Outcome of Patients with Beta-Thalassemia Major Given Either Bone Marrow and Frozen Cord Blood of Same Sibling or Bone Marrow Transplantation from Sibling Donors

Abstract Background: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for thalassemia major (TM). Bone marrow (BM) and cord blood (CB) are biologically different stem cell sources. Methods: We analyed the results of a retrospective study of HSCT in 29 chlidren (median age at transplantation was 6 years old) with β-TM after the combined infusion of G-CSF primed bone marrow (BM) and cord blood (CB) from the same transplantation to outcomes in children with β-TM who had received BM (n=26).Patients treated with bone marrow transplant (BMT)were closely matched to the co-transplant group in terms of age, human leucocyte antigen (HLA) matching and duration of follow-up.Compared to BMT group, the donors in co-transplant group were younger (median age 2 vs. 4 years old, p=0.015) Results: In the co-transplant group,the mean total nucleated cells (TNC) was 2.63×108/kg(range,1.26-3.72×108/kg) and the CB was 0.39×108/kg(range,0.27-0.71×108/kg), respectively.The mean TNC (3.02 vs. 2.79×108/kg, p=0.532) and CD34+cells (7.55 vs. 6.94×106/kg, p=0.227) were insignificantly difference between the co-transplant group and BMT group. Of the 53 patients who had successful engraftment,patients who received a co-transplant had a lower incidence of ≥ grade II acute (3.3 vs. 20.8, p=0.047) and chronic(0vs.16.7%,p=0.022) graft versus host disease (GVHD) compared to BM transplant (BMT) recipients. There was no graft rejection (GR) after co-transplant, but GR happened two patients (7.7%) in BMT group(p=0.132).We found insignificant difference in neutrophils (18.7vs.19.9 days, p= 0.956) and platelet (24.7vs. 26.2 days, p=0.235) engraftment time between the co-transplant and BMT group. All patients were followed up until june 30, 2014, the 5 year probability of overall survival (OS), transplant free survival (TFS) and transplant-related mortality (TRM) were similar for the two groups. The 5-year probability of OS and TFS were 89.7% and 89.7% in the co-transplant group, 92.3%and 84.6% after BMT (P=0.740 and 0.573, respectively). Conclusions: Our data suggest that the lower risk of GVHD is retained with co-transplant group. The incidence of GR lower in the co-transplant group, although a larger cohort of patients will be needed to confirm this inital obser-vation.Here,we suggest transplantation of G-CSF primed BM a,nd CB of same sibling appears to be a feasible and effective strategy to further optimize outcomes of HSCT for TM with decreasing the risk of the occurrence of GVHD. Disclosures No relevant conflicts of interest to declare.

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Combined Transplantation of Bone Marrow and Umbilical Cord Blood of Same Sibling in Twenty Three Children with Beta-Thalassemia Major

Blood ◽

10.1182/blood.v120.21.4506.4506 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4506-4506

Author(s):

Wu Xuedong ◽

Li Chunfu ◽

Xiaoqin Feng ◽

Yuelin He ◽

Xiaohui Zhou ◽

...

Keyword(s):

Bone Marrow ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Conflicts Of Interest ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Stimulating Factor

Abstract Abstract 4506 Objective: To investigate the effect of transplantation using bone marrow plus umbilical cord blood from same sibling in children with β-thalassemia major (TM). Methods: Twenty three TM patients undergoing transplantation of bone marrow and umbilical cord blood of same sibling aged from 4.0 to 12 years, 13 boys and 10 girls, were recruited at the Department of Pediatrics, Nanfang Hospital, Southern Medical University from January 2005 to June 2012. The patients were classified into three classes, class¢ñ to class ¢ò 22 cases and class ¢ó 1 case. Donors ranged 1–4 years received 10 Ìg/kg per day of subcutaneous granulocyte colony-stimulating factor (G-CSF) for 5 consecutive days. Bone marrow was harvested on the fifth day. Bone marrow and umbilical cord blood of the same sibling then were transfused into the patient. Results: Recovery of hematopoiesis was gained in all patients 4 weeks following transplantation. Seventeen patients suffered from infection of different degree. Six patients developed mild venous occlusive disease. Four patients developed grade¢ñacute graft-versus-host disease (GVHD), and one developed grade¢ñchronic GVHD. Of twenty three patients, twenty survived, three died of whom, one died of lung infection and heart failure 32 days following transplantation, one died of organ failue on 47days after transplantation, and the other one died of lung fugal infection 22 months after transplantation. Conclusion: Combined transplantation of granulocyte colony-stimulating factor primed bone marrow and umbilical cord blood of same sibling in children with β-thalassemia major is safe and effective with promising results. However, complications should be paid high attention following transplantation. Disclosures: No relevant conflicts of interest to declare.

