GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Flow Cytometry-Based Pre-Transplant Minimal Residual Disease Detection Strongly Impacts on the Outcome of Haploidentical Transplantation with Αβ T Cell Depletion in Pediatric Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4618-4618
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4618-4618
    Abstract: Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for patients with relapsed or refractory acute lymphoblastic leukemia. Patients with persistence of minimal residual disease (MRD) before HCT are at increased risk of disease relapse. Multiparameter flow cytometry (MFC) is the most commonly used method of MRD detection in clinical practice. This study aimed to evaluate MRD status before HCT on outcome of ALL patients receiving allogeneic HSCT from haploidentical donors with TCRαβ+/CD19+ depletion of the graft. Materials and methods A total of 120 pts with ALL (T-lineage ALL (T-ALL)- 37, B cell precursor (BCP)-ALL-83, 45 female, 75 male, median age 8.7 years (0.5-20) underwent allogeneic HSCT between June 2013 and June 2019. All pts received Haplo graft and were in morphologic remission. Disease status at transplant was CR1 in 35 pts, CR2 in 68 pts and CR 〉 2 in 17 pts. Transplantation in CR1 was performed according to risk stratification scheme in the current institutional ALL protocol (Moscow-Berlin 2008, 2015). MRD detection in the bone marrow prior to НSСТ was performed in all pts by MFC according the AIEOP BFM FLOW Network SOP. MRD negativity was defined as 〈 0.001% of all bone marrow nucleated cells. Seventy-nine patients were MRD negative before HSCT, 41 were MRD-positive. The median MRD level (among MRD-positive patients) prior HCT was 0.025%. Thirty (25%) pts received treosulfan-based myeloablative preparative regimen, while TBI-based regimen was used in 90 (75%) pts. Two regimens of GvHD prophylaxis were used. Regimen 1 (n=27): thymoglobulin 5mg/kg, rituximab 200 mg/m2 and bortezomib on day +2, +5; regimen 2 (n=93): tocilizumab at 8 mg/kg on day -1 and post-transplant bortezomib, 89 pts receive additional abatacept at 10 mg/kg on day +2, +7, +14, +28. TCR αβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 9.3 x106/kg (range 4.3-19.8), αβ T cells - 30x103/kg (range 1-361). Median time of follow-up for survivors was 1.6 years (range: 0.13 - 4.8). Results Primary engraftment was achieved in 116 of 120 pts (3 pts died before engraftment due to septic events, one relapsed early), the median time to neutrophil and platelet recovery was 13 and 14 days, respectively. All engrafted pts had verified morphologic remission and achieved sustained complete donor chimerism by day +30, seven of them had detectable MRD (5 of them were MRD-positive before HCT). Transplant-related mortality was 5 % (95% CI: 2-11). The cumulative incidence (CI) of relapse at 1.5 years was 25%(95%CI:18-35) for the whole cohort. Among patients, who had MRD-negative remission prior to HSCT, CI of relapse was 14 % (95%CI:8-26) with median time of relapse of 0.54 months, as compared to MRD-positive cohort, with CI of relapse of 44 % (95%CI:31-63) with median time to relapse 0.29 months, p=0.0004. pEFS (event=death or relapse) was 70% (95%CI: 61-78) for the whole cohort, in MRD (-) group pEFS was 79% (95%CI: 68-88), as compared to 56%(95%CI:40-72) in the MRD(+) group, p=0.025. CI of relapse in BCP-ALL pts, who had MRD-negative remission prior to HCT was 12 %(95%CI:6-25), in MRD(+) group 49% (95%CI:33-72), p=0.0002, in T-ALL pts in MRD (-) and MRD (+) groups CI of relapse was 17 % (95%CI:6-51) and 38 % (95%CI:20-76), respectively, p=0.14. Conclusion These results suggest that MRD detection by multiparameter flow cytometry prior to HSCT is a highly significant prognostic factor in the setting of haploidentical HSCT on the platform of ab T cell depletion. We expect that further improvement of the outcome can be achieved based on the combination of current safe haplo HSCT platform and novel targeted immunotherapy approaches. Figure Disclosures Maschan: Miltenyi Biotec: Other: lecture fee.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-129792
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    TCR Alpha/Beta and CD19 Depletion in Transplantation from Matched Unrelated and Haploidentical Donors in Pediatric Leukemia Patients: Comparison of Two Gvhd Prophylaxis Regimens
