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  • 1
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2286-2286
    Abstract: Background: Allogeneic HSCT from either an HLA-identical sibling or an unrelated donor is a potentially curative treatment for patients with hemoglobinopathies and erythroid disorders (ED), such as Thalassemia Major (TM), Sickle Cell Disease (SCD) and Diamond-Blackfan Anemia (DBA). The limited historical experience with HLA-haploidentical HSCT in this setting has reported a disease-free survival probability lower than that reported using HLA-matched donors. In the last few years, we have developed a novel method of graft manipulation, based on the selective depletion of α/β+ T-cells and CD19+ B-cells (ClinicalTrial.gov identifier: NCT01810120), which was shown to be safe and effective in children with multiple types of non-malignant disorders (Bertaina el al, Blood 2014). To further optimize this approach through the acceleration of the recovery of adaptive immunity, we designed an ongoing phase I/II trial aimed to test the safety and efficacy of post-transplant infusion of donor T-cells transduced with the iC9 suicide gene (BPX-501 cells) in children with either malignant or non-malignant disorders (ClinicalTrials.gov identifier: NCT02065869). As the transduced gene contains sequences for the CD19 marker, BPX-501 cells (CD3+/CD19+) can be easily tracked in peripheral blood. We report on 10 children with hemoglobinopathies and ED who were enrolled in the phase II portion of the study. Patients and methods: Five patients were males and 5 were females, and median age at diagnosis and at HSCT was 5.34 and 9.52 years (range 2.33-11.71), respectively. Seven patients had TM (all bo/bo), 2 DBA and 1 SCD. All 10 patients were transfusion-dependent and receiving iron-chelation therapy before haplo-HSCT. Among the thalassemia patients, 4 patients belonged to class I and 3 to class II of the Pesaro classification. All patients were transplanted from a parent. Median number of CD34+ and αβ+ T-cells infused was 22.5 x 106/kg and 0.3 x 105/kg, respectively. In all patients, conditioning regimen included busulfan (16 mg/Kg), thiotepa (10 mg/Kg) and fludarabine (160 mg/m2). Rabbit ATG (12 mg/Kg over 3 days, from day -4 to day -2) was administered to prevent graft-versus-host disease (GvHD) and graft failure and Rituximab (200 mg/ m2 on day -1) was administered to prevent EBV-related lymphoproliferative disorders. No post-transplantation GvHD prophylaxis was given. Median follow-up is 301 days (range 41-420 days). Basic phenotyping of circulating lymphocytes was assessed by flow cytometry on fresh heparinized peripheral blood samples at 10, 20, 30, 60, 90, 120 and 150 days post haplo-HSCT. Results: After haplo-HSCT, the median time to reach neutrophil and platelet recovery was 14 days (range 11-28) and 10 days (range 8-12), respectively. After engraftment of the allograft, BPX-501 cells were infused (dose: 1x106 cells/kg) at a median time of 13.5 days after HSCT (range 10-26). Nine of the 10 patients maintained sustained donor engraftment, reaching full chimerism. The patient who experienced secondary graft failure was successfully re-transplanted from the same parent and he is full donor chimeric with transfusion-independence. Grade I/II skin acute GvHD occurred in 2 patients (at 31 and 59 days after HSCT, respectively). There was no occurrence of chronic GVHD. Remarkably, no patient has died and none of the patients have been re-hospitalized after initial discharge. The last erythrocyte transfusion was administered on day +7 post-transplant (range 4-33 days). At last follow-up, the median hemoglobin value of these patients was 11.35 gr/dL (range 10.2-13.4). BPX-501 cells expanded after infusion and still persist in all patients at last follow-up. All children are alive and transfusion-independent. Details on T cell, NK cell and B cell recovery are shown in Figure 1 (Panel A-D). Conclusions: Children with hemoglobinopathies and DBA can benefit from curative haplo-HSCT after depletion of α/β T-cells followed by infusion of BPX-501 cells, which, expanding and persisting over time, contribute to speed immune recovery of adaptive T-cell immunity, thus rendering the procedure safer. Figure 1 Figure 1. Disclosures French: Bellicum Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees. Moseley:Bellicum Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 2
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 19, No. 6 ( 2013-06), p. 940-948
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
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    detail.hit.zdb_id: 2057605-5
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  • 3
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 18, No. 10 ( 2012-10), p. 1600-1607
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
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    detail.hit.zdb_id: 2057605-5
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  • 4
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1173-1173
