Transplantation of Peripheral Blood Stem Cells from Unrelated Donors Is Not Associated with Inferior Survival Compared to Bone Marrow Transplantation in Children with Hematologic Malignancies - A Registry Analysis from the German/Austrian Pediatric Registry for Stem Cell Transplantation (PRST).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3109-3109
Author(s):  
Roland Meisel ◽  
Caroline Spohr ◽  
Thomas Klingebiel ◽  
Dagmar Dilloo
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Status ◽  
Hematologic Malignancies ◽  
Stem Cell Source ◽  
Cell Source ◽  
Unrelated Donors

Abstract The optimum stem cell source for allogeneic hematopoietic stem cell transplantation (HSCT) remains highly controversial. A recent study in older children and adolescents receiving HSCT from HLA-identical sibling donors has revealed higher mortality after peripheral blood stem cell (PBSC) compared to bone marrow (BM) transplantation (Eapen et al, JCO, 2004). However, despite the increasing use of PBSC in pediatric HSCT from matched unrelated donors (MUD), comparative studies on the relative risks and benefits of both stem cell sources are lacking. We therefore analysed the outcome of unrelated PBSC (n=118) and BM (n=102) transplants reported to the German/Austrian Pediatric Registry for Stem Cell Transplantation (PRST) between 1998 and 2003. Patients with hematologic malignancies (ALL, AML, CML, or MDS), who had received unmanipulated HSCT from ≥ 5/6 HLA antigen-matched unrelated donors following myeloablative conditioning were included into the analysis. PBSC and BM groups were comparable with regard to sex, age, CMV serostatus, GvHD prophylaxis, disease status at transplant, prophylactic growth factor use and degree of HLA-matching, while differences were detected in disease category (more MDS patients in PBSC group, p=0.02), transplanted cell dose (higher CD34-cell graft content in PBSC group, p=0.001) and median year of transplant (PBSC transplantations were more recent, p=0.01). Engraftment was achieved significantly faster after PBSC compared to BM transplantation: 15 vs. 19 days for neutrophil engraftment (p=0.001) and 21 vs. 25 days for platelet engraftment (p<0.01). The rate of acute GvHD grade II–IV (PBSC vs. BM: 44% vs. 39%, p=0.48) and severe acute GvHD Grade III/IV (29% vs. 21%, p=0.17) did not significantly differ between both groups. Moreover, the incidence of chronic GvHD (PBSC vs BM: 35% vs 33%, p=0.9) and extensive chronic GvHD (18% vs 18%, p=0.85) was identical at 3 years post transplant. In the PBSC group there was a statistically non-significant trend towards a higher risk for treatment-related mortality (PBSC vs BM: 34% vs 25%, p=0.14) and a lower risk for death of disease (PBSC vs. BM: 14% vs. 23%, p=0.16). However, this did no translate into a survival difference. With a median follow up of 2.9 years (PBSC) and 3.1 years (BM) overall survival (PBSC vs. BM: 50±5% vs. 46±6%; p=0.63) and event-free survival (45±5% vs. 44±6%; p=0.59) is comparable between both groups. This clinically most relevant result was confirmed in a multivariate analysis showing that advanced disease status at transplant (RR 2.4, 95%-CI 1.5–3.8, p=0.001) is a significant, independent risk factor for treatment failure, while the stem cell source (PBSC vs BM) has no effect (RR 1.1, 95%-CI 0.7–1.6, p=0.8). In summary, our data provide first evidence from a large, registry based analysis, that in pediatric recipients of MUD transplantation the use of PBSC instead of BM is not associated with inferior survival. Therefore, PBSC is a valid alternate stem cell source for pediatric HSCT from MUDs.

Donor Lymphocyte Infusions (DLI) After Peripheral Blood Stem Cell Transplantation. A Retrospective Analysis of 357 Patients by the Chronic Leukemias Working Party EBMT.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3309-3309
Author(s):  
Grzegorz Wladyslaw Basak ◽  
Anja van Biezen ◽  
Ronald Brand ◽  
Christoph Schmid ◽  
Cesare Guglielmi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Chronic Phase ◽  
Molecular Cytogenetic ◽  
Stem Cell Source ◽  
Cell Source ◽  
Grade Ii

