Improved Outcomes with Class I and II DNA-Based HLA Typing for Matched Unrelated Donor (MUD) Allogeneic Bone Marrow Transplant (ABMT) in Hematologic Diseases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5181-5181 ◽  
Author(s):  
Ronald Sobecks ◽  
Edward J. Ball ◽  
Lisa Rybicki ◽  
Elizabeth Kuczkowski ◽  
Matt Kalaycio ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hla Typing ◽  
Class I ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Improved Outcomes ◽  
Typing Methods

Abstract Class I and II DNA-based HLA typing has resulted in improved outcomes in MUD ABMT compared to that observed with HLA serologic typing methods. Since MUDs do not necessarily possess the same linkage of HLA genes on haplotypes as found in matched sibling donors (MSD) it is important to determine the specific alleles present through DNA-based methods in order to improve matching between recipients and donors. We analyzed 146 consecutive hematologic malignancy patients (pts) who underwent ABMT at our institution from 1/7/99–2/4/04, to compare outcomes of 41 MUD and 105 MSD pts. All pts were matched at HLA-A, B, C, and DRB1 by at least low to intermediate resolution using either PCR-sequence specific priming or PCR-sequence specific oligonucleotide probing using Class I and II DNA-based HLA typing. All pts received a busulfan/cyclophosphamide (Bu/Cy)-based preparative regimen. All MUD ABMTs were CD8+ T cell depleted while all MSD ABMTs were T cell replete. GVHD prophylaxis for MUD pts consisted of FK506 and methotrexate while MSD pts received cyclosporine and methotrexate or mycophenolate mofetil. There were no differences between MUD or MSD pts in terms of sex, age, race, prior radiation therapy, or donor-pt gender. Primary diagnoses were comparable except the MSD group had more CML pts (19 vs. 0) (p=0.01 for all diagnoses). There were no differences between MUD and MSD pts regarding infection, acute GVHD, acute grade 3–4 GVHD, chronic GVHD or extensive chronic GVHD. MUD pts as compared to MSD pts had higher graft failure rates (12% vs. 3%, p = 0.019); lower relapse-free survival (median 5.4 mos vs. 10.7 mos, p=0.037); higher 100-day mortality (37% vs. 21%, p=0.05), and lower overall survival (median 5.7 mos vs.13.6 mos, p=0.036). Deaths occurred in 30 (73%) of MUD pts and 61 (58%) of the MSD pts with disease relapse followed by GVHD as the most common causes of death. Since CML pts were only in the MSD group, we repeated the analysis excluding these pts and there were no longer any significant differences between the MUD and MSD pts in 100 day mortality (p=0.12), relapse-free survival (median 5.4 mos vs. 6.5 mos, p=0.22), or overall survival (median 5.7 mos vs. 10.0 mos, p=0.18). For further purposes of comparison, we also analyzed 112 consecutive ABMT pts (31 MUD, T cell depleted; 81 MSD, T cell replete; Bu/Cy-based preparative regimens for all pts) previously transplanted at our institution from 4/93–11/98 during which time only HLA serologic and Class II DNA-based typing was used. In this earlier pt cohort, the MUD pts had a significantly higher incidence of acute GVHD (p<0.001), lower 100-day mortality (52% vs. 12%, p<0.001), lower relapse-free survival (p=0.001) and lower overall survival (2.6 mos vs. 32.5 mos, p=0.001) than the MSD patients. We conclude that Class I and II DNA-based HLA typing is important and can improve outcome in MUD ABMT. Further investigation with high resolution HLA typing methods may continue to improve outcomes with MUD ABMT.

scholarly journals Investigating the Relationship between CD34+and CD3+ Cell Doses, One-Year Graft-Versus-Relapse-Free-Survival, Graft-Versus-Host Disease, and Overall Survival in Haploidentical Hematopoietic Stem Cell Transplantation: A Single Center Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2051-2051 ◽  
Author(s):  
Mindy Hsiao ◽  
Anastasia Martynova ◽  
George Yaghmour ◽  
Chris Foss
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Optimal Dose ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Improved Outcomes ◽  
The Mean ◽  
Related Mortality

