Outcomes after Double Umbilical Cord Blood Transplantation in Children: A Survey on Behalf of Eurocord and PDWP-EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2570-2570
Author(s):  
Federica Giannotti ◽  
Annalisa Ruggeri ◽  
Gerard Michel ◽  
Jean-Hugues Dalle ◽  
Tracey O'Brien ◽  
...  
Keyword(s):  
Single Unit ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Median Number ◽  
Cell Dose ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Double UCBT (dUCBT) has been used in adults to reach an acceptable cell dose. For most children a single unit with a total nucleated cell (TNC) dose >3x107/Kg can be easily identified, but that is not always the case for heavier patients (pts). Use of dUCBT might decrease relapse and increase graft-versus-host-disease (GvHD). Data on dUCBT in children are scarce in the literature. A recent randomized study in children has described similar outcomes after double compared to single UCBT. Our study provides an overview of the use of dUCBT in the pediatric population reported to Eurocord. We retrospectively analyzed the outcomes of unrelated dUCBT in 177 children transplanted between 2002 and 2012 in 61 EBMT centres. Analysis was performed separately for pts with malignant (n=139) and non-malignant (NM, n=38) diseases. Among pts with malignancies, 76 had ALL, 40 AML, 6 MDS, 2 CML, 11 NHL, 3 Hodgkin Lymphoma and 1 Multiple Myeloma. Median age at dUCBT was 15 years (1.3-17.9) and median weight was 55 kg (13-97). Disease status at dUCBT was 1st complete remission (CR) (36%), ≥2nd CR (34%) or advanced (25%), and missing in 5% of the pts. In this group, 117pts received a myeloablative conditioning (MAC) and 22 a reduced intensity regimen (RIC). Cyclophosphamide+fludarabine+TBI was administered to 41% of the pts; 55% received ATG in the conditioning. Median number of collected TNC was 5.7x107/kg (3,6-12,8). Considering the unit with the higher number of HLA incompatibilities with the recipient, 56% had 2 mismatches. GvHD prophylaxis was cyclosporine-A (CSA) based in 93% of the pts (58% received CSA + mycofenolate mofetil). Median follow-up was 31 months. Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 88% at 60 days and 64% at 180 days after dUCBT, and it was achieved with a median time of 24 and 45 days, respectively. Among the 122 pts with PMN engraftment, 85/94 with available data on chimerism were full donor and, of these, 20% had dual chimerism. CI of acute GvHD grade II-IV and grade III-IV at 100 days was 51% and 26%, respectively; it was significantly higher in pts who did not receive ATG (grade II-IV: 35% vs 67%, p=0.004; grade III-IV: 12% vs 37%, p=0.0075). Chronic GvHD was observed in 24/104 pts at risk (60% extensive; 2-year (yr) CI: 18%). The 2-yr CI of relapse was 31%. In univariate analysis, RIC, advanced stage at transplantation and a collected TNC dose lower than the median, were significantly associated with higher rates of relapse.The 2-yr CI of transplant related mortality (TRM) was 27%. Overall, 73 pts died: 35 of relapse, 15 of infections, 9 of GvHD and 14 of other causes. The 2-yr disease free survival (DFS) and overall survival (OS) were 42% and 45%, respectively. Among pts with NM disorders, 24 had bone marrow failure syndrome (BMFS) (10 Fanconi Anemia, 13 Acquired Aplastic Anemia and 1 other inherited BMFS), 2 hemoglobinopathies, 7 immune deficiencies and 5 metabolic disorders. Median age at dUCBT was 11 years (0.7-17.9) and the median weight was 40 kg (13-70). In this group, 27 pts received a RIC (40% TBI based), 10 a MAC (90% busulfan based), and 1 no conditioning regimen. ATG was administered to 82% of the pts and GvHD prophylaxis was CSA-based in 77%. The median number of collected TNC was 8.4x107/kg (1,2-11,2) and 60% of the grafts had ≥2 HLA mismatches with the recipient. Median follow-up was 39 months. Overall, 28 pts achieved PMN engraftment and 16 PLT engraftment, with a median time of 23 and 61 days, respectively. In univariate analysis, pts with BMFS compared to others had a significantly lower CI of PMN engraftment (58% vs 100%, p=0.002). Among the 10 pts who did not engraft, 3 had autologous reconstitution and 3 had a subsequent allogeneic HSCT. Forteen pts developed acute GvHD grade II-IV and 10/25 pts at risk had chronic GvHD (3 extensive). Overall 21 pts died (17 with BMFS): 9 of infections, 5 of GvHD and 7 of other causes. The 2-yr OS was 42% and it was significantly lower in pts with BMFS compared to those affected by other NM disorders (28% vs 70%, p=0.03). In pts with malignancies, despite a higher incidence of acute GvHD, DFS and OS seem to be comparable to those reported in the literature for single UCBT or HSCT from other alternative stem cell sources. In the NM disorders group, despite the high cell dose, dUCBT did not seem to improve results in pts with BMFS. This survey suggests that dUCBT is feasible in children and should be considered when a single unit with an adequate cell dose is not available. Disclosures No relevant conflicts of interest to declare.