    Abstract: Background: Prophylactic platelet transfusion is commonly used to prevent life-threatening bleeding events in patients with severe thrombocytopenia associated with chemotherapy courses or hematopoietic stem cells transplantation (HSCT). In adults, the transfusion threshold for prophylaxis is usually set at 10x109plts/L, but in pediatric setting, it is still a matter of debate. Moreover, evidences from the PLADO trial (Slichter SJ et al. N Engl J Med. 2010) and recommendations form international guidelines (ICTMG, Nahirniak S et al. Transfus Med Rev. 2015) suggest two different platelet doses in Inpatients and Outpatients, but clinical experiences in children are still lacking. Aims: In order to confirm the safety of the recommended transfusion threshold, to test two different platelet doses in hospitalized patients and Outpatient setting and to optimize platelet clinical use, as a Children's Hospital, we applied, starting from January 2018, a new prophylactic platelet transfusion policy. Methods: Platelet dose was calculated based on body-surface area (BSA) of each patient (from age-standardized weight). As suggested by ICTMG, different platelets doses were given to Inpatients and Outpatients: (low-dose) 1.1x1011platelets per square meter (plts/m2) and (medium-dose) 2.2x1011plts/m2, respectively. The transfusion threshold for prophylaxis was set at 10x109plts/L, but higher threshold could be considered as per clinical decision (in presence of bleeding signs or risk factors for major bleeding). Patients with platelets refractoriness and newborns, were excluded from our study. Only major bleeding events (grade 3 or higher according to World Health Organization criteria) were collected during the study period. Results: From January 2018 to June 2019, 15278 platelet pediatric aliquots were transfused in our Hospital. Of all the aliquots, 8876 (58.1%) were obtained from apheresis procedures and 6402 (41.9%) from buffy-coat-derived pooled platelet concentrates. Almost 77% (11751) of the all aliquots were transfused in patients with onco-hematologic diseases. Among these, 9771 (64.0%) in the Inpatient group (N=547) and 1980 (13.0%) in the Outpatient group (N=385). Between Inpatients, 6794 (44.5%) aliquots were transfused in Onco-Hematology Ward and 2977 (19.5%) in the HSCT unit. During the study period, only 10 major bleeding events were observed. No fatal hemorrhagic episode was recorded and all of the bleedings occurred in hospitalized patients, and accounted for almost 2% of this population. Intracranial bleeding accounted for five out of six grade 4 bleeding episodes, and occurred in two patients with acute myelogenous leukemia, in one patient with Hodgkin lymphoma and in two patients with advance neuroblastoma. The other grade 4 bleeding event was a massive peritoneal and pleuric hemorrhage with a life-threatening haemodinamic instability in a patient with acute lymphoblastic leukemia (the main characteristics of these patients are reported in the table). Conclusions: our results show that a platelet transfusion policy based on recommendation mainly developed in adults may be safely applied also to pediatric patients with cancer or receiving HSCT. In fact, the lower dose used in Inpatient group resulted in a grade 4 bleeding rate similar to that observed in the PLADO trial (1.0% vs 0.7%). The double dose transfused in Oupatients was effective in preventing major bleeding events. Table. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 5
    In: Frontiers in Pediatrics, Frontiers Media SA, Vol. 9 ( 2021-11-2)
    Abstract: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by a severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. Over 95% of TTPs are acquired, due to autoantibody inhibitors. In children, acquired TTP is a very rare, life-threatening disease. To date, no consensus exists on the treatment strategy of pediatric TTP. We report the cases of two pediatric patients with a diagnosis of TTP, successfully treated with a combination of various therapeutic approaches. Although the patients complained of different sets of symptoms, laboratory data showed Coombs negative hemolytic anemia, renal impairment, and low platelet count in both cases. The diagnosis of acquired TTP was supported by the PLASMIC score and confirmed by the reduction of the ADAMTS13 activity and the presence of anti-ADAMTS13 antibodies. Intravenous immunoglobulin, corticosteroids, and plasma exchange (PEX) were performed without delay. As soon as available, caplacizumab was added to the therapy, with a prompt normalization of platelet count. Nevertheless, ADAMTS13 activity was persistently low, and anti-ADAMTS13 antibodies level was high; thus, a course of rituximab was administered, with persistent normalization of laboratory findings. No adverse events were observed during the treatment. In our experience, the combined use of PEX, caplacizumab, and immunosuppressive therapy during the acute phase of the disease is safe and may have a significant impact on the prognosis with successful clinical outcome and decrease in life-threatening events.