Abstract Abstract 3309 Poster Board III-197 Donor Lymphocyte Infusions (DLI) constitute a potent therapeutic option for treating relapse of chronic myelogenous leukemia (CML) after hematopoietic stem cell transplantation (SCT) inducing durable remissions in the majority of patients. A number of factors is known to influence the efficiency of DLI. A preliminary analysis of EBMT data had suggested that DLI efficiency might be inferior after peripheral blood stem cell transplantation (PBSCT) as compared to DLI following bone marrow transplantation (BMT) (Schmid et al. ASH, 2005). To control for a number of other factors that were not known at the time of the previous analysis, we repeated this analysis based on the results of 357 patients treated with DLI following PBSCT (N=108) and BMT (N=249). We limited the analysis to patients who relapsed after standard intensity conditioning SCT from HLA-identical family donors in first chronic phase of disease. The median age of patients was 39 years (range 18-60) with predominance of males (59%). 53% of patients with known data were CMV positive and in 44% of the patients there was a sex-mismatch with the stem cell donor. SCTs have been performed between 1994 and 2007 (median year: 1998) and the conditioning treatment included total body irradiation (TBI) in 68% and T cell depletion in 44% of patients. 92% of patients with known data achieved complete remission after SCT while grade II-IV acute GvHD occurred in 18% of patients and extensive chronic GvHD in 17% of patients. Median time to relapse was 17 months (range 0.6-129) and median time from SCT to first DLI infusion was 23 months (range 0.6-142). Looking at the patients with known data at the time of first DLI infusion, the relapse could be classified as molecular/cytogenetic in 63%, hematologic in 27% and transformed in 10% of patients. The median year of first DLI was 2000 ranging from 1995 to 2007. As the initial DLI infusion, 9% of patients received <1×10e6, 62% 1.1-10×10e6 and 29% received >10×10e6 CD3+ cells/kg. However, the comparative analysis of groups based on the stem cell source revealed that the group of patients transplanted with PBSCs included significantly more males (68 vs. 56%), were older (median age 42 vs. 39) and underwent more frequently T cell depletion at SCT (72 vs. 34%,). PBSCTs have been performed more recently (median year 1999 vs. 1997) and both duration of remission and time from SCT to first DLI were shorter after PBSCT (median duration: 12 vs. 21 months and 14 vs. 26 months respectively). The initial cell dose in patients from PBSCT arm was significantly lower than in BMT group (≤10×10e6 CD3+/kg in 89% vs. 65% of patients). Similarly to the previous study, we also observed a trend towards superior overall survival after DLI in BMT group compared to PBSCT group, especially in the early post-transplant period. The actuarial probability of survival at five years from DLI was 77% in PBSCT group and 79% in BMT group. However the differences were not statistically significant (p=0.77). The source of stem cells did not influence the occurrence of molecular/cytogenetic remissions after DLI (80% vs. 77%) grade II-IV acute GVHD (16% vs. 16%), chronic GVHD (23% vs. 30%) and myelosuppression (10% vs. 16%). In order to search for factors having impact on survival of analyzed patients, we performed both univariate and multivariate survival analyses. The univariate analysis revealed that interval from SCT to DLI longer than 2 years (p=0.001), date of DLI after 2000 (p=0.026) and molecular/cytogenetic stage of relapse at DLI (p<0.001) were associated with favorable survival. Similarly, the multivariate Cox analysis identified interval between SCT and DLI (HR= 0.50, CI: 0.3-0.8; p=0.01 for after 2 years), date of DLI (HR=0.63, CI:0.4-1.0; p=0.07 for after 1999), and stage of relapse (HR=2.8, CI:1.2-6.5; p=0.02 for HemCR and HR=3.6, CI:1.8-7.0; p<0.001 for missing data group), but not for stem cell source (HR=0.95, CI 0.56-1.6 ;p=0.86) as independent factors affecting survival. Based on our retrospective data from EBMT registry covering a period of 14 years of SCT and DLI, it seems that the PBSCT does not affect the efficiency of DLI compared to BMT. Therefore, keeping all limitations of a retrospective analysis in mind, it seems that differences in efficacy of DLI do not influence the decision whether PBSC or BM should be used as stem cell source for allogeneic SCT in CML in first chronic phase. Disclosures No relevant conflicts of interest to declare.

High-Dose Rituximab in the Conditioning Regimen Before Allogeneic Stem Cell Transplantation Reduces the Incidence of Acute Gvhd in B-Cell Lymphomas

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4546-4546
Author(s):  
Paolo Corradini ◽  
Barbara Sarina ◽  
Cristiana Carniti ◽  
Francesca Patriarca ◽  
Angelo Michele Carella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
High Dose ◽  
Unrelated Donors

