Complementary Transplantation with Haploidentical Stem Cells and Unrelated Cord Blood in Thalassemia Major

Abstract Background Effects of haploidentical stem cells (Hap-SC) and unrelated cord blood (UCB) transplant are unsatisfactory in thalassemia major (TM) so far. High rejection and low TM-free survive (TFS) were key clinical issues. Increased rejection often offset the effort of lowered GVHD. The effect of alloreactive clone destruction in post-transplant cyclophosphamide (Cy, PTCy) transplant resulted in low GVHD and high relapse but nice immuno-recovery and immuno-tolerance by keeping antivirus and regulatory T cells. These may just complement the congenital insufficiency, delay engraftment and slow immuno-recovery, of UCB transplantation. Conversely, graft vs. leukemia effect and controllable GVHD from naive T cells of UCB offset the lack above of hap-SC transplant with PTCy. Therefore, we developed a novel complementary transplant with Hap-SC and UCB (CT-hap-CB) for leukemia and TM patients. Patients and method Thirty-six TM patients received CT-hap-CB between December 2013 and June 2016. Median age was 8 (range, 3-24) years old. Median follow-up time was 19 (2-25) months. Conditioning (Regimen, CT-13) included Cy on day-8 to -7, Busulfan on day-6 to -4, Fludarabine on day-6 to -2 and Thiotepa on day-3. GVHD prophylaxis consisted of Cy on day+3 to +4, Mycophenolate mofetil and Tacrolimus from day+6. Noteworthily, UCB was infused on day+6. The latter 26 TM patients received additionally Thymoglobuline on day -11 to -9 (Regimen, CT-14). Results Preponderance engraftment of hap-SC, UCB, mixed stem cells (MSC) and rejection in16, 14, 3 and 3 patients, respectively, at the last follow-up. Initial (day+28) full hap-SC, UCB and MSC chimerism occurred in 15, 7 and 12 patients. Cells derived from UCB overtime were dominant instead of initial majority from hap-SC (Fig. 1) in MSC group. 7/10 UBS with centromeric B motif engrafted. Median times to neutrophil ≥ 0.5x109/L, platelet ≥ 20 x109/L and hemoglobin ≥ 80 g/L were day+20.0 (range; 14-47), 11.0 (9-162) and 11 (1-39); 47.0 (34-113), 66.0 (12-227) and 46.0 (13-63); and 24 (1-46), 14 (11-116) and 8 (4-91), respectively, in initial hap-SC (n, 15), UCB (n, 7) and MSC (n, 12) groups. Overall survive, thalassemia free survive (TFS), rejection and mortality related transplant were 91.2%, 85.7%, 5.6% and 8.8%, respectively. Impressively, all of the 26 patients who received CT-14 protocol were alive without TM (Fig. 2). Grade II, III and IV acute GVHD occurred in 3 patients, respectively. One patient died of grade IV GVHD and another died of infection when the parents abandoned therapy after rejecting graft. Chronic GVHD was mild and rare. Summary CT-hap-CB resulted in high OS and TFS, especially CT-14 leaded to 100% TFS with low GVHD rate. MSC engraftment improved hematopoietic recovery of UCB. KIR and HLA typing impacted what stem cells engraftment. The multicenter study should be developed in the future. Figure 1 Kinetics of Mixed Chimerism in TM-SCT Figure 1. Kinetics of Mixed Chimerism in TM-SCT Figure 2 Thalassemia-free survive resulted from regimen CT-14 in thalassemia transplant Figure 2. Thalassemia-free survive resulted from regimen CT-14 in thalassemia transplant Disclosures No relevant conflicts of interest to declare.

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Complementary Transplantation with Haploidentical Stem Cells and Unrelated Cord Blood for Leukemia and Thalassemia

Blood ◽

10.1182/blood.v128.22.1235.1235 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1235-1235

Author(s):

Chunfu Li ◽

Yuelin He ◽

Xuedong Wu ◽

Xiaoqin Feng ◽

Jianyun Liao ◽

...