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COMBINED UMBILICAL CORD BLOOD AND BONE MARROW TRANSPLANT ATION IN THE TREATMENT OF BETA-THALASSEMIA MAJOR

Pediatric Hematology and Oncology ◽

10.1080/088800100276299 ◽

2000 ◽

Vol 17 (4) ◽

pp. 307-314 ◽

Cited By ~ 12

Author(s):

Evgenios Goussetis ◽

Julie Peristeri ◽

Vasiliki Kitra ◽

Antonios Kattamis ◽

Demetrios Petropoulos ◽

...

Keyword(s):

Bone Marrow ◽

Cord Blood ◽

Bone Marrow Transplant ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Thalassemia Major ◽

Marrow Transplant ◽

Beta Thalassemia ◽

Beta Thalassemia Major

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Third party cord blood transplant boosts autologous hematopoiesis in a case of persistent bone marrow aplasia after double transplant failure for β-thalassemia major

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2013.029 ◽

2013 ◽

Vol 5 (1) ◽

pp. e2013029

Author(s):

Giuseppe Visani ◽

Paola Picardi ◽

Barbara Guiduccu ◽

Claudio Giardini ◽

Moira Lucesole ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Cord Blood ◽

Conditioning Regimen ◽

Thalassemia Major ◽

Third Party ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Donor Chimerism ◽

Transplant Failure

A 9-year-old female received a double allogeneic stem cell transplant (SCT) from an ABO-incompatible HLA-matched sibling for β-thalassemia major, without achieving a complete donor chimerism. Subsequently, the patient received autologous SCT and five donor lymphocyte infusion, without increasing donor chimerism. After the double transplant failure, we performed an unrelated transplant from a full-matched umbilical cord blood (UCBT). Due to the severe immunosuppression of the patient, we did not administer any conditioning regimen nor GVHD prophylaxis. On day +40 after UCBT, trilinear engraftment was documented. Surprisingly, the hematopoietic reconstitution was related to the re-expansion of the autologous (β-thalassemic) hematopoietic stem cell, as documented by chimerism studies on both peripheral blood and bone marrow. At present, 30 months after UCBT, there is stable hematopoietic autologous reconstitution. This is the first description of the restoration of autologous hematopoiesis obtained with cord blood infusion in a thalassemia-major patient after a double transplant failure.

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Encouraging Outcome of Using Sibling HLA-Matched Fresh Cord Blood for Children β-Thalassemia Major Transplantation

Blood ◽

10.1182/blood-2018-99-118973 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3459-3459 ◽

Cited By ~ 1

Author(s):

Jianyun Wen ◽

Libai Chen ◽

Sixi Liu ◽

Yuelin He ◽

Yongsheng Ruan ◽

...

Keyword(s):

Stem Cell ◽

Cord Blood ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Thalassemia Major ◽

Effective Treatment Option ◽

Hematopoietic Stem ◽

Advantages And Disadvantages

Abstract Background: Hematopoietic stem cell transplantation(HSCT) is currently the only curative treatment for thalassemia major (TM). Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source. Methods: We conducted a retrospective study of fresh cord blood transplantation (F-CBT) from the matched human leukocyte antigen (HLA)-identical sibling donors in 35 children (median age at transplantation: 4 years, range:1-7 years) with β-TM from June 2010 to December 2016. The conditioning protocol included intravenous busulfan, cyclophosphamide, fludarabine, and thiotepa. Results:The median collected CB volume was 130ml (range: 79-209ml). The median infused total nucleated cell (TNC) dose was 9.38×107/kg (range: 2.73-18.91×107/kg). One patient had graft failure (GF) on +30day after F-CBT and one patient died from respiratory and heart failure that developed from a pulmonary infection. Of the 33 patients who had a successful engraftment, two patients developed grade II~III acute graft-versus-host disease(GVHD); and one with grade I extensive chronic GVHD was observed during the long-term follow-up period. The median time to neutrophil recovery was +27 days (range: +14 to +49days). The platelet and hemoglobin engraftment times were +33 days (range: +19 to +73 days) and +26 days (range: +11 to +74 days), respectively. All the patients were followed up by December 31, 2017; the median follow-up time was 45 months, and the estimated 5-year overall survival (OS) and TM-free survival (TFS) of F-CBT were 97.1% and 94.2%, respectively. Conclusions: F-CBT from a matched HLA-identical sibling donor is an effective treatment option for β-TM in children with less GVHD. Disclosures No relevant conflicts of interest to declare.