Abstract Abstract 4546 Background: Reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed lymphomas. The present GITMO study is a prospective multicenter phase II trial for patients affected by relapsed CD20 positive lymphomas. Compared with the previous thiotepa/fludarabine/cyclophosphamide GITMO protocol (Leukemia 2007), the thiotepa dose is increased, and high-dose Rituximab is included in the regimen to improve the outcome and possibly modulate the incidence of acute GVHD. Aims: Primary end-point was 1-year progression-free survival; secondary endpoints were non-relapse mortality and incidence of acute and chronic GVHD. Methods: Fifty-seven patients (pts) were enrolled so far in the study and 49 are evaluable for analysis. Treatment plan consisted of high-dose R (500 mg/ms on day -6) followed by thiotepa (12 mg/kg), fludarabine (60 mg/kg) and cyclophosphamide (60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mini-methotrexate; ATG (7.5 mk/kg) was only added for pts allografted from one antigen mismatched sibling or unrelated donors. Histopathological subtypes included 24 aggressive (HG) (n= 17 diffuse large B-cell lymphomas, n= 7 mantle cell lymphomas) and 25 indolent lymphomas (LG) (n= 13 follicular lymphomas, n= 12 small lymphocytic/chronic lymphocytic leukemia). Patients were allografted from related siblings (SIB) (n= 32 matched, n=1 one single mismatched) or unrelated donors (UD) (n=11 matched, n=5 mismatched). All the pts had chemosensitive disease (n=20, 41% in complete remission) and 26 (53%) came from a failed autoSCT. Results: At a median follow-up of 13 months (range, 5–44 months), 36 pts are alive [n=27 (75%) in CR] and 13 died from any cause [n=6 for non-relapse mortality (NRM), n=7 for disease progression]. All the patients engrafted (94% had full donor chimerism at 3 months). The cumulative incidence (CI) of NRM was 13% at 1 year: 9% vs 19% for SIB and MUD (p=0.3), and 9% versus 16% for for LG and HG (p=0.3), respectively. In total only 11 of 49 pts had acute GVHD (n=8 grade II, n=3 grade III) with an estimated CI of 21% at 100 days. In the previous GITMO study the incidence was 35% with SIB only. Forty pts are evaluable for chronic GVHD with an estimated CI of 41% and 47% at 1 and 2 year, respectively (n=11 limited, n=3 extensive). Infections after engraftment requiring hospitalization or intravenous treatment were evaluable in 46 pts (n=3 excluded for early death). The overall incidence of infections was 58% (n=27) including 5 pts experienced sepsis and 10 pts pneumonia. Preliminary data on immune-reconstitution at 1 year showed: 1) low number of circulating B cells (median CD19+/ul: 129/ul) with an expansion of naive cells (IgD+, CD27-); 2) the median value of IgM was 89 mg/dl whereas IgG and IgA remained at low levels. The CI of relapse was 26% and 37% at 1 year and 2 years, respectively. In the indolent and aggressive groups, OS estimates at 2 years were 79% (95%CI, 52%-91%) and 61% (95 CI, 38%-77%) and PFS estimates were 53% (95%CI, 23%-76%) and 48% (95% CI, 27%-66%), respectively. Conclusions: The present data suggest that the administration of high-dose R is feasible and causes an unexpected reduction of the incidence of acute GVHD without increasing the NRM and the incidence of severe infections complications. Complete data evaluating the effects of R on immune reconstitution are ongoing. Disclosures: No relevant conflicts of interest to declare.

Clinical Outcomes of Cord Blood Transplantation from Unrelated Donors Comparable with Marrow or Blood Transplantation from Related Donors in Adults: A Single Institute Analysis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 306-306
Author(s):  
Satoshi Takahashi ◽  
Jun Ooi ◽  
Akira Tomonari ◽  
Takaaki Konuma ◽  
Kenji Fukuno ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Cord Blood ◽  
Acute Gvhd ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Blood Transplantation ◽  
Stem Cell Source ◽  
Cell Source ◽  
Unrelated Donors

Abstract We previously reported some promising results of cord blood transplantation (CBT) compared with bone marrow transplantation (BMT) from unrelated donors in terms of graft-versus-host disease (GVHD), transplant-related mortality (TRM), and disease-free survival (DFS) in our institute (Blood104: 3813, 2004). If the patient was eligible for allogeneic transplantation without any related donors, we performed CBT immediately, rather than waiting for the results of an unrelated marrow donor search. This might be one of the reasons for our favorable CBT results in adults compared with most previously published studies. We studied the clinical outcomes of 163 adults with hematological malignancies who received unrelated CBT (n=92), or BMT or peripheral blood stem cell transplantation (PBSCT) from related donors (n=71, 55 BMT and 16 PBSCT) between January 1997 and February 2005. All patients received myeloablative regimens including 12 Gy of total body irradiation and almost the same supportive care. We analyzed the hematopoietic recovery, rates of GVHD, risks of TRM and relapse, and DFS using Cox proportional hazards models. The age, sex, cytomegalovirus serological status, time from diagnosis to transplantation, and GVHD prophylaxis regimens were not significantly different between both groups. Overall rates of high-risk patients in the CBT and in BMT/PBSCT groups were 58% and 63%, respectively. Human leukocyte antigen (HLA) was scored serologically for HLA-A and B and genetically for DRB1 alleles. There were no complete matches in CBT and 54 (76%) matched grafts in BMT/PBSCT. Median numbers of leukocytes and CD34+ progenitor cells before freezing of cord blood grafts were 2.4x107/kg and 0.9x105/kg, respectively. Median follow-up was 27 months for CBT and 50 months for BMT/PBSCT. Significant delays in neutrophil and platelet engraftment rates occurred after CBT; however, overall myeloid engraftment rates were almost the same for both grafts (94% in CBT and 98% in BMT/PBSCT). The cumulative incidences of grades II to IV acute GVHD, of grades III and IV acute GVHD, and of requiring steroids for treating acute GVHD among CBT recipients were 58%, 8%, and 18%, respectively. Those among BMT/PBSCT recipients were 58%, 19%, and 38%, respectively. Chronic GVHD affected 68 of 75 CBT and 49 of 60 BMT/PBSCT evaluable recipients. Twenty-two CBT and 30 BMT recipients developed extensive GVHD. The 1-year cumulative incidence of TRM, the 3-year cumulative incidence of relapse, and the 3-year probability of DFS in CBT recipients were 9%, 18%, and 71%, compared with 13%, 26%, and 60% in BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent difference in those outcomes between both groups. Taken together, engraftment speed was slower and severe acute GVHD and extensive chronic GVHD tended to be lower in CBT recipients compared with BMT/PBSCT recipients; however TRM, relapse and DFS were comparable in both groups. These data suggest that cord blood from unrelated donors could be as safe and effective a stem cell source as bone marrow or mobilized peripheral blood from related donors for adults when it is used as a primary unrelated stem cell source.