Keyword(s):

Stem Cells ◽

Cord Blood ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Mixed Chimerism ◽

Gvhd Prophylaxis ◽

Grade Ii ◽

Unrelated Cord Blood ◽

Kinetics Of

Abstract Background Unrelated Cord Blood (UCB) Transplantation is a potentially curative therapy for leukemia and thalassemia; however, engraftment failure and slow immune reconstitution remain key clinical issues. We hypothesized that complementary transplantation (CT) of UCB with haploidentical stem cell graft (hap-SC) tolerized with post-transplant cyclophosphamide would result in rapid engraftment and low relapse rate without additional risk of graft-versus-host disease (GVHD). Therefore, we developed a novel complementary transplant approach. Patients and Method Sixty-six patients received CT between December 2012 and June 2016. Of them, 30 patients had malignance diseases (MD), including 11 lymphoid and 19 myeloid diseases, and 36 had thalassemia major (TM). Median age was 12 (range; 2-13) and 8 (3-17) years in the MD and TM group, respectively. Median follow-up time was 13 (7-32) and 19 (2-25) months, respectively. Conditioning (Regimen CT-13) included Cyclophosphamide on day-8 to -7, Busulfan on day-6 to -4, Fludarabine on day-6 to -2 and Thiotepa on day-3. Hap-SC was infused on day 0. GVHD prophylaxis consisted of Cyclophosphamide on day+3 to +4. UCB was infused on Day+6. Mycophenolate mofetil and Tacrolimuswas started on day+6 for GVHD prophylaxis. For 26 TM patients transplanted since 2014, they received identical regimen except with the additional Thymoglobulin on day -11 to -9 (Regimen CT-14). Results The chimerism status at last follow-up was Hap-SC, UCB, mixed stem cells (MSC) and rejection in 20, 9, 1 and 0 patient in the MD group; and 16, 14, 3 and 3 patients in the TM group. Interesting, the initial chimerism on day+28 in the TM group was Hap-SC, UCB and MSC engrafted in 15, 7 and 12 patients, respectively. Thus, the MSC was not stable in TM patients; UCB typically became dominant overtime instead of the initial majority from hap-SC (Fig. 1). In the MD group, the time to neutrophil >= 0.5x109/L, platelet >=20 x109/L and hemoglobin >=80 g/L was day+18 (14-36), +10.0 (6-51) and +7 (1-20) in the final hap-SC engrafted group; and+30 (22-35), +25 (1-64) and +7 (3-28) in the final UCB engrafted group. Overall survive (OS), disease-free survive (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were 75.6%, 64.3%, 24.7£¥ and 13.7%, respectively, in all 30 MD patients; and 79.3%,73.8%,15.5% and 12.3% (Fig.2), respectively, in the 25 cases with complete remission (CR) at the time of transplantation. The corresponding data were 89% vs. 88.9%£¬65.0% vs. 77.8%£¬31.1 % vs.12.5% and 10.3% vs.11.1%£¨p>0.05 in all pairs), respectively, in hap-SC and UCB engrafted groups. Donor carrying KIR centromeric B motif was associated with reduced RI (10 % vs. 33.9%). In TM group, OS, thalassemia free survive (TFS), rejection and transplant-related mortality were 91.2%, 85.7%, 5.6% and 8.8%, respectively in all 36 patients. Impressively, all of the 26 patients who received the newer CT-14 protocol were alive without TM (Fig. 2). 7/10 UCB carrying KIR centromeric B motif engrafted. In the MD group, 23.3% had grade II-IV and10.0% had III-IV acute GVHD. Grade II, III and IV acute GVHD occurred in 3 patients, respectively, in TM group. One MD patient had severe chronic GVHD (lung) after DLI for relapse. No moderate chronic GVHD occurred in TM groups. Summary The CT-13 regimen resulted in high OS and DFS, especially in CR patients in the MD group. The CT-14 leaded to 100% TFS in thalassemia patients. Acute and chronic GVHD were acceptable. Donor carrying centromeric B motif promoted engraftment and reduced RI. A multicenter study should be developed in the future based on our favorable results. Figure 1. Kinetics of mixed chimerism in thalassemia patients Figure 1. Kinetics of mixed chimerism in thalassemia patients Figure 2. Results of malignance diseases in CR status at the time of transplant Figure 2. Results of malignance diseases in CR status at the time of transplant Figure 3. Thalassemia-free survive resulted from regimen CT-14 Figure 3. Thalassemia-free survive resulted from regimen CT-14 Disclosures No relevant conflicts of interest to declare.

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Unrelated Cord Blood Transplants in Children/Adolescents in Multi-Racial Singapore.

Blood ◽

10.1182/blood.v110.11.5089.5089 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5089-5089

Author(s):

Poh-Lin Tan ◽

Ah-Moy Tan ◽

Mei-Yoke Chan ◽

Mariflor Villegas ◽

Allen Yeoh ◽

...