    Elsevier BV ; 2016
    In:  Biology of Blood and Marrow Transplantation Vol. 22, No. 3 ( 2016-03), p. S385-
    Details
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 22, No. 3 ( 2016-03), p. S385-
    Type of Medium: Online Resource
    ISSN: 1083-8791
    URL: Article
    DOI: 10.1016/j.bbmt.2015.11.901
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Transplantation from Matched Unrelated and Haploidentical Donor in Pediatric Severe Aplastic Anemia: Experience with TCR Alpha/Beta and CD19 Depletion As Graft Processing Method
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2294-2294
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2294-2294
    Abstract: Introduction Hematopoietic stem cell transplantation from non-sibling donors remains the only curative option for severe aplastic anemia patients refractory to ATG/CsA immunosuppression. Although the results of MUD and haploidentical transplantation in SAA have improved significantly, graft-versus host disease (GVHD) remains a serious problem, associated with significant morbidity and mortality. We investigated the role of new method of graft processing - TCR alpha/beta depletion as a way to improve the results of MUD and haploidentical transplants in SAA. Patients and methods Forty two patients with SAA were treated since November 2012 till February 2016. Median age at HSCT was 11(3-22) years, 27 male/15 female. All pts. were refractory/relapsed (36/6) after at least two courses of ATG/CsA, 3 pts. had concurrent severe hemolytic PNH. Time from diagnosis to transplant was 17(143-8,6)/15(99-5,5) months. Donors were unrelated volunteers in 32 cases, haploidentical parents in 10 cases. Preparative regimen included cyclophosphamide 100-150 mg/kg, fludarabine 150mg/kg, ATG and 2-6Gy thoraco-abdominal irradiation, in haplo transplants patients additionaly received thiophosphamide at 10mg/kg. Two patients recieved alemtuzumab instead of ATG because of anaphylaxis. Post-transplant GVHD prophylaxis included Tacro and Mtx on days +1, +3, +6. PBSC grafts were depleted of TCR alpha/beta cells and CD19 cells with CliniMACS device as recommended by the manufacturer. Patients received a median of 10(6,0-23) x106 CD34 per kg, 8(1-39) x104 TCR alpha/beta per kg. Results All patients engrafted with a median of 15 days for WBC and 13,5 days for platelets. In 4 patients after MUD transplantation secondary graft failure (rejection) developed, two of them were successfully retransplanted. Cumulative incidence of aGVHD 2-3 was 9% (95% CI: 3-27%) and 40%(95% CI: 18-85%) in MUD and haplo respectively, 90% patients with aGVHD had only skin involvement. No grade 4 aGVHD detected. Cumulative incidence of grade 3 aGVHD was 3%(95% CI: 0,5-21%) and 10%(95% CI: 2-64%) in MUD and haplo, respectively. Cumulative incidence of cGVHD was 12%(95% CI: 0,5-58%) and 30%(95% CI: 11-77%) in MUD and haplo respectively. A median follow up is 2 years. Seven patients died of viral infection - CMV (2 pts.), viral infection - CMV plus GVHD (2 pts.), microangiopathy (1 pt), 2 pts. died after second transplantation (1 - disseminated toxoplasmosis, 1 - ADV and CMV and GVHD). Event and GVHD-free survival is 73%(95% CI: 57-89%) and 60% (95% CI: 30-90%) in MUD and haplo respectively (pic.1) Overall survival is 86%(95% CI: 74-99%) and 78%(95% CI: 50-100%) respectively for MUD and haploidentical (pic.2). Prolonged stable mixed chimerism in T-cells was detected in recipients of MUD grafts in contrast to haploidentical grafts (pic/3). Conclusion TCR alpha/beta depletion is a robust platform for allogeneic transplantation from MUD and haploidentical donors in severe aplastic anemia. Results should be further improved by additional measures to control viral infections and prevent rejection in MUD transplants. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2294.2294
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Tcrαβ+/CD19+-Depletion in Hematopoietic Stem Cells Transplantation from Matched Unrelated and Haploidentical Donors Following Treosulfan or TBI-Based Conditioning in Pediatric Acute Lymphoblastic Leukemia Patients
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 4672-4672