Outcome After 9/10 Mismatched Unrelated Donor or Cord Blood Cells Allogeneic Stem Cell Transplantation (allo-SCT) in the Setting of Reduced-Intensity Conditioning (RIC)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 956-956
Author(s):  
Florent Malard ◽  
Sabine Furst ◽  
Marion Loirat ◽  
Patrice Chevallier ◽  
Jean El-Cheikh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Blood Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Group Versus ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Cell Source ◽  
Unrelated Donors ◽  
Cord Blood Cells

Abstract Abstract 956 Background. Unrelated umbilical cord blood cells (UCB) have emerged as an alternative stem cell source for allo-SCT in patients who lack a matched-related or unrelated donor (MUD). Several studies found a similar outcome between HLA 4–6/6 matched UCB and HLA 8/8 matched and 7/8 mismatched unrelated donors, mainly in the setting of standard myeloablative conditioning. However, currently it is more common practice in many centres to search for 10/10 or 9/10 MUD or for double UCB. Thus far, no study focussed on the comparison of outcome of patients who received double UCB allo-SCT versus allo-SCT using 9/10 mismatched donors. With this background, this retrospective analysis assessed outcome after allo-SCT using double UCB cells or 9/10 mismatched donors in the setting of a RIC regimen. Patients and Methods. This analysis was performed in a series of 152 consecutive adult patients treated for hematological malignancies in 2 centers adopting similar transplant procedures. 85 patients were males (56%) and the median age at time of allo-SCT was 53 years (range, 16–69). Diagnoses included 59 AML (39%), 21 MDS/MPN (14%), 42 NHL (28%), 5 Hodgkin diseases (3%), 18 ALL (12%) and 7 Myelomas (5%). 35 patients (23%) had standard risk disease and 117 patients (77%) presented with high risk disease. Conditioning regimen consisted of fludarabine, cyclophosphamide and low dose TBI for 108 patients (71%), fludarabine and busulfan for 35 patients (23%); and other regimens in the remaining 9 patients (6%). 50 patients (33%) received antithymocyte globulin. The donor was double UCB in 110 cases (“dUCB” group) and 9/10 mismatched unrelated in 42 cases (“9/10” group). During the study period, both participating centers adopted the same strategy for donor search and choice: in the absence of matched-related siblings or 10/10 MUD, 9/10 donors were searched. UCB cells were used if no 9/10 donor could be identified within a reasonable time frame (usually 2–3 months after search initiation). Results. With a median follow-up of 30.3 months (range, 6–72.4), the Kaplan-Meier estimate of overall survival (OS) at 2 years was comparable between both groups [52% (95%CI, 42–61%) in the dUCB group versus 48% (95%CI, 32–62%) in the 9/10 group, P=0.55]. The cumulative incidence of NRM was 26% in the dUCB group versus 24% in the 9/10 group (P=0.95). Grade 3–4 acute GVHD and extensive chronic GVHD incidences were 20% versus 21.4% (P=0.83), and 6% versus 21% (P=0.02), in the dUCB group versus the 9/10 group, respectively. The cumulative incidence of relapse was 34% in the dUCB group versus 38% in the 9/10 group (P=0.63). Finally, the estimate of progression-free survival (PFS) at 2 years was 43% (95%CI, 34–52%) in the dUCB group versus 38% (95%CI, 23–53%) in the 9/10 group (P=0.55). In multivariable analysis including the most important parameters associated with outcome (patient's age at transplantation, patient's sex, diagnosis, disease status at transplantation, use of ATG, GVHD prophylaxis), the stem cell source (dUCB versus 9/10) did not have any significant impact on OS (HR=0.92 (95% CI, 0.41–2.08); P=0.86) Conclusion. These data suggest that dUCB is likely a valid alternative graft source compared to 9/10 mismatched unrelated donors in the setting of RIC allo-SCT since both donor types showed similar results in terms of OS, PFS, disease relapse, and acute GVHD incidence. However, the significantly lower incidence of extensive chronic GVHD in the dUCB group is an important and major finding, highlighting the need for a prospective randomized study in this field. Disclosures: No relevant conflicts of interest to declare.

Related Vs Unrelated Donors After Auto-Allo Tandem Stem Cell Transplantation for Newly Diagnosed Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1201-1201
Author(s):  
Nicolaus Kröger ◽  
Tatjana Zabelina ◽  
Marion Heinzelmann ◽  
Georgia Schilling ◽  
Christine Wolschke ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Unrelated Donor ◽  
Newly Diagnosed ◽  
Stem Cell Source ◽  
Cell Source ◽  
Unrelated Donors