Keyword(s):

Cord Blood ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Chronic Gvhd ◽

Severe Combined Immunodeficiency ◽

Hla Antigen ◽

Cell Dose ◽

Malignant Group ◽

Unrelated Cord Blood

Abstract Alternative donor choices are limited in multi-racial, multi-ethnic societies with small families such as Singapore. Unrelated cord blood transplant (UCBT) provides a feasible alternative to patients lacking adult stem cell donors. We reviewed the Singapore experience in UCBT for 29 children/adolescents with malignant (N = 19) and non-malignant diseases (N = 10) from 1998 – 2006. A significant 25% of patients were of varied South-East Asian (SEA) descent with majority being SEA-Chinese. The median age at UCBT was 6.7 (0.5 – 17.7) years with younger patients in the non-malignant compared to the malignant group (4.7 versus 8.8 years). Malignant indications for UCBT included acute lymphoblastic leukemia (ALL, N = 12), acute myeloid leukemia (N = 4), chronic myeloid leukemia (N = 2) and hemophagolymphohistiocytosis (N = 1); and non-malignant indications severe combined immunodeficiency disease (N = 3), CD40 ligand deficiency (N = 2), chronic granulomatous disease (N = 1), leukocyte adhesion disease (N = 1), thalassaemia (N = 2) and Fanconi anemia (N = 1). Seventeen patients received myeloablative conditioning (MAC), 12 received reduced intensity conditioning (RIC). Of the 12 RIC patients, 8 received dual UCBT with a median total nucleated cell dose (TNC) of 7.2 (3.4 – 12.2) x 10(7)/kg, CD34 cell dose of 1.7 (0.7 – 3.7) x 10(5)/kg compared to a median 6.2 (2.4 – 21.8) x 10(7)/kg, CD34 of 3.1 (0.2 – 297.6) x 10(5)/kg in MAC patients who received single UCBT.All except 3 patients received 1 – 2 HLA antigen mismatched cords. Sixteen of 19 and 6 of 10 patients in the malignant and non-maligant groups engrafted at a median of 19.5 (2 – 21) days and 20 (14 – 41) days, respectively. Nine and 2 of 17 malignant patients and none of non-malignant patients developed grade 1- III aGVHD and chronic GVHD, respectively. Thirteen of 19 patients and 8 of 10 patients in the malignant and non-malignant groups are alive at a median follow-up of 23 (9 – 48) months and 31 (14 – 73) months, respectively. The main cause of death was disease relapse in the malignant group (5 of 6 patients). In the malignant group, a select group of ALL patients (ALL-RIC, N = 6) was given dual UCBT after RIC with the aim to reduce transplant-related morbidity/mortality while preserving chances of engraftment, graft-versus-leukemia effects and long-term neuro-endocrine outcome. These patients received a median total nucleated cells (TNC) dose of 7.2 (3.4 – 12.2) x 10(7)/kg and CD34 cell dose of 2.0 (0.8 – 3.7) x 10(5)/kg recipient BW and were discharged at a median of 17 (12 – 16) days. Compared to another 6 ALL patients who received single UCBT after MAC (ALL-MAC), these received a median TNC of 5.4 (2.6 – 8.1) x 10(7)/kg and CD34 of 2.8 (0.6 – 297.6) x 10(5)/kg recipient BW and were discharged at a median of 59 (31 – 118) days. ALL-RIC and ALL-MAC patients engrafted at a median of 6 (2 – 28) days and 21 (14 – 37) days, respectively, with one primary graft failure in the ALL-MAC group. There were 4 relapses, 2 in each group at a median follow-up of 23 (12 – 30) months and 16 (3.5 – 48) months, respectively. More patients in ALL-RIC group developed acute GVHD compared to the ALL-MAC (83% versus 33%). All patients except 1 from each group are alive as of last follow-up, with death occurring from a road-traffic accident while in complete remission and one from relapse in the ALL-RIC and ALL-MAC groups, respectively. UCBT successes in children/adolescent is high in multi-racial Singapore using conventional and novel approaches.

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A Prospective Study on the Feasibility of Related and Unrelated Donor Search and Hematopoietic Cell Transplantation for Adults with Acute Leukemia at 31 European Transplant Centers

Blood ◽

10.1182/blood.v112.11.2385.2385 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2385-2385

Author(s):

Vanderson Rocha ◽

Mutlu Arat ◽

Vladimir Koza ◽

Norbet C Gorin ◽

Augustin Ferrant ◽

...

Keyword(s):