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4672-4672
    Abstract: Introduction Relapse, graft-versus-host disease (GvHD) and GvHD-associated mortality are major obstacles to success of transplantation from unrelated and haploidentical donors in children with acute lymphoblastic leukemia. Future directions will focus on optimizing conditioning regimens and enhancing graft-versus-leukemia effect. Negative depletion of α/β(+) T cells and CD19+ B lymphocytes, which permits to maintain mature donor-derived natural killer cells and γδ(+) T cells in the graft may improve GvHD control, immune reconstitution and prevent the relapse. Patients and methods : A total of 67 pediatric patients with acute lymphoblastic leukemia (T-ALL- 26, B-ALL-41, 29 female, 38 male, median age 9,4 years, range 0,15-20) underwent allogeneic HSCT between May 2012 and May 2016. Forty two patients received haploidentical graft, 25 - a graft from matched unrelated donor. Disease status at transplant was CR1 in 19pts., CR2 in 35 pts. and CR 〉 2 13 pts. Transplantation in CR1 was performed according to risk stratification scheme in the current institutional ALL protocol.Fifty patients recieved treosulfan-based myeloablative preparative regimen (74%), TBI-based regimen was used in 17 patients (26%). Two regimens of GvHD prophylaxis were used: regimen 1 (n=28): ATG (horse, ATGAM) 50mg/kg, post-grafting immunosuppression consisted of short course Tacro/MTX (n=20) before day +30 or no post-transplant prophylaxis (n=8[ММ1] ); regimen2 (n=39): ATG (rabbit, thymoglobuline) 5mg/kg, rituximab 200mg/m2 (n=30), bortezomib (n=24) and post- transplant bortezomib (n= 19) or Tacro (n=19). All patients with TBI- based regimen received rabbit ATG. TCRαβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases according to manufacturer's recommendations. The median dose of CD34+ cells in transplant was 10 x106/kg (range 3,9-18,8), TCRα/β - 19x103/kg (range 0,2-300). Results Primary engraftment was achieved in 64 of 67 pts. (two patients died before engraftment), the median time to neutrophil and platelet recovery was 13 and 14 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by day +30. Early (100 day) mortality was pTRM was 7,5% (95% CI: 0,3-17),2-year pTRM - 17% (95%CI: 9-30). The 3 early deaths included bacterial sepsis (n=2) and viral infections (n=1), seven late: viral infection in four pts. (ADV=2, ADV+CMV=1, CMV=1), bacterial sepsis in two pts. and rhinocerebral mucormycosis in 1 pt., all late deaths were associatedwith chronic GvHD and prolonged corticosteroid therapy. Cumulative incidence of acute graft-versus-host disease (GvHD) grades II - IV and III - IV was 23,9% (95% CI: 16-36), and 7,5% (95% CI: 3-17) respectively. CI of cGvHD was 22,9% (95% CI: 14-36). Regimen 2 was more effective in prevention of aGvHD II-IV: CI at 2 year after HSCT was 12,8% vs 35,7% in regimen 1, p=0,05 and in cGvHD 8,8% vs 35,7%, p=0,028. No correlation between graft composition, donor type in aGvHD and cGvHD was noted Cumulative incidence of relapse at 2 years was 32% (95%CI: 22-47). Two years pEFS (event=death or relapse) was 49,6% (95%CI: 36-63), 2-year pOS - 50% (95%CI: 40-67). In patients, who received TBI-based conditioning pEFS was 62% (95%CI: 37-86), as compared with treosulfan-based 46,5% (95%CI: 31-62), p=0,65. There was no significant difference in survival and relapse rate according leukemia subtype and donor type. Median time of follow-up for survivors was 2 years (range, 0,3 - 4). Discussion: We confirm that the depletion of TCR-alpha/beta and CD19 lymphocytes from the graft ensures high engraftment rate and acceptable transplant-related mortality in pediatric ALL patients. Viral infections and leukemia relapse await further improvement of control. All major outcomes were equivalent between transplantation from unrelated and haploidentical donor. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.4672.4672
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Improved Control of GvHD with Rabbit ATG, Rituximab and Bortezomib Among Pediatric Leukemia Patients after Tcrαβ/CD19-Depletion of Transplant from Matched Unrelated and Haploidentical Family Donors: A Single-Center Retrospective Analysis of Two Gvhd-Prophylaxis Regimens