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CD133 Is a Positive Marker Of Human Cord Blood-Derived CD34-Negative Hematopoietic Stem Cells

Blood ◽

10.1182/blood.v122.21.1177.1177 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1177-1177

Author(s):

Masaya Takahashi ◽

Yoshikazu Matsuoka ◽

Keisuke Sumide ◽

Ryusuke Nakatsuka ◽

Tatsuya Fujioka ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Cord Blood ◽

Conflicts Of Interest ◽

Expression Profiles ◽

Severe Combined Immunodeficiency ◽

Human Cord Blood ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Nog Mice

Abstract Background We have previously identified very primitive human cord blood (CB)-derived CD34-negative (CD34-) severe combined immunodeficiency (SCID)- repopulating cells (SRCs) using the intra-bone marrow injection (IBMI) method (Blood 2003:101;2924). A series of our studies suggests that the identified CD34- SRCs are a distinct class of primitive hematopoietic stem cell (HSC) and that they are at the apex of human HSC hierarchy. Recently, we developed a high-resolution purification method for primitive CD34- SRCs using 18 lineage (Lin)-specific antibodies, which can enrich CD34- SRC at 1/1,000 level (Exp Hematol 2011: 39:203). In the present study, we tried to identify the positive marker of CD34- SRCs in order to further purify and characterize the CD34- SRCs (HSCs). Materials and Methods First, we extensively analyzed candidate positive markers, including known HSC markers and various adhesion molecules by FACS using highly purified CB-derived 18Lin-CD34+/- cells. Finally, we identified CD133 as a positive marker of human CB-derived CD34- SRCs. Then, CB-derived 18Lin- CD34+/-CD133+/- cells were sorted by FACS, and hematopoietic stem/progenitor cell (HSPC) capacities of these four fractions of cells were extensively investigated. HSPC capacities were evaluated using (1) colony-forming cell (CFC) assays, (2) measurement of maintenance/production of CD34+ cell capacities in co-cultures with human bone marrow-derived mesenchymal stromal cells (BM-MSCs) (Blood 2010:24:162), (3) SRC activities using NOG mice, (4) limiting dilution analyses (LDA) to determine the SRC frequency in the 18Lin-CD34-CD133+ fractions, and (5) comparison of gene expression profiles between 18Lin-CD34+/-CD133+/- cells by real-time RT-PCR. Results Seventy-five percent of 18Lin-CD34+ and 13.5% of 18Lin-CD34- cells highly expressed CD133. In the CFC assays, the plating efficiencies of 18Lin-CD34+CD133+, CD34+CD133-, CD34-CD133+ and CD34-CD133- cells were 57%, 65%, 39% and 19%, respectively. Interestingly, most of 18Lin-CD34-CD133+/- cells formed erythroid-bursts (71% and 73%) and erythro/megakaryocytes-containing mixed colonies (25% and 27%). On the contrary, they formed few granulocyte/macrophage colonies (4.2% and 0%). Then, we co-cultured these four fractions of cells with human BM-MSCs. One thousand of 18Lin-CD34+/-CD133+/- cells were seeded into each well and cells were co-cultured for 7 days in the presence of SCF+TPO+FL+IL-3+IL-6 +G-CSF. Both the 18Lin-CD34-CD133+/- cells produced CD34+ cells. However, the percentage and absolute number of CD34+ cells produced from 18Lin-CD34-CD133+ cells (31.7 % and 3.2 x 104 cells) were greater than those of 18Lin-CD34-CD133- cells (13.2 % and 0.4 x 104 cells). In addition, both the 18Lin-CD34- CD133+/- cells generated higher percentages (13.5 % and 11.5%) of CD41+ cells compared to those of the 18Lin- CD34+CD133+/- (1.8% and 4.2%) cells. Collectively, 18Lin-CD34+/-CD133+/- cells showed different in vitro lineage differentiation potentials. Then, these four fractions of cells were transplanted into NOG mice by IBMI. We performed primary and secondary transplantations for up to 36 weeks. In the results, all of the mice received 18Lin-CD34+CD133+ cells (n = 5) or 18Lin-CD34-CD133+ cells (n = 9) showed primary and secondary human CD45+ cell repopulations. However, neither 18Lin-CD34+CD133- cells nor 18Lin-CD34-CD133- cells showed human cell repopulations (n = 6 in each group). These results clearly demonstrated that the CD133 expression clearly segregated SRC activities in the 18Lin-CD34+/- cells. Moreover, LDA demonstrated that the frequency of SRCs in the 18Lin-CD34-CD133+ fraction was 1/142. Interestingly, HSC self-renewal maintenance genes, such as Notch1, HoxB4, HoxA9, and Bmi-1, were highly expressed in both 18Lin-CD34+/-CD133+ cells. Conclusion These results clearly demonstrated that CD133 is a positive marker of human CB-derived CD34- SRCs (HSCs). Furthermore, CD133 segregated SRC activities of 18Lin-CD34- as well as 18Lin-CD34+ cells in its positive fractions. More importantly, these findings suggest that number of CD133+ cells in cord blood units is a more appropriate marker to detect/predict HSC potentials in cord blood stem cell transplantation in comparison to currently used CD34+ cell numbers. Disclosures: No relevant conflicts of interest to declare.