Acute Leukemia ◽

Cord Blood ◽

Hla Typing ◽

First Year ◽

Unrelated Donor ◽

Alternative Donor ◽

Family Donor ◽

Unrelated Cord Blood ◽

One Year

Abstract Currently, a donor can be virtually found for all patients with an indication for allo-transplantation due to the increased number of hematopoietic stem cell (HSC) donors and increasing use of umbilical cord blood and haplo-transplants. In this study, we have addressed the question of the feasibility of searching HSC donors grafts [HLA-matched sibling donor (MSD), and alternative donors] and performing such transplants or other treatments (such as autologous HSC transplant or chemotherapy) for adults with acute leukemia for whom an indication of allo-HSCT could be planned during the course of their disease. The second objective was to compare in an “intent to treat” analysis, LFS according to planned strategy treatment. Patients were included at HLA typing test. A specific questionnaire was completed specifying the initial strategies planned for each patient and their changes over the period: at HLA typing, after 3, 6, 9, 12 months after the registration, and twice a year for the following 2 years. From 2003 to 2006, 702 adults were enrolled by 31 EBMT centres, 490 had AML, 212 ALL. HLA typing was performed for 443 patients at diagnosis, 172 after first CR, 11 after CR2, and 64 in more advanced phase. Median follow-up was 31 months, median age was 42-years (18–75); 207 patients were aged more than 50 years. A MSD was found for 309 patients (44%). Of 309 patients, 290 patients had 1 MSD, 17 patients 2 MSD and only 2 patients more than 2 donors. In 40 cases where the MDS was found the transplant centres did not planned to perform the transplant. A transplant using a haploidentical donor was planned in 4 cases. At the end, 273 patients were planned to be transplanted from a family donor (269 from a MSD and 4 from an haplo). For the remaining 429 patients, the indication of an auto-HCT was made in 85 (20%) patients, use of chemotherapy as post-remission therapy in 142 (33%) and indication of an allo-HSCT with an alternative donor in 202 (47%). Of those 202 patients, the transplant centres were keen to search for a cord blood donor in 72 cases and for a haplo donor in 11 cases. Analysing the treatment received at the last follow-up and comparing with the strategy planned at the registration, 215 of 270 (80%) patients were transplanted with a family donor, 112 of 142 (79%) patients were still receiving chemotherapy, 53 of 85 (62%) received an autograft and 118 of 202 (58%) received an unrelated transplant. At last follow-up, 448 patients of 702 patients included received an HSCT (64%). Probability of survival at 2 years for 702 patients was 55%. Interval from HLA typing and HSCT was 125 days for MSD, 148 days for unrelated donor, 167 days for unrelated cord blood and 149 days for autologous transplantation. Cumulative incidence function at one year (CIF; using death as a competing event) for receiving an allograft was 81% if the strategy planned was an allograft with a MSD, 57% for those patients for whom an alternative donor was searched and 6% for those patients for whom an allo-transplant was not planed at inclusion. However, CIF at 1-year for really receiving an allograft was 74% in case of MSD, and only 30% for those patients not having an HLA identical siblingAt 2-years, LFS by initial planned strategy at HLA typing was 43% for those patients in whom a donor search was planned, 47% for those with a planned autologous HSCT, 46% for those with planned chemotherapy and 49% for those with a family transplant. In conclusion, the majority of patients (80%) with AL in European centres are HLA typed at diagnosis or CR1. The majority of patients received a MSD as planned treatment in the first year after HLA typing, in the absence of MSD an alternative donor was searched only for 51% of patients and CIF at one year for performing an allotransplant was 30% however in case of searching for alternative donor, transplantation could be performed in 57% of the cases in the first year. Surprisingly, searching for other alternative donors such as unrelated cord blood or haplo-identical donors, was only done for a small proportion of patients, in spite of encouraging results with both strategies. Therefore, in retrospective studies comparing outcomes of HLA identical sibling, and other alternative donor transplants there is a potential bias linked to the decision to search or not in half of the cases, that is probably linked to patients-, disease- and centre-related factors.

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Direct Intra-Bone Injection of Unrelated Cord Blood Cells Overcomes the Problem of Delayed Engraftment and Improves the Feasibility of Hematopoietic Transplant in Adult Patients.

Blood ◽

10.1182/blood.v110.11.334.334 ◽

2007 ◽

Vol 110 (11) ◽

pp. 334-334 ◽

Cited By ~ 1

Author(s):

Adalberto Ibatici ◽

AnnaMaria Raiola ◽

Marina Podesta ◽

Francesca Gualandi ◽

Nadia Sessarego ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Cord Blood ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Significant Proportion ◽