Background: Haploidentical hematopoietic cell transplantation (haplo-HCT) has emerged as a popular alternative to traditional HLA-matched hematopoietic cell transplant. As the number of haplo-HCT's rises, investigating the factors that may affect outcomes is necessary in order to improve overall survival and reduce transplant-related mortality. The optimal dose of CD34+ cells used during haplo-HCT to ensure favorable outcomes using PTCy has not yet been reported though a range of 2 to 5.00x106 cells/kg is commonly used.Furthermore, the optimal dose of CD3+ cells is unknown however recent data has suggested less than 3.00x108 cells/kg may prevent the development of acute GVHD. The importance of studying the impact of CD34+/CD3+ cell dosing may help to improve outcomes in this setting. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 21) who received haplo-HCT from 2014 to 2019. The primary end-point assessed was 1-year GVHD-free/relapse-free survival (GRFS) defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. Secondary end-points included 1-, 2-, and 3-year relapse-related mortality (RRM) and overall survival (OS) in addition to 1-year transplant related mortality (TRM) and incidence of both acute and chronic GVHD. Results: A total of 67 adult haplo-HCT recipients were reviewed. Of the patients evaluated, approximately 50% (n = 33) were male and 49% (n = 32) were female. The age range was 21-71 years old (median = 44), and the most common underlying hematologic disorders included AML (40%), ALL (38%), aplastic anemia (7.7%), and others (MDS, lymphoma, myelofibrosis, and HLH) (13.8%). 67% of patients received myeloablative conditioning regimens while 33% received reduced intensity regimens. 70% (n = 47) of patients received peripheral blood as a stem cell source with 30% (n = 20) receiving bone marrow. The mean CD34+ dose infused was 6.07x106 cells/kg and the mean CD3+ dose was 2.94x108 cells/kg. The mean time to recovery of platelets, neutrophils, and lymphocytes was 25, 18, and 37 days respectively. CD34+ stem cells ≥5.00x106 cells/kg was significantly associated with shorter time to lymphocyte recovery (p = 0.0265) though recovery less than 30 days was not significantly associated with OS (p = 0.5268). Incidence of 1-year GRFS was 71% (n= 46) and 1-, 2-, and 3-year RRM were 4.6%, 6%, and 7.7% respectively. 1-year TRM was 15.3% with 50% of deaths from acute GVHD. 1-, 2-, and 3-year OS were 80%, 78%, and 77% respectively. Factors significantly associated with increased mortality included use of RIC regimen (p = 0.004) and disease status at time of transplant (p = 0.04). Cumulative incidence of GVHD was 63% (n = 42) with 33% (n = 22) and 30% of patients (n = 20) with acute and chronic GVHD respectively. Lack of mild chronic GVHD was associated with increased mortality (p = 0.0029) and use of a myeloablative regimen (p = 0.0029) was significantly associated with GVHD. Subgroup analysis of those who received CD34+ dose ≥7.00x106 cells/kg (n = 24) and ≥10x106 cells/kg (n = 7) were found to have 1-year OS of 87.5% and 85.7% compared with 77% and 80% in those that received lower doses (p= 0.2229 and p = 1.00) respectively however this was not found to be significantly associated with increased incidence of GVHD, relapse, or mortality. Discussion: Our results demonstrate improved outcomes specifically 71% survived 1 year without experiencing at least 1 GRFS event compared with 24-35% reported by CIBMTR, Holtan et al 2015, and Solh et al 2016 with 3-year OS of 77% when compared with a previously reported 48%. The mean CD34+ cell dose of our population is higher than the standard range which may account for the improved outcomes however the dosing of CD34+/CD3+ cells were not significantly associated with our primary and secondary end-points. It was significantly associated, however, with shorter time to lymphocyte recovery, a factor that has been reported to be associated with decreased RRM and therefore improved OS. Furthermore, subgroup analysis of higher CD34+ dose did show a better 1-year OS though this was not statistically significant. Limitations of this study include small sample size and short follow-up period. Further research with a prospective study identifying the optimal CD34+/CD3+ cell dose in addition to comprehensive evaluation of immune recovery is warranted in order to improve haplo-HCT outcomes. Figure Disclosures Yaghmour: Jazz Pharmaceutical company: Consultancy, Speakers Bureau; Astella company: Speakers Bureau; Takeda: Speakers Bureau.

