scholarly journals Family Mismatched Donor Transplantation for Myelofibrosis: A Retrospective Analysis of the EBMT Chronic Leukaemia Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4655-4655 ◽  
Author(s):  
Kavita Raj ◽  
Eduardo Olavarria ◽  
Diderik-Jan Eikema ◽  
Liesbeth C de Wreede ◽  
Linda Koster ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Graft Failure ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Mismatched Donor

Abstract Background: Allogeneic stem cell transplantation is a treatment option for patients with advanced myelofibrosis. Problems encountered include an increased risk of delayed or poor engraftment and in the mismatched unrelated donor setting a higher rate of GVHD and particularly poor outcomes. As for other indications for allogeneic stem cell transplants, patients for whom either a matched sibling or matched unrelated donor is not available are considered for either a double umbilical cord blood, a mismatched unrelated donor or haploidentical stem cell transplant. Data on the latter option are limited and we reviewed registry data on all family mismatched donor transplants performed between 2001 and 2015 and reported to the EBMT registry. Results: Records retrieved 69 patients with myelofibrosis transplanted between November 2001 and November 2015. 44 (64%) were male. 50 (74%) had primary myelofibrosis,18 (27%) had secondary myelofibrosis (6 from ET, 5 from PRV and 7 others) and unknown 1(2%). Of 25 patients for whom the JAK2 V617F mutation status was known, 15 (22%) harboured the mutation. Patient Karnofsky performance status was > 70% in 98%. Of the mismatched family donors, 47 (68%) were male and 22 (31%) female. Donors were HLA mismatched at 1 locus in 12 (17%) and 2 or more loci in 48 (69%). Donor-recipient serology combinations were CMV -/- in 8 (12%), +/- in 4 (6%), -/+ in 15 (22%) and +/+ in 34 (49%) missing 8 (12%). Bone marrow was the stem cell source in 34 (49%) and peripheral blood in 35 (51%). The median total nucleated cell count (TNC) infused was 7.5x108/kg (range 2.3-21x108/kg) from data available in 17 patients. The median CD34+ cell dose was 6.9x106/kg (range 1.9-18.18x106/kg) from data available in 19 patients. Conditioning was myeloablative in 48 (70%) and RIC in 21 (30%) The conditioning regimes were varied but the predominant ones were Fludarabine, Busulphan, ATG (FBATG) and Thiotepa, Busulphan, Fludarabine (TBF). TBI was administered in 8 (12%) and in vivo T cell depletion in 22 (32%), ex-vivo T cell depletion in 5 (7%) patients. GVHD prophylaxis varied with post transplant Cyclophosphamide administered in 34/67 (49%) and ATG in 19/67 patients (28%). Neutrophil engraftment was established in 53 (82%) at a median of 20 days (range 11-83). Primary graft failure occurred in 8 (12%) and secondary graft failure in 4 (6%). This occurred at a median of 12 months (range 4.5-35 months). Eleven of these patients had a second allograft at a mean interval of 6.4 months. Responses to the first allograft (censoring for patients who had a second allograft) with data available in 45 patients, showed that complete remission was achieved in 35 patients (78%), 6 (13%) were never in CR and 4 (9%) were not evaluable. The cumulative incidence of grade II-IV acute GvHD at 100 days was 12% (95% CI 4-21%) and for grade III-IV acute GvHD at 100 days it was 5% (95% CI 3-11%). Data for chronic GVHD was valid in 49 patients. The cumulative incidence of chronic GvHD at 2 years was 62% (95% CI 47-76%). The cumulative incidence of limited cGvHD was 45% (95% CI 31-59%) whereas the cumulative incidence of extensive cGvHD was 10% (95% CI 2-19%). The median follow up was 24 months (95% CI 13-35 months). The 2-year OS was 51% (95% CI 37-76%) and the 5-year OS was 38% (95% CI 21-55%). The 2-year RFS was 44% (95% CI 30-59%) and the 5-year RFS was 31% (95% CI 15-48%). The 2 year cumulative incidence of relapse was 14% (95% CI 5-24%). The 2 year NRM was 41% (95% CI 28-55%), which increased to 54% (95% CI 37-72%) at 5 years. The main causes of death were infection (16, 24%), GVHD (7, 10%) organ damage or failure (3, 5%), relapse/disease progression (1, 2%) and secondary malignancy or PTLD (1, 2%). On univariate analysis there was no significant effect of recipient gender, donor gender, degree of HLA mismatch 1 vs >1 Ag MM, CMV matching between donor and recipient, primary or secondary MF, disease stage at transplant (chronic versus advanced phase), conditioning intensity, conditioning regimen, GVHD prophylaxis with ATG or post transplant cyclophosphamide or stem cell source on overall survival. Conclusion: Concerns regarding engraftment and secondary graft failure have excluded patients with myelofibrosis from clinical trials of mismatched related donor transplant. The data suggest that engraftment is feasible, and PFS and OS can be attained with limited severe chronic GVHD with family mismatched donors in this setting. Disclosures Ciceri: MolMed SpA: Consultancy.