Hla Antigen ◽

Hematopoietic Stem ◽

Seeding Efficiency

Abstract Background. Cord blood transplants (CBT) are associated with delayed or failed engraftment in a significant proportion of patients (pts). Two of our previous observations suggested (i) that, in the animal model, direct intra-bone (i.b.) injection improves seeding efficiency and (ii) that the delayed engraftment was not related to an insufficient number of hematopoietic stem cells but rather to some difficulties to differentiate and maturate. Methods. Unrelated CB cells were selected for 29 consecutive pts (18 CB units were 4/6 HLA antigen matched, 10 were 5/6 and one 3/6 antigen matched). Median cell dose infused was 2.3 x10^7/kg (range 1.4 – 4.2). CB cells were concentrated in 4 syringes of 5 ml each and injected in the supero-posterior iliac crest (SPIC) under rapid general anesthesia (10 min. with propofol). Pts’ median age was 38 years (18–63); 25 had acute leukaemia (21 with refractory or relapsed disease and 4 high risk first remission leukemia); 2 chronic myeloid leukemia in advanced phase; 2 refractory Hodgkin’s disease. Most pts (n=24) were prepared with conventional conditioning regimen (TBI-cyclophosphamide). Results. The infusion of cells i.b. in SPIC (11 pts bilaterally; 18 pts monolaterally) was uneventful. Five pts are not evaluable because they died within 14 days from transplant. All pts surviving more than 14 days engrafted (100%). Median time for PMN (>0.5x10^9/l) and platelets (>20x10^9/l) engraftment was day +23 (14–40) and +38 (range 22–60) respectivelly. Four pts died of infection; one patient died of PTLD on day +140. Four patients relasped and 3 died of relapse. Fifteen out of 16 alive patients are in hematologic or molecular remission at a median follow up of 7.5 months (range 2–17). From day +30 full donor chimerism was documented in CD3, bone marrow cells and progenitor cells from both the injected and in non-injected SPIC; from day +30, CFC progenitors had already reached the lower values of the range of normal individuals in bilateral sites. These findings document the colonization of the hematopoietc system and the recovery of stem cell reservoir possibly due to an improvement of seeding efficiency. Only 3 pts (8%) experienced acute GvHD (2 grade II and 1 grade I); 4 pts. have moderate chronic GVHD. It is known that lymphocyte trafficking is one of the crucial factor in immunity. Two combined factors might contribute to the low incidence of acute GvHD: few of the transplanted T cells do not reach/circulate primarily in the lymphatic organs, where they would be immediately confronted with host antigen presenting cells as probably occurs after i.v. injection; injected T cells come immediately in contact with mesenchymal stem cells (MSC) and osteoblasts, known to be potent immunosuppressants. Conclusion. Direct intra-bone transplant of CB cells overcomes the problem of graft failure and is associated with reduced incidence of acute GvHD even when low numbers of HLA mismatched CB cells are transplanted. Nearly all patients searching for a CB unit were able to undergo CBT. This approach may change our policy of hemopoietic cell transplants.

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Engraftment of Donor Cells after Allogeneic Stem Cell Transplantation: Comparison and Impact of Chimerism in Whole Blood and Peripheral CD3+ T-Cells

Blood ◽

10.1182/blood.v128.22.5866.5866 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5866-5866

Author(s):

Yannick Le Bris ◽

Berger Florian ◽

Audrey Menard ◽

Thierry Guillaume ◽

Pierre Peterlin ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cord Blood ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Whole Blood ◽

