation in idiopathic AA investigating rates of successful engraftment, acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), transplant-related mortality (TRM), and posttransplantation viral infections (including cytomegalovirus [CMV]) in patients with AA. The effects of reduced-intensity conditioning (RIC) and nonmyeloablative conditioning (NMA), as well as various GvHD prophylaxis regimens on these outcomes were evaluated. In total 15 studies were identified, (577 patients, 58.9% males), successful engraftment was observed in 97.3% of patients (95% CI, 95.9-98.7) while grades II-IV aGvHD and cGvHD were reported in 26.6% and 25.0%, respectively. The pooled incidence of TRM was 6.7% per year (95% CI, 4.0-9.4). RIC regimens were associated with higher proportions of successful engraftment (97.7% vs 91.7%, P = 0.03) and aGvHD (29.5% vs 18.7%, P = 0.008) when compared with NMA regimens with no differences in cGvHD or mortality incidence. When compared with methotrexate-containing regimens and other regimens, posttransplant cyclophosphamide-containing regimens reduced the rates of aGvHD (28.6%, 27.8%, and 12.8%, respectively, P = 0.02), CMV viremia (55.7%, 38.6%, and 10.4%, respectively, P < 0.001), and CMV disease in initially viremic patients (2.1%, 33.0%, and 0%, respectively, P < 0.001). We have concluded that Haploidentical HSCT was associated with promising outcomes in terms of successful engraftment and reduced complications. Future prospective trials are needed to identify the preferred conditioning regimen, GvHD prophylaxis, and graft source in the setting of haploidentical transplant for AA.
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http://dx.doi.org/10.1038/s41409-020-0897-2DOI Listing
October 2020

Treatment of steroid resistant acute graft versus host disease with an anti-CD26 monoclonal antibody-Begelomab.

Bone Marrow Transplant 2020 08 13;55(8):1580-1587. Epub 2020 Mar 13.

Dipartimento di Oncoematologia Pediatrica, IRCCS, Ospedale Pediatrico Bambino Gesu', Sapienza, Università di Roma, Roma, Italy.

We have treated 69 patients with steroid refractory acute graft versus host disease (SR-aGvHD), with an anti-CD26 monoclonal antibody (Begelomab): 28 patients in two prospective studies (EudraCT No. 2007-005809-21; EudraCT No. 2012-001353-19), and 41 patients on a compassionate use study. The median age of patients was 42 and 44 years; the severity of GvHD was as follows: grade II in 8 patients, grade III in 33, and grade IV in 28 patients. There were no adverse events directly attributable to the antibody. Day 28 response was 75% in the prospective studies and 61% in the compassionate use patients, with complete response rates of 11 and 12%. Response for grade III GvHD was 83 and 73% in the two groups; response in grade IV GvHD was 66 and 56% in the two groups. Non relapse mortality (NRM) at 6 months was 28 and 38%. Overall there were 64, 56, 68% responses for skin, liver, and gut stage 3-4 GvHD. The overall survival at 1 year was 50% for the prospective studies and 33% for the compassionate use patients. In conclusion, Begelomab induces over 60% responses in SR-aGvHD, including patients with severe gut and liver GvHD, having failed one or more lines of treatment.
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http://dx.doi.org/10.1038/s41409-020-0855-zDOI Listing
August 2020

CD4+ T-cell alloreactivity after haploidentical hematopoietic stem cell transplantation.

Haematologica 2021 Feb 1;106(2):585-588. Epub 2021 Feb 1.

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

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http://dx.doi.org/10.3324/haematol.2019.244152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849555PMC
February 2021

Bone marrow haploidentical transplant with post-transplantation cyclophosphamide: does graft cell content have an impact on main clinical outcomes?

Cytotherapy 2020 03 11;22(3):158-165. Epub 2020 Feb 11.

Fondazione Policlinico A. Gemelli IRCCS, Roma, Italy; Istituto di Ematologia, Università Cattolica del Sacro Cuore, Roma, Italy.