HLA-DP Mismatches Increase the Risk of Acute GVHD after Unrelated Donor Hematopoietic Transplantation (UDT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3125-3125 ◽  
Author(s):  
Marcos de Lima ◽  
Simrit Parmar ◽  
Ping Liu ◽  
Poliana A. Patah ◽  
Pedro Cano ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii

Abstract The HLA class II DP locus encode for both subunits of DPB1 heterodimers, which have low levels of expression on the cell surface of antigen presenting cells. We hypothesized that donor-recipient HLA-DP mismatch would lead to an increased incidence of acute (a) graft-versus-host disease (GVHD), and that 2 mismatches would likely be even more significant. Methods: We studied 84 consecutive patients (pts) with myeloid leukemias in complete remission (CR) transplanted from 01/02 to 02/06. Preparative regimens were ablative IV Busulfan-based (n=58) or Cy/TBI (n=2), and reduced intensity (Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=8), and Flu/Melphalan 140 mg/m2 (n=16). Stem cell (SC) source was bone marrow (n=70) or peripheral blood (n=14). ATG was given in 78 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 31 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, and SBT/SSOP for HLA-C. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free (RFS) survival. Variables with a p-value <0.25 by univariate analysis were included in the multiple regression analysis (MV). Variables were age, gender, weight, conditioning regimen, GVHD prophylaxis, diagnosis, cytogenetics, SC source, ABO group, infused CD34 and CD3 cell dose, and HLA matching. AGVHD-free survival was calculated from transplant date to date of development of grade II–IV GVHD or completion of 100 days of follow-up. Results: Median age was 48 yrs (range, 14–72). Diagnoses were MDS (n=5), AML (n=58), and CML (n=21). 54 pts (64%) were beyond 1st CR; all CML pts were in >1st chronic phase (CP). Sixty-one pts were 10/10 HLA match (A, B, C, DRB1, DQB1), and 23 had one or more mismatches. All but one pt engrafted neutrophils at a median of 13 days. 33 pts (39%) and 13 pts (15%) developed grade II–IV and III–IV aGVHD, respectively. Chronic GVHD incidence was 51%. With a median follow-up of 18 mo. (range,1.3–52) 60 pts are alive; 40 pts have relapsed or died. Median survival has not been reached. Number of DP mismatches and incidence of aGVHD is shown in the table. The following covariates influenced aGVHD-free survival by MV analysis: Flu-based regimen (P=0.005; HR 0.25 (95%CI 0.1–0.66), reduced intensity regimens (p=0.02; HR 0.35 (95%CI 0.15–0.83) and presence of 2 DPB1 mismatches (p=0.02; HR 3.07 (95%CI 1.19–7.95). Presence of 1 DPB1 mismatch was not significantly associated with aGVHD. There was no statistically significant correlation between presence of 2 DP mismatches and RFS (P=0.17;HR 0.3 (95%CI 0.06–1.65);HR 0.75 for 1 mismatch) or with cGVHD. Actuarial 2-yr survival for 10/10 matched pts without DP mismatches (12/12) versus those with DP mismatches is 82% versus 71%(P=0.6). In the 10/10 matched group, GVHD was the cause of death only among recipients of 2 DP mismatches transplants (n=4). Conclusion: Mismatching at HLA-DPB1 may increase the risk of aGVHD following UDT. The role of DP in the development of GVHD and GVL effects merits future study. Incidence of acute GVHD 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 8% 0% 1 23% 8% 2 45% 18% < 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 45% 15% 1 82% 36% 2 80% 40%

Reduced-Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) for Patients Aged ≥60 Years: a Retrospective Study of 629 Patients From the Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 194-194 ◽  
Author(s):  
Patrice Chevallier ◽  
Didier Blaise ◽  
Noel-Jean Milpied ◽  
Mauricette Michallet ◽  
Jean-Paul Vernant ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Older Age ◽  
Unrelated Donor ◽  
Age Group ◽  
Grade Ii ◽  
Grade Iii

Abstract Abstract 194 Age has been previously demonstrated to be a major prognostic factor for outcome after allo-SCT. Many centres usually use an age threshold around 50 years for considering a standard myeloablative conditioning regimen, and around 65 years for considering a RIC regimen. The aim of this report was to assess the outcome of 629 patients aged ≥60 years who received RIC allo-SCT, with a special emphasis on the comparison of the outcome of patients aged 60–65 years (y.) and patients aged >65 y. Between 1998 and 2008, 629 patients with different haematological diseases were treated with RIC allo-SCT, and reported to the SFGM-TC Registry. This series included 417 males (66%) and 212 females (34%). The median age for the whole cohort was 62 (range, 60–71) y. 378 patients (55%) were diagnosed with a myeloid malignancy, while 240 (38%) had lymphoid malignancies, and 11 (2%) had other non-classifiable diseases. 478 patients (76%) had high risk disease features, and 151 (24%) had a standard risk disease. 386 patients (61%) received allo-SCT from an HLA-matched related donor, while 199 patients (32%) received the graft from a matched-unrelated donor, and 44 (7%) from mismatched donors. Peripheral blood stem cells were used in 83% of patients (n=520). The conditioning regimen consisted of Fludarabine and Busulfan in 280 cases (44.5%), Fludarabine and low dose TBI in 150 cases (24%). The remaining 199 patients (32%) received other so-called RIC protocols. With a median follow-up of 9 (range, 1–90) months after allo-SCT, grade II-IV and grade III-IV acute GVHD occurred at a median of 31 days after allo-SCT in 29% (n=182) and 12% (n=76) of patients, respectively. Chronic GVHD was observed in 145 patients (23%; limited: n=67; extensive: n=72; unknown stage: n=6). At last follow-up, 347 patients (55%) were still alive (of whom 205 in CR; 65%): 147 patients (16%) died of disease progression, and 180 patients died of transplant-related causes (TRM: 29%). The Kaplan-Meier (KM) estimates of overall survival (OS) at one and 2 years were 57% (95%CI, 53–62%) and 47% (95%CI, 42–52%), respectively. In order to assess the applicability of RIC allo-SCT to the older age group, we next compared the outcome of patients aged from 60 to 65 y. (n=516) and those aged >65 y. (n=113; median 66 y.; range, 65–71). Except for age, in univariate analysis, these 2 groups were not statistically different in terms of demographic, disease or transplant characteristics. Overall, the median time to ANC>500/μL was 18 (range, 1–102) days, with this being comparable between the younger (60–65 y.) and elderly (>65 y.) age groups (p=0.19). The incidences of grade II-IV and grade III-IV acute GVHD were comparable between both groups (60–65 y.: 29% vs. >=65y.: 30%, p=NS; and 12% vs. 12%; p=NS). The TRM incidence was 29% in the younger group vs. 27% in the older group (p=NS). The KM estimates of OS at 1 and 2 years were 58% (95%CI, 53–62%) and 47% (95%CI, 42–52%) in the younger age group and 55% (95%CI, 44–65%) and 48% (95%CI, 37–60%) in the older age group (p=NS). In a Cox multivariate analysis accounting for all relevant factors, age >65 y. was not found to be a statistically significant factor associated with worsened survival. Despite its retrospective nature and the inherent selection biases, this data support the use of RIC-allo-SCT in patients >60 y. Moreover, outcome of patients aged >65 y. appears to be comparable to that of patients aged 60–65 y. Physiologic aging is likely more important than chronologic aging. With the refinement of comorbidities scoring systems, age per se (at least up to 70 y.) should not be a contraindication to perform RIC allo-SCT and this should be tested prospectively. Disclosures: No relevant conflicts of interest to declare.