Post Transplant Cyclophosphamide (PTCy) with Anti-Thymocyte Globulin (ATG) Effectively Reduces the Severe (Grade III-IV) Acute Graft-Versus-Host Disease (GVHD) When Compared to ATG Alone in Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplants

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3430-3430 ◽  
Author(s):  
Uday Deotare ◽  
David Loach ◽  
Fotios V. Michelis ◽  
Dennis D. Kim ◽  
Santhosh Thyagu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Historical Cohort ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source ◽  
Grade Iii ◽  
Severe Grade

Abstract Introduction: Acute Graft-versus-Host Disease (aGVHD) is a frequent complication of Allogeneic Hematopoietic cell transplants (allo-HCT). It can be lethal with increased morbidity and mortality and can occur in upto 40-50% of allo-HCT. Various agents such as calcineurin inhibitors, anti-metabolites and anti T cell antibodies, have been variably used for GVHD prophylaxis. Use of Post-transplant Cyclophosphamide (PTCy) has recently been used extensively in haplo-identical transplant setting with promising results, but has mainly been used in patients with BM as a stem cell source. In those patients receiving PBSC as a stem cell source, PTCy alone could reduce the risk of acute and chronic GVHD significantly. Anti-Thymocyte Globulin (ATG) has been associated with decrease in chronic but not acute GVHD. As most of our patients use PBSC as a graft source, we hypothesized that combination of ATG and PTCy can reduce the incidence of both acute and chronic GVHD. Since we had also used ATG for GVHD prophylaxis in a historical cohort, we compared the results of this approach with the current GVHD prophylaxis regimen. Methods: A total of 28 patients with hematological malignancies, who had an unrelated donor underwent allo-HCT at our center from 1 Oct 2015 to 31 Mar 2016. After interim analysis, when increased non-hematological toxicity was observed with myeloablative conditioning, all patients subsequently received reduced intensity conditioning. Peripheral blood was used as a stem cell source in all patients. The GVHD prophylaxis consisted of a combination of ATG-PTCy-CsA, with rabbit ATG administered on Days -3 (0.5 mg/Kg), -2 (2 mg/Kg) and -1 (2 mg/Kg), PTCy at dose of 50 mg/kg on Days +3 and +4 and CsA from Day+5 onwards. Filgrastim was used from day +7 onwards for 13 patients. Emphasis was given to incidence of acute GVHD, especially Steroid Refractory (SR-GVHD). Results: Out of total of 28 patients, aGVHD was seen in 6 (21.4%) patients, five of which had skin involvement (Grade I- II) and one suspected liver involvement (Grade III), all of which responded rapidly to steroids with no cases of SR-GVHD. Secondary graft failure and EBV reactivations; each were seen in 10% of cases. Primary disease relapse was seen in 3 patients, two of which had minimal residual disease prior to transplantation. These results were then compared to the historical cohort of 27 patients who received a combination of ATG-CsA plus Mycophenolate Mofetil (MMf) (Table 1). The incidence of acute GVHD was 26% vs 22% (p=0.99), with severe Grade III-IV aGVHD of 4% vs 20% (p=0.085) in the ATG-PTCy-CsA and ATG-CsA-MMf cohorts, respectively; both were statistically not signifcant. There were five patients with SR-GVHD in the ATG-CsA-MMf cohort and none in the current GVHD prophylaxis arm. In the historical cohort, the main cause of death in 7 out of 11 patients was severe GVHD as compared to 1 out of 9 in the ATG-PTCy-CsA cohort. Conclusions: Combination of ATG-PTCy-CsA is an effective strategy to reduce aGVHD; especially severe Grade III-IV and doesnot increase the risk of SR-GVHD, in unrelated donor transplants as compared to ATG-CsA-MMf. However, a long term follow up is needed to assess relapse and cGVHD. Disclosures No relevant conflicts of interest to declare.