Abstract Abstract 1201 Poster Board I-223 Introduction: Autologous stem cell transplantation followed by a dose-reduced conditioning and allogeneic stem cell transplantation from HLA-identical siblings has become a treatment option for patients with multiple myeloma. However, only a minority of the patients with multiple myeloma has an HLA-identical sibling and the experience using unrelated donor in this setting is limited. Patients and Methods: From 1997 to 2007, 73 patients (male:45; female:28) with multiple myeloma stage II/III and a median age of 49 years (r, 29-64) were included in a prospective trial to determine the efficacy of a tandem auto-allogeneic stem cell transplantation SCT) from HLA-identical sibling (n=24) or unrelated donors (n=45). Unrelated donor were either fully HLA matched (n=29) or had one mismatch (n=16).Deletion 13q14 could be analyses in 64 pts was found to be positive in 66% of the pts. Del13q14 was more present in patient with unrelated (n=42) than with related (n=22) donors. Stem cell source was PBSC (n=69) or bone marrow (n=4). Induction-chemotherapy consisted of a median of 4 cycles anthracycline-based therapy in 60 pts, or of thalidomide- (n=3) or bortezomib- (n=8) based regimen. 6 pts did not respond to induction therapy and received salvage chemotherapy before autologous SCT. Conditioning prior auto SCT consisted of melphalan 200mg/m2. After a median of 110 days (range 39-228) patients received a reduced intensity regimen with melphalan (140 mg/m2)/fludarabine regimen followed by allogeneic SCT from related (n=24) or unrelated (n=45) donors. GvHD prophylaxis consisted of anti-lymphocyte globulin (ATG-Fresenius®), cyclopsorin A and short course of MTX. Results: No primary or secondary graft failure was observed and leukocyte engraftment was achieved after a median of 15 days (range, 9-27), respectively. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 38% and chronic GvHD in 22% of the patients. Limited GvHD was seen in 16 % and extensive GvHD was seen in 6 % of the patients. There was no difference regarding incidence of GvHD between HLA-identical sibling and unrelated donors. Overall response rate at day 100 was 94% including 55% complete remission (CR) and did not differ between related and unrelated SCT. Cumulative incidence (CI) of non-relapse mortality at one year was 20% (95% CI:11-29%) and did not differ between MUD and MRD (21 vs 17%, p 0.35). The cumulative incidence of relapse at 3 and 5 years was 30% (95% CI:19-41%) and 42% (95% CI: 29-55%), respectively with no difference between related and unrelated SCT at 5 years: 36 vs 44%(p= 0.6). The only significant factor for higher relapse incidence at 5 years was the presence of del13q14 (60 vs 20%, p= 0.007). After a median follow up of 40 months (r., 26-100), the estimated 5-year progression-free (PFS) and overall survival (OS) rates were 31% (95%CI: 19-43%) and 54% (95% CI: 42-64%), respectively, with no difference between related and unrelated SCT. Due to the higher relapse incidence only presence of del13q resulted in a significant worse 5- year OS and DFS (45 vs 77%, p=0.02 and 18 vs 57%, p=0.04). Conclusions: Unrelated donors as stem cell source for auto-allogeneic tandem stem cell transplantation for newly diagnosed myeloma patients resulted in similar NRM, relapse-incidence, DFS and OS than HLA-identical sibling transplantation and can therefore be used as alternative stem cell source. Outcome after transplantation is better for patients lacking del 13q14. Disclosures: No relevant conflicts of interest to declare.

HLA-DRB4 Mismatch Is Associated with Worse Outcomes in Unrelated Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4540-4540 ◽  
Author(s):  
Marie Y. Detrait ◽  
Ibrahim Yakoub-Agha ◽  
Valerie Dubois ◽  
Françoise Dufossé ◽  
Myriam Labalette ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Stem Cell Source ◽  
Cell Source

Abstract Abstract 4540 Introduction The impact of HLA DRB3 and DRB4 allele mismatch after allogeneic HSCT using unrelated donors is unclear. We therefore examined retrospectively the outcome of 35 patients who received HLA-10/10 unrelated hematopoietic stem cell transplantation with a DRB3 or DRB4 mismatch between 2005 and 2011. This cohort of 35 patients was a part of a cohort of 132 consecutive patients who underwent allogeneic HSCT between 2005–2011 with a 10/10-HLA matched donor. There were 18 males (51.4%) and 17 females (48.6%) with a median age of 48 years (range, 6–64), there were 13 (37%) AML, 9 (26%) ALL, 4 (11.5%) MDS, 3 (8.5%) multiple myeloma and 6 (5.7%) other (CML, CLL, NHL). Twenty patients (57%) received a myeloablative conditioning (MAC) and 15 (43%) received a reduced intensity conditioning (RIC). At transplantation, 21 patients (60%) were in complete remission (CR), 4 patients (11.5%) in partial remission (PR) and 10 (28.5%) in relapse; 13 (37%) patients received peripheral blood stem cell (PBSC) and 22 (63%) received bone marrow (BM). Twelve (34%) patients had a mismatched DRB4 donor and 23 (66%) patients had a mismatched DRB3 donor. In the remains of 97 patients, there were 55 male (57%) and 42 female (43%), 28 (29%) patients received a MAC and 69 (71%) a RIC as regimen before allogeneic HSCT. The stem cell source was BM for 32 (34%) patients and PBSC for 65 (66%). At transplantation, 34 (35%) patients are in CR and 63 (65%) were in PR. The distribution of diagnosis was acute leukaemia and MDS for 44 (45%), CLL for 2 (2.5%) and other diagnosis (aplastic anemia, NHL, CML, MPS) for 51 patients (52.5%). Results After HSCT, 124 (94%) patients engrafted. After a median follow-up of 11.5 months (range, 0–76), the cumulative incidence of acute GvHD≥2 at 3 months was 20% (95%CI,16.5–24) and the cumulative incidence of chronic GvHD at one year was 19 % (95%CI, 15–22). In univariate analysis, the mismatch DRB3 or DRB4 had no effect on engraftment and no effect on acute GvHD (p=0.08) or chronic GvHD (p=0.63). There was no impact of DRB3 or DRB4 mismatch on relapse (p=0.33 and p=0.53, respectively) and on PFS (p=0.63 and p=0.07, respectively). We found an impact of the DRB4 mismatching (p=0.016) on overall survival. The median survival for patient without DRB3 or DRB4 mismatch was 23 months (14-NR), for patients with DRB3 mismatch 32 months (12-NR), and for DRB4 mismatched patients 5 months (3-NR). The probability of survival at 24 months, for patients without mismatch DRB3 or DRB4 is 47% (36–61), for patients with DRB3 mismatch 51% (32–82) and for DRB4 mismatched patients 19% (6–66%). (figure1). The multivariate analysis that studied age, type of disease, DRB3 or DRB4 mismatch, sexmatching, TBI, ATG, disease status at transplantation and type of conditioning and stem cell source showed a significant impact of mismatch DRB4 on survival (HR= 2.5 [95%CI, 1.2–5.5] p=0.019); there was no impact for DRB3 mismatch (HR= 1.3 (95%CI,0.5–3.9 p=0.58). We found also an impact of the DRB4 mismatch on TRM (HR= 3.5; [95%CI, 1.6 –8] p= 0.026). The incidence of TRM at 24 months for patients without DRB3 or DRB4 mismatch is 29% (24–34), for patients with DRB3 mismatch 17% (9–26%) and for DRB4 mismatched patients 50% (34–66%). (figure 2). Conclusion The HLA DRB4 matching donor is relevant for survival of patients who undergo allo-HSCT from unrelated donor in the HLA-10/10 matching settings. In view of the important impact of these loci mismatches on clinical outcome, it seems to be important to consider this matching loci in the unrelated donor selection. Disclosures: No relevant conflicts of interest to declare.