We analyzed data relative to cell content in 88 consecutive patients receiving HLA haploidentical bone marrow (BM) transplants with post-transplantation cyclophosphamide (PT-CY). Median age was 54.5 (range, 17-72); diagnoses were acute leukemia (n = 46), lymphoproliferative disorders (n = 24), myelofibrosis (n = 11) and myelodysplastic syndromes (n = 5). Total nucleated cell (TNC) and CD34+, CD3+, CD4+ and CD8+ cell doses were stratified as higher than first, second and third quartile and the dose effect on various clinical outcomes was assessed. Median time to engraftment was 17 days for neutrophils and 24 days for platelets. To receive a dose of TNC ≥3.2 x 10/kg or CD34+ cells ≥2.7 x 10/kg significantly shortened the time to neutrophil and platelet engraftment and reduced the blood product requirements in the 30-day period after transplantation. Overall, TNC and CD34+ cell doses had no effect on acute graft-versus-host disease (GVHD) incidence, whereas patients receiving higher CD3+ and CD8+ cell doses seemed to have less chronic GVHD. No effect on non-relapse mortality, progression-free survival and overall survival was observed at different cell dose thresholds. These data suggest that in HLA haploidentical BM transplant with PT-CY, appropriate cell doses are relevant to the engraftment. The association between low CD3+/CD8+ cells and chronic GVHD deserves further investigation.
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http://dx.doi.org/10.1016/j.jcyt.2020.01.007DOI Listing
March 2020

Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation.

Lancet Haematol 2020 Feb;7(2):e157-e167

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

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large-scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews; second, expert opinion was added for specific issues following several rounds of debate; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome; and the addition of newer treatment options for resteroid-refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.
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http://dx.doi.org/10.1016/S2352-3026(19)30256-XDOI Listing
February 2020

Rabbit ATG/ATLG in preventing graft-versus-host disease after allogeneic stem cell transplantation: consensus-based recommendations by an international expert panel.

Bone Marrow Transplant 2020 06 22;55(6):1093-1102. Epub 2020 Jan 22.

University Hospital Eppendorf, Hamburg, Germany.

This collaborative initiative aimed to provide recommendations on the use of polyclonal antithymocyte globulin (ATG) or anti-T lymphocyte globulin (ATLG) for the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). A comprehensive review of articles released up to October, 2018 was performed as a source of scientific evidence. Fourteen clinically relevant key questions to the domains indication, administration, and post-transplant management were developed and recommendations were produced using the Delphi technique involving a Panel of 14 experts. ATG/ATLG was strongly recommended as part of myeloablative conditioning regimen prior to matched or mismatched unrelated bone marrow or peripheral blood allogeneic HSCT in malignant diseases to prevent severe acute and chronic GvHD. ATG/ATLG was also recommended prior to HLA-identical sibling peripheral HSCT with good but lesser bulk of evidence. In reduced intensity or nonmyeloablative conditioning regimens, ATG/ATLG was deemed appropriate to reduce the incidence of acute and chronic GvHD, but a higher risk of relapse should be taken into account. Recommendations regarding dose, application, and premedication were also provided as well as post-transplant infectious prophylaxis and vaccination. Overall, these recommendations can be used for a proper and safe application of polyclonal ATG/ATLG to prevent GvHD after allogeneic HSCT.
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http://dx.doi.org/10.1038/s41409-020-0792-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269907PMC
June 2020

Allogeneic Hemopoietic Stem Cell Transplants in Patients with Acute Myeloid Leukemia (AML) Prepared with Busulfan and Fludarabine (BUFLU) or Thiotepa, Busulfan, and Fludarabine (TBF): A Retrospective Study.

Biol Blood Marrow Transplant 2020 04 23;26(4):698-703. Epub 2019 Dec 23.