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 3427-3427
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3427-3427
    Abstract: Introduction: Graft-versus-host disease (GvHD) remains to be a factor associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Bortezomib was shown in vitro to induce selective depletion of alloreactive T-lymphocytes, decrease the production of Th1 cytokines (Blanco et al. 2006), and to suppress the maturation and cytokine production by dendritic cells (Naujokat et al. 2007). Bortezomib was successfully used to prevent and treat GVHD in different settings (Al-Homsi et al. 2015; Koreth et al. 2015). As GvHD-prophylaxis agent Bortezomib was implemented since 2014 in aim to improve the results in a cohort of pediatric patients with acute leukemia who underwent HSCT from HLA-matched unrelated and haploidentical family donors after TCRαβ/CD19-depletion. Here we present the results of a retrospective comparison of two GvHD-prophylaxis regimens. Patients and methods: Between May 2012 and July 2016 eighty-one transplantation from 40 HLA-matched unrelated and 41 haploidentical donors were performed for children (56 boys and 25 girls with median age 9 years, range 0,6-23 years) with acute lymphoblastic (n=31) and acute myeloblastic (n=50) leukemia in complete remission. TCRαβ/CD19-depletion of HSC with CliniMACS technology was implemented in all cases. For all patients it was first allogeneic HSCT. The majority (93%) of the patients received Treosulfan-based condition regimen. Remaining 7% of patients received TBI-based conditioning regimen. Patients were divided retrospectively in two groups according to GvHD prophylaxis regimens. "Regimen 1" (n=35), which was used in 2012-2013 yrs.: horse ATG 50 mg/kg and post-transplant tacrolimus with short course of methotrexate. "Regimen 2" (n=46) started in 2014: rabbit ATG 5 mg/kg, rituximab 200mg/m2 and peri-transplant bortezomib 1,3 mg/m2 on days -5, -2, +2 and +5. The median dose of CD34+ cells in the transplant was 9 x106/kg (range 7-17), TCRαβ - 21x103/kg (range 1-305). Results: Groups differed significantly in regards to diagnosis: 57% of patients in "Regimen 1" had ALL, while most of the patients (78%) in "Regimen 2" were with AML (P= 0,002). Cumulative incidence of neutrophil and platelet engraftment at 30 days was 98% and did not differ between the groups. Median time to neutrophil and platelet engraftment was 14 days, (range, 9-33 and 9-25 days, respectively). Neutrophil engraftment was significantly faster among patients with "Regimen 2", 13 days vs. 16 days for patients with "Regimen 1" and CI of engraftment at day 30 after HSCT 98% (95% CI: 98%) vs. 94% (95% CI: 87-100, P 〈 0,01). Overall cumulative incidence of acute GvHD II-IV grade was 23% (95% CI: 16-35); grade III-IV - 5% (95% CI: 2-13) and chronic GvHD - 18% (95% CI: 11-20). Cumulative incidence of acute GvHD II-IV was significantly lower within the group with "Regimen 2": 15% (95% CI: 7-30) vs. 34% (95% CI: 22-54), P=0,05. Amid patients with "Regimen2" there was one case of grade IV acute GvHD, most of the patients with grade II to IV developed visceral damage involving lower gut. "Regimen 2" was also more effective in prevention of chronic GvHD: CI at 1 year after HSCT was 7% vs. 31%, P=0,005. Only one patient with "Regimen 2" had extensive form of chronic GvHD. Median time of follow-up for survivors was 2 years (range, 0,3 - 4). Cumulative incidence of relapse at 2 years also differed between "Regimen 1" and "Regimen 2" groups, 31% (95% CI: 19-51) vs. 21% (95% CI: 11-39), respectively, though without statistical significance. TRM was 10% (95% CI: 5-20), without significant statistical difference between leukemia type, donor type or GvHD-prophylaxis regimens. EFS (event=death or relapse) at 2 years was 64% (95%CI: 53-75), OS - 69% (95%CI: 58-80). Statistically there was no significant difference in event-free or overall survival probabilities between leukemia type, donor type or GvHD-prophylaxis regimens Conclusion: In our retrospective single-center study we revealed that rATG, rituximab and bortezomib improve the control of acute and chronic GVHD in recipients of TCRαβ- depleted grafts in comparison to hATG, tacrolimus and methotrexate. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.3427.3427