Randomized Phase II Trial Comparing Cyclosporine (CSP) and Tacrolimus (TAC) for Methotrexate (MTX)-Free Graft-Versus-Host Disease (GVHD) Prophylaxis after Allogeneic Transplantation from a Matched Related Donor (MRD) with a Reduced-Intensity Regimen Containing Cladribine and Busulfan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1170-1170 ◽  
Author(s):  
Sung-Won Kim ◽  
Takahiro Fukuda ◽  
Shotaro Hagiwara ◽  
Tsunehiko Komatsu ◽  
Tetsuya Goto ◽  
...  
Keyword(s):  
Whole Blood ◽  
Acute Gvhd ◽  
Trough Level ◽  
Chronic Gvhd ◽  
Gvhd Prophylaxis ◽  
Starting Dose ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii ◽  
Neutrophil Engraftment

Abstract Background: Although GVHD prophylaxis without MTX might enhance a graft-versus-leukemia effect, no randomized controlled trial (RCT) of GVHD prophylaxis has investigated this possibility in a reduced-intensity stem cell transplantation (RIST) setting. Therefore, we conducted a prospective randomized trial to compare CSP and TAC without MTX as GVHD prophylaxis in RIST from a MRD. Methods: Patients with hematological malignancies in complete remission or with a chemosensitive status were eligible for this study if they were either older than 50 years or had significant medical contraindications for conventional transplantation. The primary endpoint was the incidence of grade II-IV acute GVHD on day 100. Regimen-related toxicities (RRT) between day −8 and day 28 were assessed by NCI-CTC ver 2.0. The conditioning regimen consisted of cladribine (0.11 mg/kg × 6 days) and oral busulfan (4 mg/kg × 2 days). All patients received unmanipulated G-CSF-mobilized peripheral blood stem cells from a MRD. CSP (starting dose 3 mg/kg/day, target whole blood conc. 250–350 ng/mL, target trough level 150–250 ng/mL) or TAC (starting dose 0.03 mg/kg/day, target whole blood conc. 10–20 ng/mL, target trough level 5–10 ng/mL) was given as GVHD prophylaxis from day −1. G-CSF was administered from day +6 until neutrophil engraftment. Results: Sixty-eight patients were enrolled between 2/2003 and 2/2008, but 3 were removed before transplant because of disease progression or infection. The diagnoses included lymphoma (n=27; 10 FL, 6 DLBCL, 6 PTCL and 5 HL), AML (n=14), MDS (n=12), MM (n=5), MPD (n=4) and ALL (n=3). The median age of the patients (56 y vs. 55 y) and the median number of CD34+ cells infused (3.7 ×106/kg vs. 3.1 ×106/kg) were similar in the CSP and TAC arms. The median day of neutrophil engraftment in both arms was day 11. The proportion of patients in the CSP or TAC arm who achieved complete chimerism in CD3+ cell fraction on days 28, 56 and 90 was, respectively, 61% vs. 48%, 80% vs. 76% and 80% vs. 97%. Grade 4 RRT was hepatic disease (n=1, CSP arm), and grade 3 RRT included cardiac (n=1, CSP), renal (n=1, CSP), hepatic (n=2, CSP), oral mucosal (n=1, TAC) and gastrointestinal disease (n=4, CSP vs. n=3, TAC). The incidence of grade II–IV acute GVHD in the TAC arm was significantly lower than that in the CSP arm (Table & Figure). The incidences of grade III–IV acute GVHD and extensive chronic GVHD were not significantly different between the two arms. The non-relapse mortality (NRM) in the TAC arm was significantly lower than that in the CSP arm. The causes of death that contributed to NRM were infection in 6 (CSP arm), GVHD in one (CSP), ARDS in one (TAC) and lung cancer in one (CSP). The relapse rate and relapse-related mortality were not significantly different between the two arms. The median follow-up for surviving patients was 1295 days (169–1954). The overall survival (OS) and progression-free survival (PFS) rates in the TAC arm tended to be higher than those in the CSP arm. Figure Figure Conclusions: A regimen with TAC alone without MTX as GVHD prophylaxis was associated with significantly lower rates of grade II–IV acute GVHD and NRM compared to a regimen with CSP alone after RIST from a MRD. OS and PFS with TAC alone tended to be higher than those with CSP alone. Nevertheless, these results must be considered with care due to the small number of patients, and the optimal use of both drugs is still under investigation. A large-scale RCT to identify suitable GVHD prophylaxis in the RIST setting is warranted. Table: Study Outcomes CSP arm (n=33) TAC arm (n=32) P P value was evaluated with logrank test or Wilcoxon test*. Grade II–IV acute GVHD 64% 39% 0.040 Grade III–IV acute GVHD 30% 23% N.S Extensive chronic GVHD 63% 61% N.S 1-year/3-year NRM 26%/38% 0%/5% 0.008 1-year/3-year relapse 35%/43% 25%/49% N.S 1-year/3-year relapse mortality 27%/33% 10%/42% N.S 1-year/3-year OS 57%/45% 90%/56% 0.135 (0.039*) 1-year/3-year PFS 48%/35% 75%/48% 0.120 (0.047*)