Targeting Mycophenolate Mofetil for Graft-Versus-Host Disease Prophylaxis after Allogeneic Blood Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 756-756
Author(s):  
Jens Freiberg-Richter ◽  
Ingmar Hantzschel ◽  
Andreas Jenke ◽  
Petra Lorenz ◽  
Gerhard Ehninger ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mycophenolate Mofetil ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Graft Versus Host ◽  
Unrelated Donors

Abstract New immunosuppressive compounds are currently investigated to reduce the rate of lethal Graft-versus-Host disease (GvHD) after allogeneic hematopoietic cell transplantation without adding relevant toxicity. Although positive reports on the efficacy of Mycophenolate Mofetil (MMF) in patients with acute and chronic GvHD are available, there is only limited data on the optimal prophylactic dosing schedule in patients at high risk for GvHD. Since very low trough-levels of MPA are measured in recipients of allogeneic stem cell transplants, we performed a prospective phase I/II trial targeting daily MMF doses according to MPA AUC levels determined at several time-points after transplantation. Twenty-nine patients (18 male, 11 female) with a median age of 53 years were included. The indication for allogeneic transplantation from matched sibling (n=7) and unrelated donors (9/10 alleles matched as minimum requirement; n=22) was high-risk AML/MDS (n=19) or relapsed lymphoma/multiple myeloma (n=10). Conditioning therapy included 30 mg/m2 Fludarabine on days −9 to −6 (4 x 20 mg/m2) combined with intravenous Busulfan 3.45 mg/kg from day −5 to day −2 (4 x 3.45 mg/kg i.v.). Tacrolimus was given orally starting on day −1 at 0.03 mg/kg in order to achieve trough blood levels of 5–10 ng/ml. MMF was started on day 1 at 1500 mg intravenously every 12 hours. AUC measurements of mycophenolic acid (MPA) and its metabolite MPAG by HPLC were scheduled on day 3, 8, 14, 21 and 28 after transplantation. The MMF dose was modified in order to achieve an AUC of 35–60 μg/m*h. MMF was tapered from day 56 on, if possible The dose of MMF had to be increased in 15/29 (52%) patients to 1750–2500 mg every 12 hours on day 4. No patient required a reduction of dosing on day 4. With the respective dose adjustments 52% and 80% of patients reached the AUC target on day 8 and 14, respectively. There was no direct association between dose level and extramedullary toxicity. Early grade 3–4 gastrointestinal toxicity occurred in 4 patients and lead to a reduction of MMF back to 1000 mg every 12 hours. Trilineage engraftment and complete donor chimerism was observed in all patients included. Only one out seven patients with a matched related donor experienced acute GvHD &gt; grade II. The respective proportion of grade III–IV acute GvHD in the unrelated setting was 7/20 (33%). The rate of viral (CMV) and fungal infections was not increased compared to historical controls using standard antimicrobial prophylaxis. With a median follow-up of 18 months 15 (52%) patients are alive and 14 are in complete remission. Reasons for death were relapse (n=5; 17%), pneumonia/sepsis (n=2; 7%), GvHD (n=5; 17%) and organ failure (n=2; 7%). So far, 8 out of 24 evaluable patients (33%) suffer from limited (n=3) or extensive (n=5) chronic GvHD. A retrospective analysis revealed a significant correlation between Cmax levels and the AUC for MPA. The respective target Cmax was shown to be 16 μg/ml. Given the high-risk patient population and the high proportion of unrelated donors (70%) the clinical results observed with the combination of tacrolimus and MMF as prophylactic regimen are encouraging. The regimen has to be optimised for recipients of unrelated transplants. MMF doses of up to 2500 mg every 12 hours can be infused early after stem cell transplantation without an increased risk of toxicity. A simplified MMF targeting strategy based on MPA Cmax levels seems to be warranted in future trials.