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Results of Hematopoietic Stem Cells Transplantation with Tcrαβ and CD19-Depletion from Matched Related Donors and Infusions of CD45RA Depleted Donor Lymphocytes in Pediatric Severe Aplastic Anemia
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 558-558
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 558-558
    Abstract: Introduction HSCT from matched family donors results in most favorable outcomes among children with severe aplastic anemia (SAA). Despite overall success, morbidity, associated with acute and chronic graft-versus-host disease (GVHD) is not completely prevented with current standard of pharmacologic prophylaxis. Depletion of ab T cells from the graft prevents GVHD, and improves outcome of hematopoietic stem cell transplantation from haploidentical donors, while infusions of donor memory lymphocytes (mDLI) (CD45RA-depleted) are able to transfer pathogen-specific immunity without the risk of GVHD. We evaluated the outcomes of ab T cell depletion and add-back of intermediate-dose mDLI among the pediatric SAA recipients of matched related grafts. Materials and methods A total of 16 children with SAA (8 female, 8 male, median age 10,9 y) underwent allogenic HSCT from matched family donors (MFD) between february 2015 and may 2021. For 15 (94%) pts it was the first allo HSCT, for 1 pts it was the second HSCT. TCR αβ+/CD19+ depletion of HSCT with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells was 7,1 x10 6/kg (range 2,6-13), αβ T cells - 28x10 3/kg (range 5,6-184). All pts received an additional injection of memory T-cell (CD45RA-depleted) on day 0 at 1 million T cells per kg. All patients received cyclophosphamide at 100 mg/kg, fludarabine at 100 mg/m 2, rituximab 100mg/m 2 and serotherapy with either rabbit ATG at 5 mg/kg (n-2) or horse ATG at 100 mg/kg (n-14). Post-transplant GVHD prophylaxis included calcineurin (CNI)-based regimen and abatacept 10mg/kg on days -1, +7, +14 and +28. All pts received a graft from a 10/10 HLA-matched sibling. Median time of follow-up for survivors was 1,1 years (range: 0.14 - 6.38). Results Primary engraftment was achieved in all evaluable patients (100%) with full donor chimerism, and the median time to neutrophil and platelet recovery was 11 (10-20) and 14 (11-20) days, respectively. One patient had aGVHD grade I, there were no incidence of grade II-IV aGVHD and TRM. Event-free and overall survival were 100%. CMV viremia was detected among two patients after a median of 40 (35-73) days after HSCT. No cases of ADV and Epstein-Barr virus (EBV) viremia and EBV disease were recorded. The median recovery of T cells on day+60 was 0,26 (0,04-0,9). Conclusion ab T cell-depleted transplantation with intermediate dose memory T cell add-back definitively prevents GVHD and provides a platform for safe HSCT from matched family donors in patients with SAA. Disclosures Maschan: Miltenyi Biotec: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-152769
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Replacement of Polyclonal Anti-Thymocyte Globulin By Targeted Immunomodulation Is Associated with Improved Outcome of Alfa\Beta T Cell-Depleted Hematopoietic Stem Cells Transplantation in Children with Acute Leukemia
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 481-481
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 481-481
    Abstract: Introduction Relapse, graft-versus-host disease (GvHD) and associated non-relapse mortality are the main obstacles to successful hematopoietic stem cell transplantation in children with leukemia. αβ T cell depletion was developed to prevent GvHD and improve immune reconstitution in recipients of mismatched grafts. Most current protocols use rabbit anti-thymocyte globulin (ATG) as an essential component of preparative regimen to secure engraftment and GVHD control. In order to avoid damaging effects of circulating ATG on graft NK and gd T cells, we have replaced ATG with pharmacologic blockade of IL-6 and CD80/CD28 co-stimulation axis in our ongoing study. Patients and methods Major transplantation outcomes were compared between participants of the current prospective trial (ATG-) and