Post-Transplant Cyclophosphamide and Bortezomib Combination for Prevention of GvHD after Allogeneic Blood and Marrow Transplantation Is Feasible and Produces Favorable Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3920-3920
Author(s):  
A. Samer Al-Homsi ◽  
Tara S Roy ◽  
Kelli Cole ◽  
Marlee Bogema ◽  
Stephanie F Williams ◽  
...  
Keyword(s):  
T Cells ◽  
Marrow Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Post Transplant ◽  
Blood And Marrow Transplantation ◽  
Gvhd Prophylaxis ◽  
Cmv Reactivation ◽  
Grade Iii

Abstract Graft versus host disease (GvHD) remains a major barrier to the progress of blood and marrow transplantation and limits its wide applicability. Standard prophylactic regimens essentially targeting T lymphocytes are partially effective and burdensome. Cyclophosphamide (Cy) administered post-transplant selectively deletes alloreactive proliferating T cells, promotes expansion of regulatory T cells, and induces long-lasting depletion of intrathymic host-reactive T cells. It is an attractive option for prevention of GvHD and has already been used alone in matched related and unrelated donor transplants. However, despite a low incidence of chronic GvHD, acute GvHD still occurs in 50% of cases and is grade III-IV in 15% of cases. Dendritic cells (DCs) play a pivotal role in the early phase of GvHD. Proteasome inhibitors such as bortezomib (Bor) have a number of immunomodulatory effects including inhibition of DCs maturation and function. We therefore initiated a phase I feasibility study combining post-transplant Cy & Bor. Twelve patients with hematological malignancies undergoing peripheral blood allogeneic transplantation from matched related (n=6) or unrelated (n=6) donors have so far been enrolled. Disease risk index (DRI) was low in 4, intermediate in 3 and high or very high in 5. The conditioning regimen combined fludarabine and busulfan (total 6.4 mg/kg). Patients receiving graft from unrelated donors also received rabbit anti-thymocyte globulin at 5-8 mg/kg. The dose of Bor was escalated in standard fashion. Three patients in each of cohorts 1 and 2 received 0.7 and 1 mg/m2 respectively. The subsequent 6 patients received 1.3 mg/m2. All patients received 2 IV doses, 6 hours after graft infusion and 72 hours thereafter. Cy was given at 50 mg/kg IV on days +3 and +4. Steroids were not allowed after day 0. Engraftment was prompt in all patients. Median time to neutrophil engraftment was 15.5 days (range 14-25). One patient failed to meet criteria for platelet engraftment. The patient had acyclovir-resistant herpes genitalis and CMV reactivation requiring protracted therapy with foscarnet. The remaining patients had a median time to platelet recovery of 28 days (range 15-109). All patients achieved full chimerism by day 20 except one who had residual CLL and did not reach full chimerism until day +119. No patient developed secondary graft failure. Two treatment-related deaths occurred on day +150 due to RSV pneumonitis and on day +200 due to acute sepsis. One patient with recurrent multiple myeloma after autologous transplantation died due to progressive disease. No other Common Toxicity Criteria grade 3 or 4 occurred in any patient. With a median follow-up of 21 months (range 1-27), the overall 2-year predicted disease free survival and overall survival were both 60%. Incidence of acute GvHD in 11 patients with follow-up > 100 days, was 64%: grade I 55%, grade II 9%, and grade III-IV 0%. GI and liver acute GvHD were not encountered. Only 4 patients received systemic steroids for acute GvHD; only one required > 20 mg/day of prednisone. One patient developed chronic GvHD of the liver (biopsy-proven). Another patient developed poor appetite and weight loss on day +138. Endoscopy showed gastric ulceration. No biopsy was obtained. Neither calcineurin nor m-TOR inhibitors were ever used. Two patients developed extensive HSV-genito-rectal ulcers; one had prior history of recurrent flares. When institutional guidelines were changed to start acyclovir at the beginning of conditioning as opposed to day +5, no other cases was noted. Seven patients developed CMV reactivation and required preemptive therapy only. One patient developed BK virus-induced hematuria and 1 patient developed CNS toxoplasmosis. In summary, the calcineurin and m-TOR inhibitor-free post-transplant Cy & Bor combination for GvHD prophylaxis is feasible and safe. Although the small number of patients prevents any definite conclusion, the absence of incidence of grade III-IV acute GvHD and the sparing of the GI tract and liver are promising. Furthermore, the completion of GvHD prophylaxis by day +4 without the need for close renal and drug level monitoring are both practical and appealing. Updated results with longer follow-up will be reported at the meeting. A confirmatory phase II study is underway. Disclosures Al-Homsi: Millennium Pharmaceuticals: Research Funding. Off Label Use: Bortezomib use for aGvHD prevention.