Mixed Chimerism ◽

Post Transplant

Abstract Introduction: After allogeneic stem cell transplantation (allo-SCT), engraftment can be assessed by quantitative polymerase chain reaction (qPCR) using differing donor/recipient markers (Alizadeh et al. Blood, 2002), identified in peripheral blood DNA cells before transplant. We report here on the concomitant examination of the proportions of donor and recipient DNA in peripheral whole blood (WB) and sorted CD3+ T-cells on days +60 and +90, looking at their impact on survival. Patients, material and methods: This monocentric study evaluated the impact on outcomes of early WB and sorted CD3+ T cells chimerism independently and of the four possible combinations of chimerism between WB and sorted CD3+ T-cells. All follow-up chimerism samples from allo-SCT patients performed in adults at Nantes University Hospital between October 2009 and October 2016 were reviewed, focusing on those where both PB and/or CD3+ T-cells were evaluated on days +60 (45-75) and/or +90 (75-120) after allo-SCT. A global cohort of 229 patients (239 grafts) was retrieved, which includes 52 patients evaluable on day +60 only, 67 evaluable on day +90 only and 120 evaluable on both days +60 and +90. A threshold of >95% donor DNA was considered for complete chimerism. Disease free survival (DFS) was calculated from the date of graft until relapse, death or last follow-up. Overall survival (OS) was calculated from the date of graft until death or last follow-up. Chi square tests were used to compare incidences. Log rang test and Kaplan Meier were used to evaluate DFS and OS. Results: The whole cohort comprised 62% males and had a median age of 58 years old (20-74) at the time of allo-SCT. Patients were treated for myeloid-lineage disease in 59% of the cases. Reduced-intensity conditioning was used in 89% (n=212), donors were familial in 45% (n=107), registry in 48% (n=114). Unrelated cord blood units were used in 8% of the cases (n=18). Post-transplant cyclophosphamide (PTCY) was performed in 48 procedures including 33 and 15 with haplo (HG) and matched donors respectively. Considering the 239 allograft procedures, the median follow-up was 5.8 years (95% CI: 3.1-5.8), the rate of relapse 27% and the rate of death 31%. Complete WB chimerism was observed for 80% and 71% of the cases on day +60 and day +90 respectively. Complete CD3+ chimerism was present for 53% and 51% of the grafts at days +30 and +90 respectively. Thus, cases displaying both complete WB and CD3+ chimerism on days +60 and +90 were 53% and 51% respectively, while 27% and 20% were documented with full WB and mixed CD3+ chimerism on days +60 and +90. Mixed chimerism was observed in both WB and CD3+ cells in 14% of the cases on day +60 and 22% on day +90. Finally, a small proportion of patients (6% and 7% at days +60 and +90) displayed an intriguing complete chimerism in CD3+ cells yet mixed WB chimerism. None of these features appeared associated to disease lineage (lymphoid or myeloid) nor cord blood allo-SCT. Interestingly, of the 27 grafts with myeloablative conditioning, only 14 had full WB/CD3+ engraftment on day +60 or +90, and thus all 27 were retained for the study. None of the four WB/CD3 chimerism combinations at the two times considered had an impact on DFS in this cohort. Surprisingly, although full or mixed WB chimerism had no impact on DFS and OS at days +60 and +90, the presence of a mixed CD3+ chimerism (vs full) at day+90 was associated with a significantly better OS (median: 5.8 months years [95%CI: -not reached] versus 3.1 years [95%CI: 2.2- 3.1]; p=0.025). CD3+ chimerism at day+60 has no impact on OS. All HG resulted in full CD3+ chimerism at both time points compared to non HG (100% vs 52%, p<0.0001). The same was almost true when considering PTCY procedures: 90% at day+60 and 92% at day +90. Of note, there was no influence on DFS nor OS of WB or CD3+ chimerism status when considering only HG or PTCY grafts vs others in this series. Discussion: In this large series, early WB chimerism status did not predict outcome. Surprisingly, mixed CD3+ chimerism at day+90 appears to be significantly associated with a longer OS, suggesting that remaining recipient memory lymphocytes could be beneficial. This result has to be confirmed prospectively. It remains also to define the place of donor lymphocyte infusions (DLI) to prevent relapse in patients with full or mixed CD3+ chimerism post-transplant (analyses of DLI received in our patients are on-going). Disclosures Moreau: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria.

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Extended-cycle elutriation to adjust T-cell content in HLA-disparate bone marrow transplantation

Blood ◽

10.1182/blood.v82.1.307.bloodjournal821307 ◽

1993 ◽

Vol 82 (1) ◽

pp. 307-317 ◽

Cited By ~ 19

Author(s):

RR Quinones ◽

RH Gutierrez ◽

PA Dinndorf ◽

RE Gress ◽

AB Ney ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Bone Marrow Transplantation ◽

T Cell ◽

Marrow Transplantation ◽

Chronic Gvhd ◽

Lymphocytic Leukemia ◽

Mixed Chimerism ◽

Cell Content

We report the development of a double-cycle elutriation (DCE) technique separating 3 or greater logs of T cells from a stem-cell-enriched marrow fraction and the results of phase I T-cell depletion studies with HLA-disparate related bone marrow transplantation (BMT) donors in two patient groups. In group 1, 10 patients with refractory hematopoietic malignancies received combination chemotherapy, total body irradiation (TBI), and immunosuppression (pre- and post-BMT), and hematopoietic rescue with a marrow transplant, depleted of T cells by elutriation. Potentially to promote engraftment and a graft-versus- leukemia (GVL) effect, 0.5 to 0.75 x 10(5) T cells/kg were added back. All 10 patients engrafted. Five patients developed acute graft-versus- host disease (GVHD; four grade II, one grade III) and two subsequently developed chronic GVHD. Two patients have relapsed (median follow-up, 206 days; range, 46 to 1,035). Four patients died of BMT-related complications (three of infection, one of veno-occlusive disease [VOD]). Four patient are disease-free survivors (median follow-up, 960 days; range, 670 to 1,035). Group 2 included five infants, four with congenital lymphohematopoietic deficiencies and one with refractory acute lymphocytic leukemia (ALL). In these infants, busulfan and increased cyclophosphamide were substituted for TBI. Only the ALL patient received added T cells. Three patients engrafted: one has stable mixed chimerism, one relapsed with ALL, and one rejected the marrow. One patient had primary autologous recovery, while another failed to engraft. None developed GVHD. We conclude that, in this setting of HLA-disparate BMT with post-BMT antithymocyte globulin (ATG) and corticosteroids, DCE significantly depletes T cells from the marrow and that a defined number of T cells can be added without the occurrence of severe GVHD.