A Comparison of Stem Cell Source in Recipients of T-Cell Depleted Myeloablative Transplants for Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 46-46
Author(s):  
B.E. Shaw ◽  
Nigel H. Russell ◽  
A. Pagliuca ◽  
J. Apperley ◽  
G. Cook ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Increased Risk ◽  
Significant Difference ◽  
Cell Source ◽  
The Impact

Abstract The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in >90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.

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.

A Comparison of Stem Cell Source in Adult and Paediatric Recipients of T-Cell Depleted Myeloablative Transplants for Standard Risk Leukaemia: No Difference in Mortality Using BM or PBSC.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1205-1205
Author(s):  
Bronwen E Shaw ◽  
Jane Apperley ◽  
Nigel H. Russell ◽  
Charles F. Craddock ◽  
Effie Liakopoulou ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Stem Cell Source ◽  
Significant Difference ◽  
Cell Source ◽  
Standard Risk

Abstract Abstract 1205 Poster Board I-227 The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in non relapse mortality (NRM) and decrease in survival (OS) in T-cell replete transplants. We have previously reported outcome data in 145 patients who received an unrelated donor transplant for leukaemia. In that study we reported an increase in mild acute GvHD using PBSC, but no other significant differences in outcome. We have now doubled the cohort and report our findings on 320 patients here. In this group all of the patients received pre-transplant serotherapy (Alemtuzumab = 306, ATG = 14) as part of myeloablative conditioning prior to an HLA-matched UD allograft. Patients were transplanted between January 2000 and August 2007: CML in 1CP (n=102) and acute leukaemia in CR1/2 (AML in 105, ALL in 144). 190 patients received BM and 130 PBSC. The median age of the recipients was 28.9 years (10months - 58years). There was no significant difference in age between those receiving BM or PBSC.98% and 96% of patients receiving PBSC and BM achieved neutrophil engraftment (NS), with a significantly faster time to engraftment in recipients of PBSC compared to BM (14 vs 20 days; p<0.001). The incidence of acute GvHD was significantly higher in recipients of PBSC (64%) compared to BM (51%; p=0.022), however there was no increase in grade III/IV (p=0.420) disease in PBSC recipients. The incidence of chronic GvHD at 6 years was 61% in the BM recipients and 55% in the PBSC recipients (NS), with no difference in the incidence of extensive disease. The 5-years OS was 55% in BM recipients, with a median follow-up of 59 months, compared to 54% in PBSC recipients at a median follow-up of 38 months (NS). The incidence of neither disease relapse nor NRM was significantly different between groups (relapse at 5 years: BM 44%, PBSC 36%; p=0.112, and NRM at 5 years: BM 22%, PBSC 24%; p=0.751). In view of the fact that there were more CML patients in the BM group and more AML patients who received PBSC (the distribution of ALL patients was similar) (p=0.051), we performed a subgroup analysis. The pattern of results for each outcome, dependant on the use of BM or PBSC, in patients with CML and those with acute leukaemia were similar to those reported in the group overall. In conclusion, we have confirmed the results of our previous smaller study, showing the only significant difference in clinical outcome between PBSC and BM to be a higher incidence in the occurrence (but not grade) of acute GvHD. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM. We suggest that either stem cell source can be used with a similar outcome in adult and paediatric recipients of T-cell depleted allografts for standard risk leukaemia. Disclosures: Apperley: Novartis: Consultancy, Honoraria.