Allogeneic Stem Cell Transplantation for Acquired Aplastic Anemia: Better Outcome with Bone Marrow as Compared to Peripheral Blood in HLA-Matched Sibling Donor Transplantation and Improved Outcome Over Time After Matched Unrelated Donor Transplantation. A Retrospective Analysis of Transplants Reported to the German Registry for Stem Cell Transplantation (DRST).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 876-876
Author(s):  
Hubert Schrezenmeier ◽  
Ulrike Feldmann ◽  
Hellmut Ottinger ◽  
Matthias Eder ◽  
Monika Führer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Probability Of Survival ◽  
Stem Cell Source ◽  
Cell Source ◽  
Matched Sibling ◽  
German Registry

Abstract Abstract 876 Background: Transplantation of bone marrow (BM) from a HLA-matched sibling donor is an effective treatment for severe aplastic anemia (AA) with long-term survival in excess of 80%. In the recent years there were two trends in allogeneic stem cell transplantation (SCT) for AA: (1) increasing proportion of transplants performed from matched unrelated donors (MUD) and (2) increasing proportion of transplants using peripheral blood progenitor cells (PBSC) as stem cell source instead of BM. A similar switch to PBSC over BM grafts is reported in leukemia transplants. PBSC grafts for leukemia are associated with higher rates of chronic graft-versus-host disease (cGVHD). This adverse consequence may be offset by lower rates of leukemia relapse in some settings. In contrast, there is no perceived benefit of cGVHD for AA. A recent retrospective analysis of EBMT/CIBMTR reported worse outcome after PBSCT compared to BMT in young patients after HLA-matched sibling (sib) transplantation. The impact of stem cell source on outcome after MUD transplants has not been studied in detail so far. Some reports on favourable results after MUD SCT prompted the discussion whether MUD SCT should be performed earlier in the treatment algorithm in AA instead of considering it as salvage treatment after failure of immunosuppressive treatment. Therefore we performed a retrospective study on the dataset of the German Registry of Stem Cell Transplantations (DRST) to (1) analyze outcome after MUD compared to sib SCT and (2) to study impact of stem cell source (PBSC vs BM) on both sibling and MUD SCT and (3) to analyze impact of transplant period (1998-2002 vs. 2003-2008). Results: We analyzed 182 sib SCT and 114 MUD SCT (first transplants only). The interval between diagnosis and transplant was significantly longer for MUD SCT as compared to sib SCT (median 98.5 days vs. 511.5 days; p<0.001 ) suggesting that the majority of sib SCT were performed upfront whereas MUD SCT in the majority of cases was performed after failure of other treatments. Median age was 28.5 years (sib SCT) and 30 years (MUD) years (p=0.41). PBSC were used as stem cell source in 50.5% of sib SCT and 61.4% of MUD (p=0.097). 5-year probability of survival was 84.6% (95%-CI: 79.3-90.3%) after sib SCT and 70.1% (95%-CI. 61.8-79.6%) after MUD (p<0.003). In univariate comparison age at transplant has significant impact on survival: After sib SCT 5-year probability of survival in patients ≤ 30 years vs. > 30 years was 94.5% (95%-CI: 90.0-99.3%) vs. 73.5% (95%-CI: 64.3-84.1%)(p<0.001) . 5-year probability of survival after MUD SCT in patients ≤ 30 years vs. > 30 years was 77.7% (95%-CI: 67.3-89.7%) and 60.6 (95%-CI: 48.2-76.2%) (p=0.044). In the most recent period (2003-2008) 2-year probability of survival was 81.6% (95%-CI: 72.9-91.3%) after sib SCT (n=80) and 75.6 (66.1 – 86.5%) after MUD SCT (n=73) (p=0.34). After sib SCT survival was significantly better with BM as compared to PBSCT (5-yr. prob. 95.3%; 95%-CI: 90.9-99.9%; n=89 vs. 74.1%, 95%-CI: 65.1-84.2%; n=92; p<0.001) and cumulative incidence of chronic GvHD was significantly higher with PBSCT as compared to BM (47.0% vs. 18.4%; p<0.01). Cumulative incidence of acute GvHD II-IV did not differ significantly between BM and PBSC. In contrast, stem cells source did neither significantly affect overall survival nor cumulative incidence of acute or chronic GvHD after MUD. In multivariate analysis of the sib SCT older age (>30 years) and use of PBSC were significant risk factors for mortality (Hazard Ratio (HR) 3.4 (1.2-9.3) and HR 4.0 (1.3-12.2). Other variables in the model (conditioning regimen; GvHD prophylaxis; sex match; time diagnosis to transplant and transplant period) were not significant. For MUD SCT none of these variables were significant in a multivariate model. Conclusion: These results indicate that BM grafts should be preferred to PBSC in patients undergoing HLA-identical sib SCT for AA. In contrast, no negative impact of stem cell source on outcome after MUD SCT could be demonstrated. Results of MUD SCT substantially improved over time. In the most recent period from 2003- 2008 the probability of survival after MUD and HLA-identical sib SCT was no longer different. So far majority of MUD transplants were performed late after diagnosis, mostly after failure of immunosuppression. Re-assessment of both the indication of MUD SCT for AA and the timing of MUD SCT is warranted. Supported by the Deutsche José Carreras Leukämie-Stiftung. Disclosures: No relevant conflicts of interest to declare.