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

Blood ◽  
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.

scholarly journals A Prospective Multicenter Study of Nonmyeloablative Conditioning with TBI or Fludarabine/TBI for HLA-Matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies with Post Grafting Immunosuppression with Tacrolimus and Mycophenolate Mofetil: 10-Year Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1949-1949
Author(s):  
Huiying Qiu ◽  
Brenda M. Sandmaier ◽  
Barry E. Storer ◽  
Thomas Chauncey ◽  
Finn Petersen ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Autologous Hct ◽  
Grade Iii

Abstract Background: Nonmyeloablative conditioning with 2-Gy TBI alone or in combination with fludarabine (FLU/TBI) and HLA-matched related donor peripheral blood allografts followed by cyclosporine (CSP) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD) is an effective therapy for many hematologic malignancies with reliable engraftment and moderate toxicity. The major causes of non-relapse mortality (NRM) are the development of acute and chronic GVHD. Several studies have demonstrated that tacrolimus may offer advantages compared with CSP for the prevention of GVHD in patients treated with myeloablative conditioning. The combination of tacrolimus and MMF, which has been used for GVHD prophylaxis after myeloablative hematopoietic cell transplantation (HCT), was well tolerated with low toxicity. Pilot data suggested an improved and perhaps superior GVHD prophylaxis with tacrolimus/MMF compared to our extensive historical experience using CSP/MMF with nonmyeloablative HCT. The purpose of this study is to evaluate the incidence of grade III-IV and II-IV acute GVHD, extensive chronic GVHD, along with the rate of NRM, relapse/progression, and overall survival after nonmyeloablative conditioning and post-grafting immunosuppression with tacrolimus and MMF. Methods: In a phase II multicenter clinical trial we evaluated the effect of post grafting immunosuppression with tacrolimus and MMF for the prophylaxis of GVHD following nonmyeloablative conditioning with 2-Gy TBI alone or in combination with 90mg/m2 FLU (FLU/TBI) for patients with hematologic malignancies. Patients at low risk of graft rejection (preceding autologous HCT within 6 months) received TBI alone (n=50) while the remaining patients received FLU/TBI conditioning (n=100). Tacrolimus was administered orally (0.06 mg/kg, Q12 hr) from days -3 to +56 and in the absence of GVHD tapered off by day +180. Tacrolimus was targeted to 15-20 ng/ml for the first 28 days and 10-20 ng/ml subsequently while on full dose. MMF was given orally (15 mg/kg, Q12 hr) from day 0 until day 27. Results: 150 patients were enrolled from 2004 to 2013 and received peripheral blood stem cells (median doses of 8.1×106 CD34+ cells/kg and 3.5×108 CD3+ cells/kg) from HLA-matched related donors. Diagnosis at transplant included AML (n=42), ALL (n=6), CLL (n=2), MDS/MPD (n=12), NHL (n=25), HL (n=8), and MM (n=55). Median patient age was 56 (range 19-74) years. Sixty-one percent of patients had an HCT comorbidity index (HCT-CI) score of greater than 2. Five percent of patients had failed a prior autologous HCT in FLU/TBI group. Median follow-up was 5.2 years. One graft failure was observed in the FLU/TBI group and no patients rejected their graft. The early NRM at day 100 was 1%. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 120 days were 26% (FLU/TBI 25%; TBI 28%) and 4% (FLU/TBI 2%; TBI 8%), respectively. Only one patient developed grade IV acute GVHD. Forty-eight percent of patients had chronic GVHD by 5 years (FLU/TBI 44%; TBI 54%). Five-year NRM was low at 12%. The overall cumulative incidence of relapse/progression at 5 years was 52%. Five-year overall and progression-free survivals were 51% and 37%, respectively. Conclusions: Post-grafting immunosuppression and GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute and chronic GVHD, which compares favorably with our experience in a concurrent trial using CSP/MMF with FLU/TBI conditioning (46% grades II-IV acute and 72% chronic GVHD with CSP/MMF, respectively; BBMT, 2013, 19: 1340-1347). Furthermore, we recently reported that the active metabolite of MMF (MPA) concentration at steady state (MPA Css) was lower in patients who received concomitant CSP than patients receiving tacrolimus. Low total MPA Css was associated with an increased risk of severe acute GVHD following nonmyeloablative HCT (BBMT 2013, 19: 1159-1166). Together these data warrant consideration of a randomized phase III trial to investigate the role of tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT. Figure 1. Cumulative incidences of grade II to IV acute GVHD (A) and chronic GVHD (B) Figure 1. Cumulative incidences of grade II to IV acute GVHD (A) and chronic GVHD (B) Disclosures Maloney: Seattle Genetics: Honoraria; Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria.