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.

scholarly journals Post-Transplant Cyclophosphamide Versus Antithymocyte Globulin in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation from HLA-Identical Sibling Donors: A Retrospective Analysis from the Acute Leukemia Working Party of the EBMT

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 148-148
Author(s):  
Giorgia Battipaglia ◽  
Myriam Labopin ◽  
Rose-Marie Hamladji ◽  
Didier Blaise ◽  
Patrice Chevallier ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cyclosporine A ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
The Other ◽  
Free Survival ◽  
Stem Cell Source ◽  
Gvhd Prophylaxis ◽  
Cell Source

Introduction. In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an HLA-identical matched sibling donor (MSD), use of cyclosporine A in association with methotrexate has been the main graft-versus-host disease (GVHD) prophylaxis strategy. Addition of antithymocyte globulin (ATG), especially when using peripheral blood stem cells (PBSC) as source, has also been shown to favor lower rates of chronic GVHD. More recently, use of post-transplant cyclophosphamide (PTCY) in the haploidentical setting resulted in low incidences of both acute and chronic GVHD. Its use has therefore been subsequently reported in other donor settings, including MSD. The aim of our study was to compare GVHD prophylaxis containing either PTCY or ATG in patients diagnosed with acute myeloid leukemia and undergoing allo-HSCT from a MSD. Methods. This was a retrospective study from the EBMT registry. Included were adult patients undergoing their first allo-HSCT during the period 2008-2018 and who were in complete remission at time of allo-HSCT. Results. Globally, 197 and 1,913 patients receiving either PTCY or ATG, respectively, were identified who fulfilled inclusion criteria. Patients in the PTCY group were younger (median age 47 versus 54 years, p&lt;0.01) and had undergone allo-HSCT more recently (median year of allo-HSCT: 2015 versus 2014, p&lt;0.01). Peripheral blood was the more frequently used stem cell source, this being significantly more frequent in the ATG group (95% versus 70%) than in the PTCY group (p&lt;0.01). The conditioning regimen was more frequently myeloablative in the PTCY group (59% versus 48% in the ATG group, p&lt;0.01). Cyclosporine-A alone was the most used systemic immunosuppressive agent associated with either PTCY (22%) or ATG (28%), while 34% and 29% of patients in the ATG group and 7% and 12% in the PTCY group also received either methotrexate or mycophenolate mofetil along with cyclosporine A. No statistical differences were observed for incidence of grade II-IV acute GVHD at 100 days after allo-HSCT, this being 19% versus 17% in the PTCY and ATG groups, respectively (p=0.81). On the other hand, a significantly higher incidence of chronic GVHD at 2 years was observed with the use of PTCY (37% versus 30%, p&lt;0.02) and for extensive chronic GVHD (16% versus 12%, p&lt;0.01) as compared to ATG. There was no impact of conditioning intensity on GVHD incidence. No statistical differences were observed on univariate analysis for all other transplant outcomes, with a leukemia-free survival (LFS) of 55% versus 58%(p=0.75), overall survival (OS) of 64% versus 65% (p=0.61), GVHD-free, relapse-free survival (GRFS) of 44% versus 49% (p=0.19), relapse incidence (RI) of 36% versus 32% (p=0.56) and non-relapse mortality (NRM) of 8% versus 10% (p=0.78). Of note, the cumulative incidences of death due to GVHD were 4.4% and 4% in the PTCY and ATG groups, respectively (p=0.53). Also, there were no differences between the 2 groups for death due to infections: 6% in the PTCY group and 6.3% in the ATG group, respectively (p=0.49). On multivariate analysis, these results were confirmed, with a higher risk of chronic GVHD of any grade (HR=1.41, 95%CI 1.03-1.92; p&lt;0.01) and extensive chronic GVHD (HR=1.68, 95%CI, 1.07-2.62; p&lt;0.01) with PTCY, and no differences with respect to the other outcomes. We also observed that, regardless of the use of PTCY or ATG, use of PBSC was associated with lower RI (HR=0.64, 95% CI 0.46-0.89; p&lt;0.01), higher LFS (HR=0.71, 95% CI 0.53-0.95; p&lt;0.03), and OS (HR=0.72, 95% CI 0.52-0.99; p&lt;0.05). On the other hand, we found no statistical differences in terms of both acute GVHD (HR=0.73, 95%CI, 0.48-1.12; p=0.15) and chronic GVHD (HR=0.83, 95% CI 0.56-1.21; p=0.33) according to stem cell source. These results were also confirmed in a matched-pair analysis. Conclusion. In conclusion, our results highlight that in the HLA-identical sibling setting, the use of ATG provides similar outcomes to those seen with PTCY except for chronic GVHD for which a protective effect of ATG is confirmed as previously reported by different other studies. Disclosures Blaise: Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria. Socie:Alexion: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Outcomes of Allogeneic Stem Cell Transplantation with Individualized Dosing of Antithymocyte Globulin