scholarly journals Split Mixed Donor Chimerism Early after T-Cell Depleted Reduced Intensity Conditioned Allogeneic Haematopoietic Stem Cell Transplantation Predicts Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 423-423 ◽  
Author(s):  
Francesca A M Kinsella ◽  
Amy Gudger ◽  
Charlotte F Inman ◽  
Graham Mc Ilroy ◽  
Sandeep Nagra ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
High Risk ◽  
Chronic Gvhd ◽  
Haematopoietic Stem Cell ◽  
Prognostic Impact ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Donor Chimerism ◽  
Risk Of Relapse

Abstract The significance of mixed donor chimerism as a hallmark of an unsuccessful graft versus leukaemia effect and disease relapse is unclear. Whilst some studies have described changes in PBMC and T cell chimerism that may predict relapse, patients at high risk are not identifiable at a stage to permit early intervention. In this retrospective study, the prognostic impact of early “split” PBMC and T cell chimerism in 212 patients who underwent T cell depleted RIC-SCT at 2 UK centers is described. 118 and 94 patients were transplanted using PBMC grafts from matched unrelated or sibling donors respectively. 169 received fludarabine and melphalan, 24 other fludarabine containing regimes, 17 BEAM, and 2 TLI. 203 underwent TCD with alemtuzumab, whilst 9 received ATG. Overall survival by day 3773 days post-SCT was 67.1%, and relapse-free survival was 58.9%. 28.7% experienced acute GvHD (grade 2 or above), and 22.8% developed chronic GvHD. Patients were grouped according to percentage donor PBMC and T cell chimerism at a median of 49 days post SCT (25% and 75% percentiles, 31 and 61 days respectively). 68 Patients exhibited “split” chimerism (SC) in whom PBMC chimerism was >99%, but T-cell chimerism <98%. SC patients demonstrated comparable overall survival to the 81 patients with full donor chimerism (FC) in whom both haematopoietic compartments displayed donor chimerism >99% (HR 1.36, 95% CI 0.697 - 2.638, log-rank p= 0.3698). In contrast, 63 patients with chimerism of <98% in both compartments (MC) exhibited significantly worse overall survival, than the SC cohort (HR 2.10, 95% CI 1.13 - 3.92, log-rank p=0.019). Of that MC cohort, those entering HSCT with intermediate or high risk disease had 3 times the relative risk of relapse compared to MC patients with low risk disease. Multivariate analysis confirmed the predictive value of early SC versus MC status. Despite differences in overall survival SC and MC patients displayed comparable relapse free survival. It was therefore hypothesised that SC patients experienced improved OS compared to MC patients by responding to donor lymphocyte infusion (DLI). In this cohort, 11 original FC, 28 SC, and 33 MC patients underwent DLI at medians of 808, 325 and 227 days post SCT respectively. There were no differences between the groups in the proportion of patients receiving DLI for molecular relapse versus the presence of residual host haematopoiesis. SC patients displayed significantly improved OS after DLI than MC patients (HR 0.37 95% CI 0.15 - 0.91, log-rank p= 0.03), where all deaths were due to disease. To conclude, this is the first study to show that early “split” chimerism post SCT predicts overall survival after HSCT in a T deplete setting, and identifies patients with mixed PBMC and T cell donor chimerism at day 50 to be at significantly greater risk of relapse. This data supports a rationale to intervene early in MC patients post SCT, particularly those with an intermediate or high pre-SCT disease risk. Work to elucidate targetable mechanisms is underway. Disclosures No relevant conflicts of interest to declare.

Chimerism Analysis Is Predictive of Relapse-Free Survival After Allogeneic Transplantation for MDS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1332-1332
Author(s):  
Sanjay R. Mohan ◽  
Lisa Rybicki ◽  
Matt Kalaycio ◽  
Ronald Sobecks ◽  
Brian J. Bolwell ◽  
...  
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Multivariable Analysis ◽  
Lower Probability ◽  
Unrelated Donor ◽  
Univariable Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Chimerism Analysis