Megadose CD34-Selected Haplocompatible Donor Stem Cell Transplantation in Children.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5417-5417
Author(s):  
Barbara S. Sleight ◽  
Morton J. Cowan ◽  
Biljana Horn ◽  
Jennifer Jaroscak ◽  
Joseph McGuirk ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Malignant Diseases ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract We report a retrospective review of 18 children receiving haplocompatible related donor hematopoietic peripheral blood SCT and consecutively enrolled at four U.S. transplant centers. The median age was 8 yrs (range 1–20). Patients with malignancy (n=13) included: AML-CR1 (primary induction failure, failed cord blood transplant) [1], CR2 [3]; MDS-RA/RARS [2], RAEB [2]; AML and Fanconi anemia [1]; CML-CP2 [1]; ALL-CR3 [2]; NHL-CR2 [1]. Patients with non-malignant diseases included severe aplastic anemia [n=4] and Wiskott-Aldrich syndrome [n=1]. Thirteen donors were a 3/6 HLA match and 5 were a 4/6 match. CD34 positive selection was used to select stem cells and deplete T lymphocytes. Conditioning for 13 of the patients consisted of TBI 12–14 Gy in 6 fractions, thiotepa, fludarabine and ATG. Fractionated TBI was replaced by single fraction TBI (n=2) or melphalan (n=3). Cyclophosphamide replaced thiotepa for 1 patient with FA. No post-transplant graft-versus-host disease (GVHD) prophylaxis was given. Patients received a median of 18 × 106 CD34+ cells/kg (range 6–28) and 3 × 104 CD3+ cells/kg (range 0.3–11). Sustained primary engraftment occurred in 15/18 (83%) patients. Primary graft failure occurred in one patient. Two patients had immunological rejection following HHV-6 reactivation. Both engrafted after a second transplant; therefore the overall engraftment success was 94%. The median time to an ANC >0.5 × 109/L was 12 days (range 9–21). Platelet recovery occurred in 16/18 at a median of 17 days (range 9–22). Primary (occurring after SCT but prior to DLI) grade II acute GVHD was seen in 4/17 patients (24%). Grade III-IV GVHD was seen in 1 patient (6%) manifest as overlap syndrome in association with HHV-6 reactivation. One pt had primary extensive chronic GVHD. Of nine patients who received DLI and/or stem cell boosts, 4 had grade II GVHD (3/4 had prior acute GVHD), none had grade III-IV GVHD, 2 developed chronic GVHD and 1 developed overlap syndrome. Infections were common but manageable. All patients were at risk for CMV reactivation based on CMV serology: recipient/donor +/+ (9), +/− (3), −/+ (6). Seven patients (39%) reactivated CMV. All cases were responsive to anti-viral therapy and/or DLI. No CMV disease was seen. Seven patients had adenovirus reactivation and 6 had HHV-6 reactivation. EBV reactivation occurred in 5/18 (28%) patients. Rituximab (5) and DLI (2) yielded rapid resolution of EBV in all patients. Four of 13 (31%) at risk patients have relapsed: 1 pt with cytogenetic relapse remains in CR2 > 6 mo later and another who recently relapsed is undergoing salvage therapy. The 100 day and 1 year transplant-related mortality was 11% and 19%, respectively. The overall survival is 72% with a median follow-up of 31 months (range 7–89). Among patients transplanted for malignant diseases (13) and non-malignant diseases (5), overall survival is 69% and 80%, respectively. The K-M 2 year survival was 70% +/− 22%. All survivors were complete donor chimeras by DNA methods. The use of megadose CD34-selected PBSC without post-transplant GVHD prophylaxis yielded rapid engraftment, low 100-day mortality and incidence of severe GVHD, and excellent survival. The overall survival compares favorably with MSD and MUD HSCT.

Age and Disease Status Are Important Risk Factors for Outcome after Reduced Intensity Conditioning (RIC) Umbilical Cord Blood Transplantation (UCBT) in Adults

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4412-4412
Author(s):  
Sabine Fürst ◽  
Catherine Faucher ◽  
Jean El Cheikh ◽  
Jean Marie Boher ◽  
Patrick Ladaique ◽  
...  
Keyword(s):  
High Risk ◽  
Hematological Malignancies ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Disease Status ◽  
Significant Difference ◽  
Grade Ii ◽  
Grade Iii