Istituto di Ematologia, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; Universita' Cattolica del Sacro Cuore, Rome, Italy. Electronic address:

This is a multicenter retrospective comparison of 2 myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan, and fludarabine (TBF). Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant centers, with AML in first or second remission: 201 patients received BUFLU, whereas 253 received TBF. The 2 groups (BUFLU and TBF) were comparable for age (P = .13) and adverse AML risk factors (P = .3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA-identical siblings, unrelated donors, and family haploidentical donors. The 5-year cumulative incidence of nonrelapse mortality (NRM) was 19% for BUFLU and 22% for TBF (P = .8), and the 5-year cumulative incidence of relapse was 30% and 15%, respectively (P = .0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (P = .002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared with BUFLU (P = .03) and the risk of death (P = .03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of haploidentical grafts, TBF reduced the risk of relapse (P = .006) and there was a trend for improved survival (P = .07). Superior survival of patients receiving TBF as compared with BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.
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http://dx.doi.org/10.1016/j.bbmt.2019.12.725DOI Listing
April 2020

Haploidentical Stem Cell Transplantation With Posttransplant Cyclophosphamide Therapy vs Other Donor Transplantations in Adults With Hematologic Cancers: A Systematic Review and Meta-analysis.

JAMA Oncol 2019 Oct 17. Epub 2019 Oct 17.

Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: Use of haploidentical (HAPLO) stem cell transplantation with posttransplant cyclophosphamide is rapidly increasing in adults with hematologic cancers. However, its specific role compared with other transplant strategies has yet to be identified.

Objective: To synthesize the existing evidence regarding outcomes of stem cell transplantations comparing HAPLO stem cell transplantation and posttransplant cyclophosphamide therapy with transplantations from matched related donors (MRDs), matched unrelated donors (MUDs), or mismatched unrelated donors (MMUDs).

Data Sources: PubMed, Cochrane Library, ClinicalTrials.gov, and meeting abstracts were searched for the key words haploidentical and cyclophosphamide from inception through March 1, 2019.

Study Selection: Studies comparing HAPLO stem cell transplantation and posttransplant cyclophosphamide therapy with transplantations from other donors in adults with hematologic cancers were eligible for meta-analysis.

Data Extraction And Synthesis: Pooled odds ratios (ORs) and 95% CIs were calculated using a random-effects model.

Main Outcomes And Measures: Main outcomes were all-cause mortality, nonrelapse mortality, and relapse.

Results: A total of 30 studies including 22 974 participants were analyzed. HAPLO stem cell transplantation with posttransplant cyclophosphamide therapy was associated with increased all-cause mortality compared with MRDs (OR, 1.17; 95% CI, 1.05-1.30), similar all-cause mortality compared with MUDs (OR, 1.06; 95% CI, 0.96-1.18), and reduced all-cause mortality compared with MMUDs (OR, 0.75; 95% CI, 0.61-0.92). Regarding nonrelapse mortality, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with worse outcomes compared with MRDs (OR, 1.20; 95% CI, 1.04-1.40) but better outcomes compared with MUDs (OR, 0.75; 95% CI, 0.61-0.92) and MMUDs (OR, 0.51; 95% CI, 0.25-1.02). In terms of relapse, HAPLO stem cell transplantation with posttransplant cyclophosphamide was associated with similar outcome compared with MRDs (OR, 1.01; 95% CI, 0.86-1.17) and MMUDs (OR, 1.06; 95% CI, 0.77-1.47) but showed increased relapse compared with MUDs (OR, 1.20; 95% CI, 1.03-1.40).

Conclusions And Relevance: Results of this meta-analysis suggest that MRDs, if available, remain the optimal donors regarding mortality and HAPLO stem cell transplantation with posttransplant cyclophosphamide may be preferred over MMUDs. Prospective comparisons with MUDs are needed.
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http://dx.doi.org/10.1001/jamaoncol.2019.3541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802371PMC
October 2019

Long-term outcome of a randomized controlled study in patients with newly diagnosed severe aplastic anemia treated with antithymocyte globulin and cyclosporine, with or without granulocyte colony-stimulating factor: a Severe Aplastic Anemia Working Party Trial from the European Group of Blood and Marrow Transplantation.

Haematologica 2020 05 3;105(5):1223-1231. Epub 2019 Oct 3.

Hemato-Onco-SCT Pole, Hematology Unit. G. Gaslini Children's Research Hospital, Genova, Italy.