a retrospective control group (ATG+). A total of 165 children with acute leukemia (67 AML, 98 ALL, 68 female, 97 male, median age 8,7 y) underwent allo HSCT between 01.11.2013 and 01.03.2018. Of them 134 - from haploidentical donor and 31 from unrelated donor. All pts were in complete remission (CR1=80, CR2=67, CR 〉 2=18). Ninety-two pts received treosulfan-based conditioning, 73 - TBI-based (all ALL). Either melphalan (n=46) or thiophosphamide (n=98) or etoposide (n=21) were added as a second agent. Fludarabine was used in all pts. Two types of GVHD prophylaxis were used: type 1 (ATG+), (n=98): thymoglobulin 5mg/kg, rituximab 200mg/m2 with either bortezomib on days +2, +5 (n=72) or tacro (n=9) or without any additional agents (n=17); Type 2 (ATG-) (n=67): tocilizumab at 8 mg/kg on day -1, bortezomib on day +2, +5 with abatacept at 10 mg/kg on day -1, +7, +14, +28 (n=63) or without added agent (n=4). αβ T cell depletion with CliniMACS was used in all cases. The median dose of CD34+ cells was 9x106/kg, αβ T cells - 16 x103/kg. Modified (CD45RA-depleted) donor lymphocyte infusions (DLI) were administered to 113 pts. Twenty-five patients received DLI on day 0 and 88 pts received DLI after engraftment. Median time of follow-up for survivors was 2 years (range, 0,3 - 4,5). Results Three patients died before engraftment due to septic event. Primary engraftment was achieved in 161 of 162 evaluable pts (99,3%), the median time to neutrophil and platelet recovery was 16 and 15 days. Among the whole cohort the cumulative incidence of acute graft-versus-host disease (GvHD) grades II - IV and III - IV was 11,5% (95% CI: 7,5-17,6) and 4,8% (95% CI: 2,5-9,5) respectively. The cumulative incidence of cGvHD was 10 % (95% CI: 6,3-15,9). The incidence of aGvHD and cGvHD was not different between ATG (+) and ATG (-). Among the whole cohort 2-year pTRM was 8% (95%CI: 4,8-13,5). pTRM was significantly lower among ATG (-) group - 1,5% (95%CI:0,2-10,4) versus 12,2% (95%CI:7,2-20,8) among ATG (+) group, p = 0,015. The cumulative incidence of relapse at 2 years was 21% (95%CI: 15,5-29), 24% (95%CI: 16-35), among ATG (+) and 19% (95%CI: 11-32), among ATG (-), p = 0,8. Two-year pEFS was 70% (95%CI: 62-77), 2-year pOS - 78% (95%CI: 71-85). Among patients, who received ATG (-) regimen, pEFS was 76% (95%CI: 68-89), as compared to 65% (95%CI: 56-75) among ATG (+), p=0,1 and pOS was 89% (95%CI: 81-97) versus 72% (95%CI: 63-81), p=0,032, respectively. αβ T cell recovery at day +30 was associated with a trend to decreased incidence of relapse, CI of relapse was 32% (95% CI:22 - 47) in those with αβ-T cell count 〈 median vs 18 % (95% CI: 11-32) in those with αβ-cell count 〉 median, p=0,08. EFS among αβ T" high" was 81% (+/-10) vs 56% (+/-14) among αβ T"low", p=0,002. Discussion We confirm that the depletion of αβ T cells from the unrelated and haploidentical graft in combination with intensive conditioning regimen ensures high engraftment rate and low transplant-related mortality. Our analysis suggests that polyclonal ATG serotherapy is not an essential part of the transplant regimen in αβ T-depleted transplantation. Combined administration of tocilizumab and abatacept after αβ T cell-depleted grafting effectively prevents GVHD, does not compromise engraftment, appears to decrease non-relapse mortality and improve survival. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116007
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Targeting Bcl-2 and CD38 As Part of Personalized HSCT Conditioning Regimen in Chemorefractory Acute Leukemia in Children
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 150-150
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 150-150