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Amany R. Keruakous ◽  
George Selby ◽  
Sarah A. Schmidt ◽  
Jennifer Holter-Chakrabarty ◽  
Mohamad O. Khawandanah ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Matched Unrelated Donor ◽  
Lymphoid Malignancies ◽  
Stem Cell Source ◽  
Individualized Dosing ◽  
Cell Source ◽  
Donor Transplant

Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. However, relapse disease and graft-versus-host disease (GVHD) remain to be the main obstacle for a successful HCT. Thus, adequate immune suppression to minimize the risk of high-grade GVHD while not over suppression of donor immunity to allow graft versus tumor effect is crucial. Matched unrelated donor transplant has a higher rate of GVHD as compared to matched sibling donor transplant due to minor histocompatibility mismatch. Rabbit antithymocyte globulin (ATG), a polyclonal antibody produced by immunizing rabbits with human thymocytes, has been utilized as prophylaxis against GVHD. ATG dosing by weight has been the standard. Recent pharmacokinetic (PK) studies revealed that ATG levels and clearance vary significantly among patients receiving weight-based dosing of ATG. Recipient lymphocyte count before receiving ATG has been described as a modulator of both ATG PK and clinical outcomes after ATG-conditioned HCT. The Parachute-Study utilizing an individualized ATG dosing approach has shown more rapid immune reconstitution without affecting the incidence of acute GVHD and graft failure. In this study, we are comparing the outcomes of individualized dosing of ATG versus weight-based dosing. Method: This is a single institutional study carried out at the Bone Marrow Transplant Program at the University of Oklahoma Health Science Center. It was started as a case-control cohort study in July 2018 when individualized dosing of ATG was initiated, and continues as a historically controlled non-randomized prospective clinical study investigating individualized versus weight-based dosing of ATG. Subjects over 18 years of age who are undergoing matched unrelated donor (MUD) stem cell transplant, with myeloablative or reduced-intensity conditioning, peripheral blood or bone marrow stem cell source, for myeloid or lymphoid malignancies were included in the study. We excluded subjects with HLA mismatch or sibling donors. Individualized dosing was based on the previously validated PK model with cumulative doses varying between 2 to 10 mg/kg, based on weight, recipient lymphocyte counts before the first dose of ATG, and stem cell source, starting day -9; while the standard weight-based dosing of ATG is 4 mg/kg divided into 3 days pre-transplant. The study endpoints are to evaluate the difference between treatment groups on (1) GVHD and its severity; (2) relapse-free survival (RFS) and (3) overall survival (OS). Univariate logistic regression analysis was used to evaluate the probabilities of GVHD in both treatment arms. Multivariable analysis was done to adjust for all covariates between study arms using adjusted logistic. OS and RFS were computed using the Kaplan-Meier curves. Results: The study included 38 subjects undergoing MUD HCT for myeloid or lymphoid malignancies. Subjects included are in 2 cohorts, 19 subjects in the intervention arm using individualized targeted ATG (tATG group), and 19 subjects in the matched control arm using weight-based dosing ATG (ATG group). In a univariate unadjusted logistic regression analysis, the risk of developing GVHD is numerically higher in the ATG group than in the tATG group (OR=1.339, p=0.70). However, the proportion of acute GVHD is significantly higher in the tATG group than the ATG group (73.68% vs 31.58%, p=0.022). Also, the proportion of higher grade acute GVHD is significantly higher in the tATG group than the ATG group (31.58% vs 0%, p=0.020). RFS is longer in the tATG group than the ATG group, tending statistical significance (p=0.063). However, there is no difference in OS between study arms (p=0.645). [Figures 1 and 2] In a multivariable-adjusted logistic regression, adjusting for age at HCT, diagnosis, disease status at HCT, prior lines of therapy, and stem cell source, no confounder was found to be significantly associated with GVHD. Conclusion: Individualized targeted dosing of ATG (tATG), based on weight, recipient lymphocyte counts and stem cell source, increases the risk of acute GVHD when compared to standard fixed-dosing method, however, it improves RFS, implying possibly better immune reconstitution providing improved graft versus leukemia effect. Disclosures No relevant conflicts of interest to declare.