Abstract Abstract 1332 Chimerism analysis permits evaluation of the extent of donor engraftment following allogeneic hematopoietic cell transplantation (HCT) via differentiation between donor- and recipient-derived cells. Though relapse remains a major cause of treatment failure post-HCT for hematologic malignancies, the clinical utility of chimerism analysis for the early detection of morphologic relapse varies between different diseases and remains controversial. The predictive value of chimerism analysis for relapse rates and mortality in myelodysplastic syndromes (MDS) is not well-described. We reviewed serial chimerism results for 72 consecutive patients (pts) who underwent allogeneic HCT for MDS between 1999 and 2009; 9 pts were excluded from analysis due to lack of appropriately timed chimerism studies. Donor engraftment was initially assessed 28 days post-HCT and then at 2-week intervals through day 100. Chimerism studies were performed with peripheral blood using a short tandem repeat assay by PCR-based analysis. Acute and chronic GVHD rate, relapse-free survival (RFS), and overall survival (OS) were assessed for patients with donor leukocyte chimerism and T-cell chimerism ≥95% and <95%. The median age was 51 years (range 20–70) and 52% were male. The median time from MDS diagnosis to HCT was 5.4 months; 9 pts (14%) were in complete remission at the time of HCT, 11 (18%) were in partial remission, 17 (27%) had relapsed or refractory disease, and 26 (41%) were untreated. HCT-comorbidity index was low in 25 pts (40%), intermediate in 18 (29%), and high in 20 (32%). 31 pts (49%) received sibling donor HCT and the remainder received an unrelated donor graft. 40 (63%) received bone marrow and 23 (37%) received peripheral stem cells. Myeloablative (MA) busulfan- or cyclophosphamide-based preparative regimens were used in 47 pts (75%) and a non-myeloablative (NMA) regimen with fludarabine and TBI was given to the remaining pts. 61 pts achieved ≥95% donor leukocyte chimerism at a median of 29 days and 39 evaluable pts achieved ≥95% donor T-cell chimerism at a median of 42 days. Two pts did not achieve donor leukocyte chimerism ≥95% and 9 did not achieve donor T-cell chimerism ≥95% at any timepoint. Univariable analysis of prognostic factors for relapse showed that donor leukocyte chimerism ≥95% was significantly associated with lower probability of relapse (hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.02–0.51, p=.005), whereas prior exposure to radiation therapy (excluding exposure during HCT preparative regimen) was associated with increased probability of relapse (HR 3.48, 95% CI 1.14–10.60, p=.028). Multivariable analysis implicated donor leukocyte chimerism <95% as the only independent risk factor for relapse. Transplant type (MA vs NMA) and cell source did not significantly impact the likelihood of relapse. Donor leukocyte chimerism ≥95% was not associated with acute or chronic GVHD. Univariable analysis of risk factors for survival showed that donor leukocyte chimerism ≥95% was associated with improved RFS (HR 0.29, 95% CI 0.09–0.97, p=.045) but not OS, both findings of which were confirmed on multivariable analysis. Donor T-cell chimerism ≥95% was not significant in univariable analysis; however, in multivariable analysis, controlling for comorbidity scores, donor T-cell chimerism <95% was associated with lower risk of chronic GVHD (HR 0.18, 95% CI 0.04–0.88, p=.034) but did not significantly impact relapse, RFS, or OS. In conclusion, achievement of a high donor leukocyte chimerism post-HCT for MDS is associated with improved RFS. Donor T-cell chimerism, however, is not predictive of outcome and its routine use for MDS pts should be reevaluated. Pts with donor leukocyte chimerism <95% might be considered for immunologic interventions such as withdrawal of immunosuppression or donor lymphocyte infusion. Disclosures: No relevant conflicts of interest to declare.

Analysis of 120 Pediatric Patients with Non-Malignant Disorders Transplanted Using Unrelated Plasma Depleted Cord Blood and the Role of Post-Thaw Wash

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4406-4406
Author(s):  
Joseph Rosenthal ◽  
Tang-Her Jaing ◽  
Lee Lee Chan ◽  
Gretchen Eames ◽  
Michael L. Graham ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cord Blood ◽  
Cumulative Incidence ◽  
Pediatric Patients ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Free Survival ◽  
Disease Free ◽  
Related Mortality