Abstract UCBT in adult patients with hematological malignancies has significantly increased over the last 5 years. In addition, the introduction of RIC regimens can allow a decreased incidence of TRM. Thus, the use of UCBT after a RIC regimen can represent an attractive treatment modality for those high risk patients who lack a suitable HLA-matched donor. The aim of this analysis was to assess the outcome of 35 patients who received RIC UCBT in a single centre between 2005 and 2008. All 35 patients had high risk hematological malignancies (AML, n=19; ALL, n=9; NHL, n=5; CML, n=1; and Hodgkin disease, n=1). 27 patients (77%) were in CR (CR1, n=18; CR2, n=8; CR3, n=1), whereas 8 had a more advanced disease (PR, n=2; refractory, n=6) at time of UCBT. Of note, 12 patients (34%) have already received and failed prior autologous transplantation. The median age and weight was 44 (range, 17–62) years and 63 (range, 44–125) kg with 13 patients (37%) older than 50 years (range 51–62). The RIC regimen included Fludarabine 200 mg/m2, Cyclophosphamide 50 mg/kg and low dose TBI (2 Gy). All patients received CSA and MMF for GVHD prophylaxis. 13 patients (37%) received a single CB unit, whereas 22 (63%) received 2 CB units in order to achieve a minimum required cryopreserved cell dose of 3.0×10e7 TNC/kg. For the entire group, the median cryopreserved and infused cell doses were 4.8×10e7 TNC/Kg (range, 3.3–7.0) and 3.7×10e7/Kg (range, 1.9–5.5) respectively. 94% of the patients received 1–2 HLA mismatched grafts. Neutrophil engraftment (ANC&gt;500/μL) occurred in 33 patients (94%) at a median of 20 (range, 6–45) days and a sustained platelets recovery (&gt;50000/μL) was observed in 25 patients (71%) at a median of 36 (range, 23–136) days after UCBT. Hematological recovery was comparable between single and double CB unit recipients. Primary and secondary graft failure occurred in 4 and 1 patients respectively (AML, n=2; ALL, n=1; CML, n=1; NHL, n=1). Two out of these 5 patients underwent and failed a second UCBT. The overall incidence of grade II–IV acute GVHD was 54% (95%CI, 41–77%; 7 grade II, 10 grade III and 2 grade IV). 19 patients were evaluable for chronic GVHD for an overall incidence of 37% (8 limited and 5 extensive cases). 20 patients (57%; 95%CI, 42–76 %) with experienced at least one episode of a “serious” or “life-threatening” infectious complication (virus other than CMV reactivation, n=11; bacteria, n=10; fungal, n=4) at a median time of 74 (range, 0–595) days after UBCT, requiring long-term hospitalization, and of whom 8 patients were in grade III–IV acute GVHD. 7 patients (20%) experienced severe interstitial pneumonia, with 4 patients (11%) developing ARDS. Most importantly, 5 patients (14%) also required transfer to ICU. With a median follow-up of 468 (range, 105–1170) days, 10 patients (28%) had relapsed or progessed with this being significantly lower in those patients transplanted in CR (P=0.01), but without a significant difference between single and double CB recipients. 14 patients have died (infection, n=5; GVHD, n=3; relapse, n=6; TRM=23%). The KM estimate of OS and DFS was 61% (95%CI, 42–75%) and 52% (95%CI, 34–67%) at 2 years respectively for the entire population. On univariate analysis younger age at transplant and disease status in CR were the only factors associated with significantly better outcome. Although our patients population is small, we conclude that RIC UCBT is an efficient therapy for high risk hematological malignancies. Age and the disease status at transplant are crucial for patients outcome and further efforts are needed to define risk factor specific transplant procedures. Infectious complications and GVHD are still a matter of concern warranting better strategies to provide optimal prophylactic approaches.

Post-Transplantation High Dose Cyclophosphamide As Gvhd Prophylaxis in 9/10 HLA-Matched Unrelated Donors Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3135-3135 ◽  
Author(s):  
Rohtesh S. Mehta ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Gabriela Rondon ◽  
Aimee E Hammerstrom ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Conventional Group ◽  
Unrelated Donor ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Background: Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent GVHD after haploidentical or HLA-matched related or unrelated donor hematopoietic stem cell transplantation (HSCT). Our study aim was to determine its efficacy in HLA-mismatched unrelated donor (MMUD) HSCT. Methods: We included 113 consecutive adult patients with high risk hematological malignancies who underwent one-antigen MMUD (9/10-matched) bone marrow (BM) or peripheral blood (PB) HSCT after myeloablative or reduced-intensity conditioning at our institution from 2009-2013. Outcomes were compared between (a) conventional GVHD group (n=71) that received in-vivo T-cell depletion with ATG, tacrolimus and methotrexate and (b) PTCy group (n=41) that received PTCy (50 mg/kg/day IV on days 3 and 4) with tacrolimus and MMF. After exclusion of 29 patients with isolated HLA-DQ mismatches, a separate analysis was performed in 84 patients with 7/8 HLA-MUD HSCT; 38 patients received PTCy while 46 patients received conventional prophylaxis. Results: Patients in the conventional group were marginally older (median 54 years; range 19-74) than those in the PTCy group (median 50 years; range 20-64). PB was used more frequently as a graft source in the conventional group (38% vs 17%, p=0.02). PTCy group included more patients with HLA class-I mismatches (87.8%) compared to conventional group (56.9%). There were no other differences between the groups. Incidence of grade II-IV (37% vs 36%, p=0.8) or grade III-IV (17% vs 12%, p=0.5) acute GVHD at day 100 post-transplant was not different between the groups. [Figure 1] Incidence of grade II-IV acute GVHD at day 30 was significantly lower after PTCy compared with conventional prophylaxis (0% vs 15%, p <0.001). Correspondingly, incidence of grade III-IV GVHD at day 30 was 0% in the PTCy group and 8% in the conventional group (p=0.08). Cumulative incidence of chronic GVHD was similar between the two groups at 6 months (20% vs 15%), 1-year (30% vs 31%) or 2-years (30% vs 42%). Risk factors analysis showed that use of PTCy was the sole independent predictor of lower risk of grade II-IV acute GVHD at day 30 (p=0.01). None of the risk factors evaluated, including PTCy use, were shown to predict the rate of grade II-IV acute GVHD within day 100. Two-year cumulative incidences of NRM (35% vs 25%), disease progression (20% vs 31%), DFS (42% vs 38%) and OS (52% vs 40%) were similar in the PTCy and the conventional groups, respectively. [Figure 1] Median times to neutrophil (18 vs. 12 days, p<0.001) and platelet (25.5 vs. 18 days, p=0.05) engraftment were prolonged in PTCy group. Disease recurrence/persistence was the leading cause of death in both groups, accounting for about 46% of all deaths. Subgroup analysis restricting to patients with BM grafts produced similar findings. In patients with HLA class-I mismatch, PTCy was associated with significantly reduced risk of grade II-IV, but not grade III-IV, acute GVHD at day 30 (p=0.01). However, there were no differences in acute grade II-IV GVHD (HR 1.1, 95% C.I. 0.5-2.5, p=0.7) or acute grade III-IV GVHD (HR 1.5, 95% C.I. 0.4-5.4, p=0.5) by day 100 between the groups. Comparing patients with 7/8-HLA-MUD HSCT, no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0.005). There were no differences in incidence of grade II-IV (HR 1, 95% C.I. 0.5-2.1, p=0.9) or grade III-IV (HR 1.1, 95% C.I. 0.3-3.3, p=0.9) acute GVHD at day 100, chronic GVHD at 6 months (HR 0.8, 95% C.I. 0.2-2.9, p=0.7), 1-year (HR 0.8, 95% C.I. 0.3-2.2, p=0.6) or 2-years (HR 0.7, 95% C.I. 0.2-1.9, p=0.5) between the groups. Conclusion: Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HSCT. Disclosures Alousi: Therakos, Inc: Research Funding.