    Type of Medium: Online Resource
    ISSN: 2296-2360
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 6
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2009-2009
    Abstract: Abstract 2009 To evaluate the role of allografting from unrelated donors in the treatment of myeloma we conducted a retrospective study through the Italian Bone Marrow Transplantation Donor Registry. Overall, from 2000 through 2009, 196 myeloma patients, median age 51 years (32–67), for a total of 199 allografts, were transplanted from an unrelated donor at 34 Centers in Italy. Fifty-two (28.1%%), 69 (37.3%), and 64 (34.6%) patients were prepared for transplant with a myeloablative, a reduced-intensity and a non-myeloablative conditioning respectively. Patient characteristics of the 3 cohorts are reported in Table 1.ConditioningMyeloablativeReduced-intensityNon-myeloablativePatient number (%)52/185 (28)69/185 (37)64/185 (35)Median Age455355Previous therapy lines 〈 2 (%)23 (27)33 (38)30 (35)Previous therapy lines ≥ 2 (%)29 (29)36 (37)34 (34)Stem Cell Source BM (%)24 (57)18 (43)0 (0)Stem Cell Source PBSC (%)28 (19)51 (36)64 (45) Cumulative incidence of acute grade II-IV graft-versus-host-disease (GVHD) was 46.4% whereas chronic GVHD was 45.1%. There was no difference in GVHD incidence among the 3 cohorts defined by type of conditioning. Complete and partial remissions in patients who survived at least 3 months post-transplant were 27% and 28% for an overall response rate of 55%. At a median follow up of 32 (0–118) months post-transplant, in the entire study population, median OS from diagnosis was 70.6 months while OS and EFS from the allograft were 18.9 and 14.9 months. Overall, the cumulative incidence of transplant related mortality (TRM) was 29.6% at 1 year and 32.4% at 5 years post-transplant. OS from diagnosis and EFS from transplant were 70.6 and 28.2 months; 66.8 and 9.1 months; and 111.9 and 22.4 months in patients who respectively underwent a myeloablative, a reduced-intensity and a non-myeloablative transplant. One-year and 5-year TRM was 33.3% and 35.7%, 32.2% and 34.4%, and 22.1% and 26.5% respectively. Univariate and multivariate analyses, assessed by multivariate Cox proportional hazards models, were performed for the following variables: number of previous chemotherapy lines (1,2 vs. ≥3), disease status at transplant, HLA- matched antigens (10/10 vs. 9/10 vs. ≤8/10), recipient/donor gender combinations, hematopoietic cell source (peripheral blood vs. bone marrow), conditioning (myeloablative vs. reduced-intensity vs. non-myeloablative), use of anti-thymoglobulin in the conditioning, acute GVHD, chronic GVHD, best response post-transplant, year of transplant (2000–02 vs. 2003–05vs. 2006–09). By univariate analysis, lower number of chemotherapy lines before the allograft, disease status at transplant, a fully HLA-identical donor, the use of peripheral hematopoietic cells rather than bone marrow were statistically significant variables for better OS whereas disease status at transplant, a fully HLA-identical donor, chronic GVHD (either limited or extensive) were statistically significant for better EFS. However, by multivariate analysis, only the development of chronic GVHD (HR 0.50; p 〈 0.001) and a better response post-transplant (HR 2.11; p 〈 0.03) were significantly associated with longer OS whereas chronic GVHD was the only variable associated with better EFS (HR 0.32; p 〈 0.001). Acute GVHD was associated with both poorer OS (HR 2.35; p 〈 0.001)) and EFS (HR 3.19; p 〈 0.001). In conclusion, with a degree of caution given the retrospective nature of this study, there appears to be a strong association between both limited and extensive chronic GVHD and graft-vs.-myeloma effects. However, long term disease control remains an issue independent of the conditioning employed. Prospective trials may allow to define which patient category may most benefit from an unrelated donor allograft. Disclosures: Patriarca: Roche: Honoraria; Celgene: Honoraria; Schering-Plough: Honoraria; Janssen: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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