Abstract Unrelated cord blood (UCB) is an important stem cell source for unrelated hematopoietic cell transplantation of patients with non-malignant disorders. Cell dosage is a critical factor for successful UCB hematopoietic stem cell transplantation (HSCT). The red cell reduced (RCR) and post-thaw wash techniques that are widely used incur significant nucleated cell loss. Three strategies were employed to maximize cell dose and improve outcome–use of cord blood processed with plasma depletion without red blood cell reduction (PD CB), avoidance of post-thaw wash, and the use of double cords (2X) when necessary. A CIBMTR-audited analysis was performed on all 120 pediatric patients with non-malignant disorders transplanted with PD CB at 29 U.S. and 17 international centers. Transplant characteristics: median age 3.5 years (range 0.1–14); median patient weight 15 kg (range 4–61); male 58%. The majority of patients (n=58; 55%) were Asian. Twenty-two (21%) patients were Hispanic, 15 (14%) were Caucasian, 6 (6%) were African-American, and three (3%) were of Middle Eastern background. HLA ABDR matches: 6/6–26; 5/6–48; 4/6–47; 3/6 or 2/6–6; median pre-freeze nucleated cell dose 10.5×107/kg; median pre-freeze CD34+ dose 3.7×105/kg; non-myeloablative regimen 24%; 58% infused without post-thaw wash (NW). Myeloid engraftment defined as ANC≥500 and 6-month platelet engraftment defined as ≥ 20K and ≥ 50K are 89±8%, 88±8%, and 84±6% respectively. The median time to myeloid and platelet engraftment are 21 days (range 11–64), 49 days (range 13–155), and 61.5 days (range 21–205) respectively. No major adverse event was observed in either the W or the NW group. The cumulative incidence of reported grade II–IV acute GVHD was 38±5%, and 19±4% had grade III–IV acute GVHD. 36±6% developed limited chronic GVHD, and 12±4% developed extensive chronic GVHD. With a median follow-up of 329 days (range 3–1928 days), the Kaplan-Meier estimates of 1-year TRM, OS and diseasefree survival were 20±6%, 88±6% and 72±6% respectively. Foregoing post-thaw wash for PD CB transplantation improved neutrophil (RR=1.75; p=0.01) and platelet engraftment (RR=1.72; p=0.02) and reduced TRM (RR=0.38; p=0.04). This series demonstrated that unrelated PD CB transplantation can be performed safely and effectively in children with life-threatening, non-malignant disorders. Additionally, the results demonstrate possible improvement in myeloid and platelet engraftment, overall and disease-free survival when post-thaw wash is not employed. Table 1. Summary of overall results Outcome All Patients N = 120 Washed CB N = 48 Unwashed CB N = 71 RR (Wash=Ref) P-value ANC500 Engraftment Cumulative Incidence Median # Days to Engraftment 87±6% d+21 86±9% d+25 89±8% d+19 1.75 0.01 Platelet 20K Engraftment Cumulative Incidence Median # Days to Engraftment 81±6% d+49 75±9% d+52 88±9% d+43 1.72 0.02 Autologous Recovery 3±2% 2±2% 4±3% 1.06 0.95 Acute GvHD II–IV Acute GvHD III–IV 38±5% 19±4% 31±7% 17±6% 45±7% 21±6% 1.74 1.38 0.11 0.50 Chronic GvHD Limited Chronic GvHD Extensive 36±6% 12±4% 14±6% 19±6% 60±10% 6±4% 5.69 0.24 &lt;0.001 0.08 Transplant-Related Mortality–100 Day Transplant-Related Mortality–3 Yr 10±3% 20±4% 11±5% 34±8% 9±4% 11±4% 0.38 0.04 Overall Survival–1 Yr Overall Survival–3 Yr 79±4% 79±4% 66±8% 66±8% 88±4% 88±4% 0.43 0.06 Disease-Free Survival–1 Yr Disease-Free Survival–3 Yr 72±5% 70±6% 58±9% 51±10% 84±5% 84±5% 0.48 0.07

Risks and Benefits of Unrelated Donor Peripheral Blood Progenitor Cells (PBPC) in Children and Adolescents with Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 977-977
Author(s):  
Mary Eapen ◽  
Olle Ringden ◽  
Franco Locatelli ◽  
Haydar Frangoul ◽  
Mats Remberger ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Unrelated Donor ◽  
Platelet Recovery ◽  
Free Survival ◽  
Grade 3