Analysis of a New graft–versus-host Disease (GvHD) Prophylaxis Regimen with Additional Enteric-coated Mycophenolate Sodium (EC-MPS) Starting 10 Days after Unrelated Allogeneic Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2202-2202
Author(s):  
Herbert G. Sayer ◽  
Lars-Olof Mügge ◽  
Sebastian Scholl ◽  
Anne Klink ◽  
Kristina Schilling ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Introduction: Acute GvHD has, despite established immunosuppressive prophylaxis regimens, significant impact on acute morbidity and mortality following allogeneic stem cell transplantation (SCT). In the unrelated or even non-matched unrelated situation new GvHD-prophylaxis regimens balancing GvHD and graft-versus-leukaemia effect are needed. EC-MPS and mycophenolate mofetil [MMF] are effective immunosuppressants by inhibition of T- and B-cell proliferation. Primary study aims in this ethical board approved, prospective, single-centre, open phase II trial were (1) feasibility of prolongatedly started oral EC-MPS and (2) reduction in the rate of GvHD in unrelated allogeneic SCT. Patients and Methods: EC-MPS [Myfortic ®] 720 mg twice a day orally starting at day +10 after SCT in addition to standard GvHD prophylaxis, consisting of cyclosporine (CSA) 3 mg/kg continuous intravenous infusion with or without methotrexate (MTX) 15 mg/m2 day +1 and 10 mg/m2 day +3,+6,+11 intravenous push, was evaluated. According to the protocol, EC-MPS was tapered from day +40, if no acute GvHD-signs were present. 54 patients, including 8 patients from a previous pilot trial, with advanced haematological malignancies (n=28) or in first remission of acute leukaemia (n=26) between 8/03 and 12/07 were evaluated. The patients had either a 10/10 HLA-matched (n=32) or a 8-9/10 HLA mismatched unrelated donor (n=22). 32 (59%) patients received 40 mg/kg antithymocyte globulin (ATG), with 8 Gray total body irradiation (TBI) and cyclophosphamide (CY), or with fludarabine 120mg/m2, busulfan 8mg/kg or treosulfan 8–12 mg/kg. 12 or 8 Gray TBI and 120 mg/kg CY followed by MTX i.v. were administered to 22 (41%) patients. Results: A median of 5.7 (range: 0.9–9.9) unmanipulated G-CSF-mobilized CD-34 positive stem cells per kg were given on day 0. All of the 23 women and 31 men (median age 48 years (range: 20–65)), except one patient, showed a leukocyte engraftment on median day +14 (range: 9–35). Platelet engraftment was observed on median day +17 (range: 9–132). In 12 patients (22%) initially i.v. MMF (1g twice a day) instead of oral study medication was given temporarily, mostly due to severe mucositis. In six patients (11%) EC-MPS (on day +14, 17, 22, 32, 37, 76) had to be discontinued, due to severe nausea (n=2), neurological toxicity (n=2), graft failure (n=1) and protocol violation (n=1). Acute GvHD grade II-IV was observed in 27 (52%) patients, including 8 (15%) with grade III and 4 (7.5%) with grade IV. The incidence of chronic GvHD was 63 % (n=29) [limited chronic GvHD: 54 % (n=15), extended chronic GvHD: 14% (n=4)] of the 46 patients surviving &gt;100 days after SCT. With 10/10 HLA-matched donors GvHD grade II-IV was seen in 44% (n= 14) [grade III and IV n=5 (16%)], whereas with non fully-matched donors the incidence was 59 % (n=13) [grade III and IV n=7 (32%)]. Chronic GvHD incidence was 50% (14/28) in the fully matched donor situation in contrast to 83% (15/18) in the non-fully matched situation. The conditioning regimen with ATG resulted in a GvHD grade II-IV incidence of 39% (n=12) [GvHD grade III/IV: 19% (n=6)], compared to 68% (n=15) [GvHD grade III/IV: 27% (n=6)] without ATG. With a median follow-up of 16 months (range: 1–56) 28 patients (52%) are alive, 18 fully HLA-matched stem cell recipients (56%) and 10 mismatched HLA recipients (45%). Survival with or without ATG was 50% (n=16) and 55% (n=12), respectively. Twenty-six (48%) patients have died; 12 (22%) due to relapse, 10 (19%) due to acute/chronic GvHD, and 4 (7%) due to infection/secondary cancer without GvHD. Conclusions: EC-MPS with a 10 day prolongated start after transplantation combined with initial standard GvHD prophylaxis in the unrelated stem cell transplantation setting seems to be feasible. Mucositis was the main course for oral intake problems. The toxicity drop-out rate of 7 % should be considered. The analysis of all evaluable patients in the pilot and the prospective trial yielded effectiveness in reducing severe GvHD Grade III/IV, especially in combination with ATG. The MPS application regimen failed to show less incidence of chronic GvHD in the non-fully matched unrelated donor setting. GvHD prevention trials in the future should incorporate new drugs with a different pathway of T-cell inhibition or tolerance induction, respectively.

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