Novel Conditioning Regimen for Haploidentical Hematopoietic Cell Transplant for Severe Aplastic Anemia in Children

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5651-5651 ◽  
Author(s):  
Hasan Hashem ◽  
Rawad Rihani ◽  
Eman Khattab ◽  
Mayada Abu Shanap ◽  
Abdelghani Tbakhi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Stem Cell Source ◽  
Cell Source

New hematopoietic cell transplant (HCT) approaches are urgently needed for patients with severe aplastic anemia (SAA) who lack an HLA-identical donor. Haploidentical HCT with post transplant cyclophosphamide (PTCy) represent a potential universal available option for almost all children with SAA. We present a novel conditioning regimen for haploidentical HCT in children with SAA in a center where horse ATG is not available. Conditioning regimen consists of rabbit ATG 2.5 mg/kg/day from day -9 to -7, Fludarabine 30 mg/kg/day from day -6 to -2, Cyclophosphamide 14.5 mg/kg/day from day -6 to -5, Thiotepa 5 mg/kg/day from day -4 to -3, and 4 Gy TBI on day -1 in in two fractions. GvHD prophylaxis consist of PTCy 50 mg/kg/day on days +3 and +4 along with Cyclosporine A and Mycophenolate mofetil (MMF) starting on day +5. Four consecutive children with SAA referred to our center for haploidentical HCT starting in 2018. Median age at HCT was 9 years (5-16) with 3 males and 1 female. All patients were heavily transfused with both blood and platelets prior to referral for HCT. Two patients had strong and one had weak positive anti-HLA antibodies (DSAs) and received desensitization with IVIG, Rituximab and plasmapheresis. One patient received buffy coat infusion on day -1 due to persistent strong DSAs despite desensitization. Median CD34+ dose received was 12 x 10e6, and median CD3+ dose was 29 x 10e6. Donors were all same blood group to patients. All patients successfully engrafted neutrophils at median of 13 days (12-14). Platelets engraftment in 3/4 patients at median of 7 days (5-10). All patients received peripheral blood as stem cell source. Three of four patients survived and doing well at last follow up. One patient had toxic death on day +38 due to chemotherapy related toxicity causing multi-organ failure. Chimerism analysis was full donor in all four patients at median follow up time of 11 months (2-12). Patients were sent home at median of 24 days post HCT. None developed grade 2-4 acute GvHD nor chronic GvHD. Acute GvHD of skin grade 1 stage 1 developed in 2 patient and managed with topical steroids. Viral reactivations consisted of CMV viremia and BK hemorrhagic cystitis in all patients, and have all resolved. No post transplant autoimmune complications. Haploidentical HCT with PTCy represents a quick and first line approach in heavily transfused children with SAA. Although yet limited number of patients, this regimen is feasible and appears to be safe. A great advantage of this regimen is the rapid engraftment of both neutrophils and platelets. Moreover, although using peripheral blood as a stem cell source, there was no severe acute or chronic GvHD. 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.