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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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Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major

Cell Transplantation ◽

10.1177/0963689721994808 ◽

2021 ◽

Vol 30 ◽

pp. 096368972199480

Author(s):

Xiaodong Wang ◽

Xiaoling Zhang ◽

Uet Yu ◽

Chunjing Wang ◽

Chunlan Yang ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cord Blood ◽

Cell Transplantation ◽

Chronic Gvhd ◽

Thalassemia Major ◽

Post Transplantation ◽

Donor Pool ◽

Unrelated Cord Blood ◽

Cmv Disease

Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.

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Acute Graft Versus Host Disease (GVHD) Is Increased in Patients Receiving Cyclosporine/Cellcept as Frontline Prophylaxis Against GVHD in Pediatric Patients Undergoing Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v108.11.2896.2896 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2896-2896

Author(s):

Sonali Lakshminarayanan ◽

Paul Szabolcs ◽

Vinod Prasad ◽

Suhag Parikh ◽

Susan Wood ◽

...

Keyword(s):

Bone Marrow ◽

Cord Blood ◽

Oral Therapy ◽

Pediatric Patients ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Grade Ii ◽

Unrelated Cord Blood ◽

Related Bone Marrow

Abstract Traditionally, pediatric patients are prophylaxed against GvHD with cyclosporine (CSA) plus either methotrexate (Mtx) or methylprednisolone (Pred). Mtx worsens the severity of mucositis and renal insufficiency while pred causes muscle wasting, hypertension, hyperglycemia and increased infections. Cellcept (myophenolic acid) is a better tolerated, less toxic agent with synergistic immunosuppressive effects when combined with cyclosporine or tacrolimus. We explored its use in combination with cyclosporine in 63 pediatric patients (49% male, 74% Caucasian, 36% CMV+) undergoing allogeneic transplantation. Patients with both malignant (n=24) and non-malignant (n=39) conditions ranging in age from 2 weeks to 26 years were transplanted after myeloablative preparative regimens with either related bone marrow or cord blood (n=11) or unrelated cord blood (n=52), using cellcept and cyclosporine for GVHD prophylaxis. Cellcept and CSA were administered intravenously through the first 40–60 days post transplant using cellcept at a dose of 15mg/kg/dose IV q8H beginning on day -2 or -3 and CSA in traditional fashion targeting trough levels of 200–450 (infusion) and 150–350 with intermittent dosing. The patient then transitioned to oral therapy at the same dose and schedule until day 100–180 for cellcept and day 270 for cyclosporine and then tapered if no active GVHD was present. There were no acute toxicities attributable to cellcept observed in patients on IV or oral therapy. Despite the lack of steroids in the GVHD prophylactic regimen, all patients required treatment with antihypertensive therapy. Grossly, infection rates did not vary from those previously observed in conventionally treated patients at our center. The cumulative incidence (CINC) of neutrophil engraftment by day 42 was 79.4% (95% CI 64.7–91.2) which is comparable to previous reports. Two patients engrafted after a second unrelated cord blood transplant. Of the six patients who did not engraft, 3 died of infectious complications, two died of VOD and multi-system organ failure and one died of congenital pulmonary hypertension. Of the 59 patients evaluable for GVHD, follow-up ranged between 52 and 994 days (median 224 days). The CINC of acute GVHD grades II–IV by day 100 was 64.1% (95% CI 47.8–82.1) and the CINC of acute GVHD grades III– IV by day 100 was 6.3% (95% CI 0–17.0). Follow-up is too short to comment on the incidence of chronic GvHD, but to date, 5 of 14 patients followed for >100 days have developed mild chronic GvHD. The incidence of grade II acute GVHD was higher than that previously reported in pediatric patients receiving CSA/Pred while the incidence of grade III–IV GVHD was comparable. While this data is early, it appears that the incidence of acute Grade II GVHD is increased compared to previous series in patients treated with cellcept instead of Mtx (related bone marrow transplantation) or pred (unrelated cord blood transplantation). Engraftment in UCBT recipients was not compromised with the use of IV cellcept administered in the peritransplant period. Overall, despite the use of steroids to treat aGVHD, there was overall steroid sparing with this regimen. Additional patients will need to be tested with this regimen and longer follow-up is necessary to fully define the risks or benefits of this therapy.

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Outcomes After Double Unit Unrelated Cord Blood Transplantation (UCBT) Compared with Single UCBT In Adults with Acute Leukemia In Remission. An Eurocord and ALWP Collaboration Study

Blood ◽

10.1182/blood.v116.21.910.910 ◽

2010 ◽

Vol 116 (21) ◽

pp. 910-910 ◽

Cited By ~ 3

Author(s):

Vanderson Rocha ◽

Myriam Labopin ◽

Mohamad Mohty ◽

Guillermo F Sanz ◽

Bernard Rio ◽

...