    Abstract: Introduction The outcome HSCT in a cohort of children with chemorefractory acute leukemia (AL) is poor. The incidence of relapse exceeds 50% and survival varies from 10 to 40%. Additional attempts at remission induction with various combinations of chemotherapy are unlikely to improve the outcome and may contribute to toxicity. We hypothesized that personalized targeted therapy combined with high-dose preparative regimen may improve the outcome of alloHSCT in a cohort of pediatric patients with refractory AL. Bcl-2 and CD38 were chosen as potential targets due to frequent expression in pediatric acute leukemia, availability of marketed targeted therapies, venetoclax and daratumumab, and expected non-overlapping toxicity profile of these agents and the conditioning regimen. Materials and methods A total of 26 pts with chemorefractory acute leukemia (AML-18, T-ALL-6, ABL-2, primary refractory - 9, refractory relapse - 17, 18 male, 8 female, median age 11.3 years), underwent HSCT between November 2017 and May 2019. All patients were transplanted from haploidentical donors, all patients had active disease (AD) at the moment of SCT. For 19 (73%) pts it was the first alloHSCT, for 7 (27%) pts it was the second HSCT. Median bone marrow leukemia burden before cytoreduction was 11% (3-90). Bcl-2 expression on the tumor cells was detected in 23 pts with the median expression of 58% (1.5-99), CD38 expression was detected in 24 pts with the median expression of 88% (11-100). Thirteen pts received treosulfan-based conditioning and 13 - TBI-based (12 Gy). TBI was used among patients with second HSCT (n=7), patients with T-ALL (n=4) and patients with massive extramedullary disease (n=2). GvHD prophylaxis included tocilizumab at 8 mg/kg on day -1 and abatacept at 10 mg/kg on day -1, +7, +14, +28. According to the expression of Bcl-2 and CD38 on tumor cells, 24pts (92%) received daratumumab (anti-CD38 monoclonal antibody) on day -7 at 10-16 mg/kg, 21 pts (81%) received venetoclax at 300 mg/m2/day on days -7 to -2 and 12 pts additionally received plerixafor at 240 mcg/kg x 3 on days -7 to -5. TCRαβ+/CD19+ depletion of PBSC with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells in the graft was 9.5 x106/kg (range 4.9-13.3), αβ T cells - 26.5x103/kg (range 5.6- 84). Modified (CD45RA-depleted) donor lymphocyte infusions (DLI) were administered prophylactically in all pts. Results Two patients died before engraftment due to septic event. Primary engraftment was achieved in 24 of 24 evaluable pts (100%), the median time to neutrophil and platelet recovery was 12 and 13 days. All pts achieved complete remission on day +30. There were no significant toxic effects after targeted therapy, 4 pts (21%) had daratumumab-related infusion reactions, one patient with T-ALL died after engraftment due to septic event. aGVHD grade I-II developed in 5 pts (20%), two of them required systemic immunosuppressive therapy. There were no cases of aGVHD & gt; grade II, neither cases of cGVHD. The median NK- cells count by the day +30 was 0.07 x 106/ml (range 0.01- 0.4), the median levels of αβ T cells and gd T cells were 0.018 x 106 /ml (range 0 - 1.1) and 0.015 x 106 /ml (range 0,01 - 1.3), respectively. Nine (37.5%) pts (5 with T-ALL, 1 with ABL, 3 with AML) relapsed, median interval to relapse was 103 days (55-345). At the moment of reporting 14 (53%) patients are alive in complete remission with a median follow up of 12.7 months (1.9-23m). Event-free and overall survival at 1 year for AML are 76% (SE13) and 76% (SE14), all patients with T-ALL and one with ABL died of disease progression. Conclusion We suggest that addition of venetoclax and daratumomab to the backbone of myeloablative haploidentical HSCT with αβ T cell depletion is not associated with increased toxicity and may lead to improved outcome in a cohort of pediatric patients with chemorefractory AML. In a subgroup of patients with T-ALL this approach does not seem to produce visible benefit. This approach can be further tested in a prospective trial with the goal to increase the anti-leukemic efficacy of HSCT. Figure Disclosures Maschan: Miltenyi Biotec: Other: lecture fee. Off Label Disclosure: venetoclax daratumomab plerixafor
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-129765
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Targeting Bcl-2 and CD38 As Part of Personalized HSCT Conditioning Regimen in Chemorefractory Pediatric Leukemia
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2084-2084
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2084-2084