Long-Term Outcome of Methotrexate-Free GVHD Prophylaxis Using Sirolimus and Tacrolimus in Matched Related (MRD) and Unrelated Donor (URD) Peripheral Blood Stem Cell Transplantation (PBSCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 757-757
Author(s):  
Corey Cutler ◽  
Shuli Li ◽  
Vincent Ho ◽  
John Koreth ◽  
Edwin Alyea ◽  
...  
Keyword(s):  
Cause Of Death ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Competing Risk ◽  
Unrelated Donor ◽  
Long Term Outcome ◽  
Gvhd Prophylaxis ◽  
Cd34 Cells ◽  
Neutrophil Engraftment

Abstract Methotrexate (Mtx) is an antiproliferative agent associated with toxicity and delayed engraftment after transplantation. Sirolimus is an immunosuppressive mTOR inhibitor that acts synergistically when administered with tacrolimus. We assessed the combination of sirolimus and tacrolimus without Mtx after MRD and URD PBSCT in concurrent trials. Methods Eligible subjects had HLA-A, B, C and DRβ1 matched MRD and URD donors. Conditioning consisted of cytoxan (1800 mg/m2 x 2 days) and TBI (14 Gy, 7 fractions with lung shielding). Tacrolimus (serum conc. 5–10 ng/mL) and sirolimus (serum conc. 3–12 ng/mL) were given as GVHD prophylaxis. No Mtx was given. G-CSF (5 μg/kg/day) was administered from day+12 until neutrophil engraftment as needed. PCP, VZV, and HSV prophylaxis was used, and CMV was treated pre-emptively. No routine anti-fungal prophylaxis was given. Results 53 MRD and 30 URD recipients were enrolled between 7/2002 and 8/2005. The median number of stem cells infused was lower in MRD recipients (7.6 x106 CD34+ cells/kg vs. 10.2 x106 CD34+ cells/kg, p&lt;0.001). Neutrophil engraftment was similar in MRD and URD patients (14 vs. 13.5 days, p=0.2). Platelet engraftment to 20 x106/ml (12 vs. 12 days, p=0.13) and to 100 x106/ml (17.5 vs. 17 days, p=0.32) were similar in the two cohorts. The median time to hospital discharge was 19 days in both groups (p=0.95), with only 2 deaths prior to discharge. Acute lung injury (IPS/DAH) occurred in only 1 subject and was not fatal. 7 (8.4%) subjects developed hepatic veno-occlusive disease (VOD) and was the cause of death in 4. Thrombotic microangiopathy (TMA) was noted in 6 subjects (MRD 5, URD 1; combined incidence 7.3%) and resolved with the elimination of tacrolimus. Renal function recovered in all individuals and TMA did not contribute to the cause of death in any subject. The cumulative incidence of grade II–IV acute GVHD was 20.5%, and was not different between cohorts (18.9 vs. 23.3%, p=0.78). There were only 3 cases of grade III–IV acute GVHD (2 MRD, 1 URD). In a competing risk model (relapse/death as competing risk) the cumulative incidence of chronic GVHD was 52.4% and was not different between groups (50.9 vs. 53.3%, p=0.67). The median follow-up of all surviving patients is 29.5 months from transplantation. Non-relapse and relapse-related mortality at 30 days was 0%. At 100 days they were 4.8% and 1.2% respectively (overall 100 day mortality 6%), without differences in cohorts. Relapse-free survival for the entire group was 72.3% and 68.1% at 1 and 2 years (MRD 71.7% and 66.0%; URD 73.3% at both times points, log rank p=0.6). Overall survival at 1 and 2 years is 77.1% and 71.7% (MRD 77.4% and 69.8%; URD 76.7% at both time points, log-rank p=0.67). The causes of death (n=24) include relapse(13), VOD(4), late pulmonary disease(3), GVHD(2), infection and organ failure(2). Conclusions Sirolimus in lieu of Mtx in a tacrolimus-based GVHD prophylactic regimen is associated with lower transplant-related toxicity, lower rates of acute GVHD and excellent outcomes than would be expected with a Mtx-based regimen. Moreover, MRD and URD outcomes appear to be equivalent, suggesting that the historical disparity in outcomes between MRD and URD transplantation can be abrogated with effective GVHD prophylaxis. This regimen is worthy of further study and broader use in MRD and URD PBSCT.

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