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF (=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (=0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942).
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http://dx.doi.org/10.3324/haematol.2019.222562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193468PMC
May 2020

Clinical applications of donor lymphocyte infusion from an HLA-haploidentical donor: consensus recommendations from the Acute Leukemia Working Party of the EBMT.

Haematologica 2020 01 19;105(1):47-58. Epub 2019 Sep 19.

Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorobonne University, and INSERM UMRs 938, Paris, France.

Donor lymphocyte infusion has been used in the management of relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. It can eradicate minimal residual disease or be used to rescue a hematologic relapse, being able to induce durable remissions in a subset of patients. With the increased use of haploidentical hematopoietic cell transplantation, there is renewed interest in the use of donor lymphocytes to either treat or prevent disease relapse post transplant. Published retrospective and small prospective studies have shown encouraging results with therapeutic donor lymphocyte infusion in different haploidentical transplantation platforms. In this consensus paper, finalized on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use of donor lymphocyte infusion from haploidentical donor, and provide recommendations on its therapeutic, pre-emptive and prophylactic use in clinical practice.
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http://dx.doi.org/10.3324/haematol.2019.219790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939532PMC
January 2020

Peripheral Blood Hemopoietic Stem Cell Mobilization Regimens in POEMS Syndrome: A Retrospective Study at 2 Hematologic Italian Centers.

Biol Blood Marrow Transplant 2019 12 21;25(12):2514-2516. Epub 2019 Aug 21.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Istituto di Ematologia, Università Cattolica del Sacro Cuore, Rome, Italy.

Autologous peripheral blood stem cell transplantation should be considered first-line therapy in young patients with POEMS. The best protocol to collect peripheral blood stem cells remains to be defined, because of the disease rarity and the heterogeneity of published case series. We collected clinical and laboratory data from 25 patients undergoing mobilization, of whom 11 were mobilized using cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF) and 14 patients using G-CSF. The incidence of poor mobilization was low and not statistically different between the 2 groups. Both schemes (CY plus G-CSF versus G-CSF alone) were able to harvest a sufficient CD34 cell dose.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.011DOI Listing
December 2019

Graft versus host disease in unmanipulated haploidentical marrow transplantation with a modified post-transplant cyclophosphamide (PT-CY) regimen: an update on 425 patients.

Bone Marrow Transplant 2019 08;54(Suppl 2):708-712

IRCCS Policlinico San Martino, Genova, Italy.

This is an update on acute and chronic graft-versus-host disease (GvHD) in 425 patients with hematologic malignancies, undergoing an unmanipulated haploidentical (HAPLO) graft from related donors, with a modified post-transplant cyclophosphamide (PT-CY) regimen. All patients received a myeloablative conditioning regimen, either based on thiotepa busulfan fludarabine (TBF), or on full-dose total body irradiation (TBI). The cumulative incidence of acute GvHD-grade II-IV was 29%, and the CI of GvHD-grade III-IV was 4%. We found older donors and older patients to have higher rates of grade II-IV acute GvHD; female donors, diagnosis, disease phase, year of transplant, and the conditioning regimen had no predictive effect on acute GvHD. There was no impact of grade II GvHD, but a significant impact of grade III-IV acute GvHD, on overall survival. The CI of moderate-severe chronic GvHD was 18%: the major predictor was a previous acute GvHD, followed by combined donor and recipients age. In conclusion, PT-CY given on days+3 + 5 results in a relatively low, but not insignificant risk of acute and chronic GvHD, in patients grafted from the related HAPLO donors. The use of young donors appears to reduce this risk.
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http://dx.doi.org/10.1038/s41409-019-0594-1DOI Listing
August 2019

Preoperative autologous blood donation in adult bone marrow donors: reappraisal of a single-centre experience.

Vox Sang 2019 Oct 11;114(7):762-768. Epub 2019 Aug 11.

Fondazione Policlinico A. Gemelli IRCCS, Roma, Italy.