Impact of Graft-Versus-Host Disease On Relapse After Allogeneic Hematopoietic Stem Cell Transplantation, an EBMT Megafile Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 469-469
Author(s):  
Martin Stern ◽  
Liesbeth C. de Wreede ◽  
Ronald Brand ◽  
Anja van Biezen ◽  
Peter Dreger ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hazard Rates ◽  
Disease Relapse ◽  
Relapse Risk ◽  
Graft Versus Host ◽  
Stem Cell Source ◽  
Cell Source ◽  
Unrelated Donors

Abstract Abstract 469 Background: After allogeneic HSCT, graft-versus-host disease (GvHD) occurs through recognition of minor or major histocompatibility mismatches by donor derived T lymphocytes. The same mechanism also operates in the elimination of residual malignant cells (the graft-versus-leukemia or GvL effect). Earlier studies have already shown reduced relapse risks for patients developing GvHD (Weiden et al, NEJM 1979; Horowitz et al, Blood 1990). In particular, a large study in CML patients (Gratwohl et al, Blood 2002) showed that increasing grades of acute and chronic GvHD are associated with a proportional decrease in relapse risk. Incidence and severity of acute and chronic GvHD might therefore be used as surrogate markers for GvL effects. Transplant procedures have changed significantly since these publications. Increased use of unrelated donors, peripheral blood as stem cell source, and the introduction of reduced intensity conditioning regimens might affect the relationship between GvHD and GvL. Furthermore, previous studies have only analyzed transplants for AML, ALL and CML, the prevailing transplant indications at the time. Today, many patients receive transplants for MDS, plasma cell disorders (PCD) or lymphoma. We hypothesized that comparing the effect GvHD on relapse incidence might provide a useful surrogate marker for the susceptibility of different diseases to allo-immune effects. Methods: We studied 48,111 first allogeneic transplants carried out and reported to EBMT between 1998 and 2007. The impact of GvHD on relapse risk was assessed by including acute and chronic GvHD as time-dependent covariates in Cox models for cause-specific hazards adjusted for patient age, year of transplant, donor type, stem cell source, and type of conditioning regimen. Results: Diseases were CML (N=7,711), AML (14,539), ALL (6,802), MDS/MPN (6,958), lymphoma (N=8,231), or PCD (3,870). Donors were HLA identical family donor (N=28,030), and HLA-identical unrelated donors (N=14,422) or mismatched donors (N=5,659). Stem cell source was bone marrow (N=13,273), peripheral blood (N=34,022), or cord blood (N=816). Conditioning intensity was myeloablative (N=28,843), reduced intensity (15,889) or unknown (N=3,379). 14,764 (31%) of grafts were T-cell depleted. Incidence of grade I-IV acute GvHD was 49%, that of grade II-IV acute GvHD 30%. Limited chronic GvHD was diagnosed in 17% and extensive chronic GvHD in 20% of patients. Incidence of disease relapse was 22%, 28%, and 31% at 1, 2, and 4 years respectively. As shown previously, development of GvHD was associated with a reduced risk of relapse in our data. In CML, a clear reduction of relapse risk occurred with hazard ratios declining proportionally to severity of both acute and chronic GvHD (Figure 1). The protective effect of severe acute (grade III-IV) GvHD was similar to that of extensive chronic GvHD, whereas the protective effect of mild acute (grade I-II) GvHD was comparable to that of limited extensive GvHD. ALL was almost equally sensitive to GvHD as CML, whereas MDS/MPN and lymphomas showed intermediate sensitivity (Figure 1). Acute and limited chronic GvHD were only associated with modest reductions in relapse risk in AML and PCD. The limited sensitivity of PCD to allo-immune effects was also evident in Kaplan-Meier curves of disease-free survival where – in contrast to other diseases – no plateau developed during follow-up (Figure 2, upper panel). Similarly, hazard rates of disease relapse failed to drop to values near zero in patients with PCD (Figure 2, lower panel). Interestingly, despite a comparatively poor association of GvHD and relapse in AML patients, a plateau in the survival curve occurred and hazard rates dropped in parallel to other diseases, suggesting that curative GvL effects operating independently of GvHD might occur in this disease. Discussion: These data confirm earlier observations of a potent GvL effect associated with GvHD. While GvHD and GvL are significantly associated in all diseases, the strength of this association strongly differs between disease entities (strongest correlation in CML and ALL, weakest correlation in AML and PCD). A poor correlation might point to either insensitivity of a particular disease to GvL effects, to GvL effects operating in the absence of and independent from GvHD, or to a significant fraction of patients already cured before allogeneic SCT. Disclosures: No relevant conflicts of interest to declare.

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