Keyword(s):

Multivariate Analysis ◽

Cord Blood ◽

Acute Gvhd ◽

Cord Blood Transplantation ◽

Chronic Gvhd ◽

Univariate Analysis ◽

Neutrophil Recovery ◽

Blood Transplantation ◽

Unrelated Cord Blood

Abstract Abstract 910 The Minnesota group has described that recipients of double unrelated cord blood transplantation (dUCBT) have a higher incidence of acute GVHD, lower relapse incidence (RI) but no difference in leukemia free survival (LFS) when compared to single unit UCBT (sUCBT) recipients. In order to confirm these results in a larger and more homogenous cohort of patients and to evaluate the effect of double UCBT in relapse and LFS, we have compared the outcomes after dUCBT (n=230) with sUCBT (n=377) in adult patients with acute myeloid or lymphoblastic leukemia in remission. There were some differences between the two groups: dUCBT recipients were heavier (median weight: 68kg vs 65kg, p<0.01), tended to be older (median age: 37 years vs 35 years, p=0.06), had lower frequency of poor cytogenetics (32% vs 36%, p=0.02), transplanted more recently (p<0.001), more frequently given RIC (53% vs 30%, p<0.001), and received less ATG/ALG (29% vs 70%, p<0.001) when compared to sUCBT recipients, respectively. No differences were observed in diagnosis (38% ALL and 62% AML), status of disease at transplant (CR1: 52%, CR2:40% and CR3:8%) and previous autograft (13%). As expected, dUCBT recipients received a graft containing a higher nucleated cell dose (median of 3.7×107/kg vs 2.6×107/kg; p<0.0001). Number of HLA disparities were not statistically different (5/6:32% and 4/6:58%) when compared to sUCB grafts. Two analyses for outcomes were performed: one in patients transplanted in CR1 and other in patients transplanted in CR2 or more. The differences between dUCBT and sUCBT remained the same in both analyses. Results: in patients transplanted in CR1, median follow-up was 17 months for dUCBT recipients (n=114) and 19 months for sUCBT recipients (n=203). Unadjusted univariate analysis showed that cumulative incidence (CI) of neutrophil recovery was 78% after dUCBT and 82% after sUCBT (p=0.11); acute GVHD was 45% and 27% (p<0.001), and chronic GVHD 21% and 27% (p=0.35), respectively. At 3 years, unadjusted CI of NRM and RI were 32% after dUCBT and 36% after sUCBT (p=0.89) and 15% and 25% (p=0.03), respectively. Estimated 3 years LFS was 53% after dUCBT and 39% after sUCBT (p=0.09). In multivariate analysis, adjusted for the differences between the 2 groups, dUCBT recipients have an increased risk of grade II-IV acute GVHD (HR 1.23, p=0.005) and decreased RI (HR:0.74, p=0.01) when compared to sUCBT recipients. In a multivariate analysis adjusted, neutrophil and platelets recovery, NRM and chronic GVHD were not statistically different after dUCBT or sUCBT. However, in a multivariate analysis, LFS was improved after dUCBT compared to sUCBT recipients (HR: 0.67, p=0.04). In patients transplanted in CR2 and CR3, median follow-up was 11 months for dUCBT recipients (n=116) and 22 mo for sUCBT recipients (n=174). Unadjusted univariate analysis showed that CI of neutrophil recovery was 85% after dUCBT and 83% after sUCBT (p=0.57); acute GVHD was 33% and 17% (p=0.003), and chronic GVHD 32% and 29% (p=0.64), respectively. At 3 years, unadjusted CI of NRM and RI were 34% after dUCBT and 36% after sUCBT (p=0.47) and 31% and 33% (p=0.68), respectively. Estimated 3 Y LFS was 35% after dUCBT and 31% after sUCBT (p=0.48). In multivariate analysis, adjusted for the differences between the 2 groups, outcomes after dUCBT recipients, namely neutrophil recovery, acute and chronic GVHD, NRM, RI and LFS were not statistically different between the two groups. In conclusion our study confirms the previous findings of higher incidence of acute GVHD, equivalent NRM and reduced relapse in adult recipients of dUCBT, mainly for those transplanted in CR1, showing a higher GVL effect with improved LFS. Outcomes after dUCBT in patients with CR2 and CR3 were not statistically different of sUCBT. Double UCBT has extended the use of UCBT for patients otherwise not eligible for single UCBT and importantly is associated with better outcomes in adults patients with AL transplanted in early phase of the disease. Disclosures: No relevant conflicts of interest to declare.

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