To avoid risk for allogeneic transfusions in healthy bone marrow (BM) donors, 1-2 preoperative autologous blood donations (PAD) are usually collected before the BM harvest. We analysed the haematological parameters in BM donors before and after the harvest, to assess the efficacy of this practice in limiting the postharvest anaemia. Overall, 102 consecutive donors underwent BM harvest preceded by one (26 cases) or two PAD (76 cases), which were infused during BM collection. We analysed the parameters related to donors, PAD timing and BM graft characteristics. PAD induced a significant decrease in Hb (from 14·6 g/dl, IQ range 13·3-15·5 to12·9 g/dl, IQ range 11·8-13·9; P < 0·0001) in all donors, with a median Hb loss at day -1 of 10·9% (IQ range 6·8-14·2). The PAD-related Hb decrease was independent of sex or number of PAD, and was inversely related to the time elapsed from first or last PAD. In comparison with values recorded at day-1, BM harvest produced an additional Hb decrease, accounting for a median Hb loss of 18·9% (IQ range 14·9-24·4). Overall, in comparison with pre-PAD values, Hb levels at day +1 were reduced of 28·9% (IQ range 23·6-32·2), independently if donors had 1 or 2 PAD reinfused. In conclusion, these data show that two PAD do not carry any advantage over one PAD. An eventual benefit of PAD can be achieved only if an adequate interval between PAD and BM harvest elapses. Prospective randomized studies could be worth to establish if any role for PAD does exist in BM donors.
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http://dx.doi.org/10.1111/vox.12834DOI Listing
October 2019

Trajectory of lung function to pleuroparenchymal fibroelastosis late after haematopoietic stem-cell transplantation.

Respir Med Case Rep 2019 27;28:100915. Epub 2019 Jul 27.

S.S. Fisiopatologia Respiratoria, Clinica Malattie Respiratorie e Allergologia, Ospedale Policlinico San Martino - IRCCS, Genova, Italy.

Pleuroparenchymal fibroelastosis is characterized by upper lobes subpleural intra-alveolar fibrosis and elastosis with visceral pleural fibrosis, which may occur after allogenic haematopoietic stem-cell transplantation (HSCT). The longitudinal changes of lung function preceding this complication have not been described. We report the case of an adult woman undergoing allogeneic HSCT for Hodgkin's lymphoma. Pulmonary function tests evolved from normal, before transplantation, to a restrictive pattern with normal residual volume 3 months after transplantation, then to an obstructive pattern consistent with bronchiolitis obliterans 18 months after transplantation, and finally to a severe mixed pattern with preserved residual volume. Computed tomography showed the distinctive features of pleuroparenchymal fibroelastosis, confirmed by histology of specimen from apical resection after pneumothorax. This case report suggests that pleuroparenchymal fibroelastosis may occur after HSCT following bronchiolitis obliterans syndrome with a mixed (restrictive-obstructive) lung function pattern.
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http://dx.doi.org/10.1016/j.rmcr.2019.100915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675970PMC
July 2019

Haploidentical donor transplants for severe aplastic anemia.

Semin Hematol 2019 07 26;56(3):190-193. Epub 2019 Mar 26.

Department of Hematology, Fondazione Policlinico Universitario Gemelli IRCCS, Universita' Cattolica del Sacro Cuore, Roma, Italy.

Haploidentical stem cell transplantation (HAPLO) is being increasingly used, and significant progress has been made both with ex vivo T-cell depleted grafts as well as with unmanipulated marrow or peripheral blood grafts. We here review the current status of HAPLO grafts in patients with acquired severe aplastic anemia. Several transplant platforms have been tested, to overcome graft severe rejection and graft vs host disease (GvHD): these include differences in the conditioning regimen, in graft source and graft manipulation, and in GvHD prophylaxis. The latter include ex vivo T-cell depletion and/or antithymocyte globulin and/or high dose post-transplant cyclophosphamide. Some programs also include the use of marrow or cord blood mesenchymal stem cells, infused at the time of transplantation. Extremely encouraging results are being reported especially in the pediatric population, but also in young adults: we will review reports on 375 patients, with an average rejection rate of 6%, grade II-IV GvHD of 23% and 1-year survival of 80%. Finally we will discuss the place of HAPLO transplants in the context of alternative donor grafts for acquired aplastic anemia.
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http://dx.doi.org/10.1053/j.seminhematol.2019.03.004DOI Listing
July 2019