    Abstract: Introduction The outcome hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory leukemia is poor. The incidence of relapse exceeds 50% and survival varies from 10 to 40%. Additional attempts at remission induction with various combinations of chemotherapy are unlikely to improve the outcome and will contribute to toxicity. We hypothesized that personalized targeted therapy combined with high-dose chemotherapy may improve the outcome of allogeneic hematopoietic stem cell transplantation in a cohort of pediatric patients with refractory leukemia. Bcl-2 and CD38 were chosen as potential targets due to frequent expression in pediatric acute leukemias, availability of marketed targeted therapies, venetoclax and daratumumab, and expected non-overlapping toxicity profile of these agents and the conditioning regimen. Materials and methods A total of 16 pts with chemorefractory disease (T-ALL - 2, AML - 8, JMML - 6, 12 male, 4 female, median age 5,7 years), underwent HSCT between November 2017 and June 2018, median follow-up - 3 months (1,6-7). All pts were transplanted from haploidentical donors, had active disease (AD) at the moment of SCT, for 12 (75%) pts it was the first allogenic HSCT, for 4 pts it was the second HSCT. Median bone marrow leukemia burden before cytoreduction was 22% (3-75). Bcl-2 expression on the tumor cells was detected in all pts (100%) with the median expression of 69% (0,7-100), CD38 expression was detected in 10 pts (AML=7, ALL=2, JMML-1) with the median expression of 96% (71-100). Ten pts received treosulfan-based conditioning, 3 - busulfan-based and 3 -TBI-based. GVHD prophylaxis included tocilizumab at 8 mg/kg on day -1, post-transplant bortezomib and abatacept at 10 mg/kg on day -1, +7, +14, +28. Three pts received thymoglobulin 5mg\kg. According to the expression of Bcl-2 and CD38 on tumor cells, 9 patients (56%) received Daratumumab (anti-CD38 monoclonal antibody) on day -6, 15 patients (94%) received venetoclax at 300 mg/m2/day on days -7 to -2. TCRαβ+/CD19+ depletion of PBSC with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells in transplant was 11 x106/kg (range 7-18), α/β T cells - 40x103/kg (range 11- 139). Modified (CD45RA-depleted) donor lymphocyte infusions (DLI) were administered to 15 pts, 9 pts received modified DLI on day 0. Result Primary engraftment was achieved in 13 (81%) of 16 pts. The median time to ANC and platelets recovery was 14 days (11-22). Engraftment was 100% (10 of 10) among patients with acute leukemia and 50% (3 of 6) among patients with JMML. Three patients with JMML had early disease progression. There were no significant toxic effects after HSCT and no cases of transplant-related mortality. The median NK- cells count by the day +30 was 0,185 x 106/ml (range 0,019- 0,472), the median levels of αβ T cells and gd T cells were 0,045 x 106 /ml (range 0 - 0,364) and 0,07 x 106 /ml (range 0 - 0,349, respectively. Acute GVHD grade 1-2 was developed in 2 pts (15%), none of them required systemic immunosuppressive therapy. There were no cases of chronic GVHD. One (7,6%) patient with AML relapsed on day +61. Three pts (1 with AML and 2 with JMML) died from disease progression, 1 patient with JMML died from complications after the second HSCT. At the moment of reporting 12 pts (9 of 10 with acute leukemia and 3 of 6 with JMML) are alive, in complete remission with a median follow up of 3 months (1,5-7m). Conclusion We suggest that addition of venetoclax and datatumumab to the backbone of myeloablative haploidentical HSCT with αβ T cell depletion is not associated with increased toxicity and may lead to improved early outcomes in a cohort of pediatric patients with chemorefractory acute leukemia. This approach can be further tested in a prospective trial with the goal to increase the anti-leukemic efficacy of HSCT. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116355
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    αβ T Cell-Depleted Haploidentical Hematopoietic Stem Cell Transplantation without Antithymocyte Globulin in Children with Chemorefractory Acute Myelogenous Leukemia
    Elsevier BV ; 2019
    In:  Biology of Blood and Marrow Transplantation Vol. 25, No. 5 ( 2019-05), p. e179-e182
    Details
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 25, No. 5 ( 2019-05), p. e179-e182
    Type of Medium: Online Resource
    ISSN: 1083-8791
    URL: Article
    DOI: 10.1016/j.bbmt.2019.01.023
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...