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Improved Outcomes in Patients with Thalassemia Major Transplanted with Peripheral Blood and Marrow Grafts in Comparison with Cord Blood and Bone Marrow Grafts from Sibling Donors

Blood ◽

10.1182/blood.v128.22.847.847 ◽

2016 ◽

Vol 128 (22) ◽

pp. 847-847

Author(s):

Qiao chuan Li ◽

Jian ming Luo ◽

Zhong ming Zhang ◽

Lian jin Liu ◽

Ling ling Shi ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Cord Blood ◽

Graft Rejection ◽

Peripheral Blood ◽

Cumulative Incidence ◽

Conditioning Regimen ◽

Thalassemia Major ◽

Matched Sibling

Abstract Background: Thalassemia major (TM) is a fatal genetic disease currently only curable with allogeneic stem cell transplantation. This is limited by the lack of suitable donors and the quantity of collected stem cells, and is often complicated by graft rejection and graft versus host disease (GVHD). Methods: The aim of the study was to compare the outcomes of TM patients transplanted with matched sibling cord blood (CB) and bone marrow (BM) grafts vs. matched sibling peripheral blood (PB) stem cell and BM grafts. The trial was designed as a prospective, open-label, single-center clinical protocol, where 204 TM patients were enrolled between January 2007 and November 2015 and transplanted with either PB + BM (n=99) or CB+BM (n=105), from an HLA-identical sibling donor. This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University and was registered at the Chinese Bone Marrow Transplant Registry (CBMTR). The primary end point was 2-year thalassemia free survival(TFS). Secondary end points included 2-year overall survival (OS), the cumulative incidence of GVHD, transplant related mortality (TRM), graft rejection (GF).The conditioning regimen were:1) busulphan (BU) (1.25 mg/kg) given orally four times per day for 4 days or 1mg/kg given intravenously (IV) four times per day for 4 days (day -9 to day -6); 2) fludarabine (FLU) (50mg/m2/day) given IV for 3 days (day -12 to day -11); 3) cyclophosphamide (CTX) (50 mg/kg/day) given IV for 4 days (day -5 to day -4); 4) anti-thymocytes globulin (ATG, Genzyme ) (2.5 mg/kg/day) given IV for 4 days (days -4 and day -1). All patients were placed on 30 mg/kg hydroxyurea orally once daily for 2-3 months before transplantation.GVHD prophylaxis consisted of a combination of cyclosporin A, methotrexate and mycophenolate mofetil regimen. [BMT 2009; 43(1):61-67]. Results : Patient and donor characteristics, and transplantation outcomes are listed in Tables 1 and 2, respectively. Data cut off for survival follow-up was March 31, 2016. The median follow-up time was 26 months (range, 4 months -105 months). Both neutrophil as well as platelet engraftment occurred significantly faster in the PB+ BM group than the CB+BM group (11 days vs. 13 days, P=0.001 and 15 days vs. 25 days, P=0.001, respectively). The rate of GF was the same in both groups (1.0%). The cumulative incidence of grade II-IV acute (a) GVHD and extensive chronic (c)GVHD in the PB+ BM group was higher than the CB+BM group: aGVHD=15.5% vs 1.0%, P=0.001; cGVHD= 6.4% vs. 0%, P=0.013. The cumulative rates of TRM at 2 years remained significantly lower in the PB+BM group compared to the CB+BM group with 2.0% and 12.5%,(P=0.005), respectively . Both OS and TFS at 2 years favored the PB +BM group compared to the CB+BM group : OS=98% vs. 86.5%,P=0.003;TFS= 97% vs. 86.5%, P=0.008.(Fig 1) Conclusion: Our results demonstrate that grafts composed of PB + BM had superior overall outcomes compared to CB + BM grafts, as evidenced by faster engraftment and lower TRM of the former despite substantially lower aGVHD and cGVHD rates of the latter. The mixed stem cell populaitons and the high cell dose achieved with the use of 2 different graft sources, toghether with the conditioning regimen used likely contributed to the superior outcomes seen with this regiem. This strategy could be of great benefit for the treatment of patient with TM and other benign hematologic disease. Disclosures No relevant conflicts of interest to declare.

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