Abstract Although PBPC is an acceptable alternative to bone marrow (BM) for transplanting children with leukemia, there are no published studies describing outcomes after unrelated donor PBPC transplants. We compared the results of 385 unrelated donor BM transplants that were allele-matched (n=186) or mismatched (n=199) at HLA A, B, C, DRB1 and 110 PBPC transplants that were matched (n=60) or mismatched (n=50) at HLA A, B, C, DRB1 in patients younger than 18 years of age. All patients had acute leukemia and were transplanted in 2000–2006. Median follow up of surviving patients was 2 years in both treatment groups. There were no significant differences in patient and disease characteristics, transplant conditioning regimen, graft-versus-host disease (GVHD) prophylaxis and donor-recipient HLA disparity by graft type. Though the early probability of neutrophil recovery (³500/ul) was faster after transplantation of PBPC (31% vs. 10% at day-14, p<0.001) the probability of recovery by day-28 was similar after PBPC and BM transplants (94% and 91%, p=0.391). In contrast, platelet recovery (³20,000/ul) was better after PBPC transplants (86% vs. 76% at day-60, p=0.022). Risks of grade 2–4 (hazard ratio [HR] 1.24, p=0.147) and grade 3–4 (HR 1.07, p=0.785) acute GVHD were similar after PBPC and BM transplants. The risk of developing chronic GVHD was significantly greater after PBPC transplants compared to BM transplants (HR 2.36, p<0.001). After adjusting for disease status, donor-recipient HLA disparity and age, the of transplant-related mortality (TRM) relapse, treatment failure (relapse or death from any cause; inverse of leukemia-free survival and overall survival were similar after PBPC and BM transplants. The Table below shows the day-100 probability of grade 2–4 acute GVHD and the 3-year probabilities of chronic GVHD, TRM, relapse, leukemiafree survival and overall survival by graft type. These results differ from transplantation of PBPC from HLA-matched siblings where higher chronic GVHD translated into higher TRM and lower LFS. It remains to be seen whether the observed higher chronic GVHD after PBPC transplants will eventually result in the long term in higher mortality or fewer leukemia recurrence. PBPC BM Grade 2–4 acute GVHD 53% 49% Chronic GVHD 58% 33% TRM 20% 24% Relapse 34% 28% Leukemia-free survival 46% 48% Overall survival 49% 49%

Evaluation of Graft Versus Host Disease and Relapse Free Survival As Novel Endpoint in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Joint Naples-Paris Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2285-2285
Author(s):  
Simona Pagliuca ◽  
Antonio M Risitano ◽  
Sylvie Chevret ◽  
Flore Sicre de Fontbrune ◽  
Alienor Xhaard ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host

Abstract The cure of hematologic disorders by allogeneic hematopoietic stem cell transplantation (HSCT) is often associated with major complications resulting in poor outcome, including acute and chronic graft-versus-host disease (GVHD), relapse and death. Classical endpoints such as overall survival (OS), desease free survival (DFS) and non relapse-mortality (NRM) had become more and more unsuitable for transplant research because of their inability to a dynamic mesure of transplant-associated comorbidity. For this reason several composite endpoints taking into account also GVHD-associated comorbidity were proposed in the last years. GVHD free/relapse free survival (GRFS), proposed by Holtan et al (Blood 2015), includes grades 3-4 acute GVHD, systemic therapy requiring chronic GVHD, primary disease relapse , or death for any cause considered as events. This endpoint seems to completely characterize the survival without mortality or ongoing morbidity. With the intent to analyse the outcomes of our transplanted cohort, we retrospectively analysed GRFS of 959 consecutive patients receiving HSCT at Federico II University in Naples (n=119) and Saint-Louis Hospital (n=840) in Paris between 2007 and 2014, identifying prognostic factors associated with a better outcome and estimating the incidences of all components of this endpoint: rates of acute and chronic GVHD, disease relapse and death. Patient, disease and transplant characteristics are listed in table 1. Median duration of follow-up after HSCT was 22.1 months (IQR: 5.6-51 months). Cumulative incidence at day 100 of grade II-IV acute GVHD and grade III-IV were 42% and 16%, respectively. Cumulative incidence of chronic GVHD requiring systemic treatment at 1 and 5 years was 23% and 33%, respectively, diagnosed according to NIH criteria [14% of patients had score 1 (mild), 58% score 2 (moderate) and 27% score 3 (severe)cGVHD]. Cumulative incidence of relapse (considering all malignant and non-malignant diseases) was 26.7% (N=219) at 5 years. Overall survival for the whole population was 57% (95%CI, 53.3-60.8) at 5 years and Disease free survival (DFS) and non-relapse mortality (NRM) were respectively 50% (95%CI, 46.6-53.8) and 23% at 5 years. GRFS was 25% (95%CI, 21.8-28.5) at 5 years. Factors identified as influencing GRFS based on univariate analyses were age higher than 45 years (HR=1.64, 95%CI, 1.40-1.92), bone marrow (BM) as stem cell source (HR=0.40, 95%CI, 0.32-0.50); reduced intensity conditioning (RIC) (HR=0.63, 95%CI, 0.53-0.74); disease type [non-malignant disorders: HR=0.24, 95%CI, 0.17-0.33; myelodysplastic and myeloproliferative syndromes (MPN/CML/MDS): HR=1.34, 95%CI, 1.10-1.63; whereas other diagnosis did not influence GRFS] and than unrelated donor (matched: HR=1.71, 95%CI, 1.41-2.07;mismatch:HR=1.81, 95%CI, 1.48-2.23). Based on a multivariable Cox model, only diagnoses (non-malignancies, HR=0.27, 95%CI, 0.19-0.38 and MPN/CML/MDS, HR= 1.35, 95%CI, 1.11-1.65), and HLA unrelated graft (matched, HR=1.42, 95%CI, 1.17-1.73 and mismatched, HR=1.55, 95%CI, 1.26-1.92) remained associated with the outcome (Figure 1 and 2). GRFS could represent the ideal endpoint following HSCT. It differs significantly based upon type of disease and donor type, essentially. This composite indicator yields more information regarding complications of HSCT than the simpler measurement of OS or DFS. Its use willbetter compare these clinically important outcomes that accompany disparate HSCT techniques. All examined prognostic factors could enhance our ability to optimally judge the risk and the probability of true recovery after allogeneic HSCT. Our data support the use of this composite endpoint to describe HSCT outcome, and also pave the way for the investigation of novel endpoints, which may also track the dynamic changes of post-transplant events in the long-term. These retrospective data represent the background to investigate the impact of novel strategies of HSCT aiming to improve the outcome of HSCT, as detectable, by using more sensitive endpoints, tracking clinical events associated with detrimental long-term outcome. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Novartis: Research Funding; Alnylam: Research Funding; Rapharma: Research Funding. Peffault de Latour:Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation

2016 ◽  
Vol 34 (19) ◽  
pp. 2212-2220 ◽  
Author(s):  
Jan Styczynski ◽  
Gloria Tridello ◽  
Lidia Gil ◽  
Per Ljungman ◽  
Jennifer Hoek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Epstein Barr Virus ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Graft Versus Host ◽  
Barr Virus ◽  
Epstein Barr

Purpose We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Patients and Methods The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Results Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P < .001; HR, 1.42; 95% CI, 1.30 to 1.56). When adjusting for confounders, higher risk was identified for both acute and chronic GVHD. In seronegative patients with seropositive donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P < .001) for chronic GVHD. Seropositive patients with seronegative donors did not have an increased risk of GVHD. Conclusion Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT.

Adjuvant Immunotherapy of Resected, Intermediate-Thickness, Node-Negative Melanoma With an Allogeneic Tumor Vaccine: Impact of HLA Class I Antigen Expression on Outcome

2002 ◽  
Vol 20 (8) ◽  
pp. 2067-2075 ◽  
Author(s):  
Jeffrey A. Sosman ◽  
Joseph M. Unger ◽  
P.-Y. Liu ◽  
Lawrence E. Flaherty ◽  
Min S. Park ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Stage Iv ◽  
Hla Class I ◽  
Antigen Expression ◽  
Hla Typing ◽  
Class I ◽  
Relapse Free Survival ◽  
Primary Tumor Site ◽  
Free Survival ◽  
Node Negative

PURPOSE: An association between expression of ≥ two of five HLA class I antigens (HLA-A2, HLA-A28, HLA-B44, HLA-B45, and HLA-C3; collectively called M5) and response to an allogeneic melanoma vaccine (Melacine; Corixa Corporation, Seattle, WA) has been described in stage IV melanoma. This study investigated whether class I antigen expression impacted relapse-free survival (RFS) after adjuvant therapy with this vaccine. PATIENTS AND METHODS: We performed class I (HLA-A, HLA-B, and HLA-C) serotyping on patients enrolled onto Southwest Oncology Group Trial 9035, a randomized, observation-controlled, phase III trial of adjuvant Melacine. All patients had clinically node-negative cutaneous melanoma (1.5 to 4.0 mm). Interactions between treatment and class I antigen expression were tested. Analyses involved all serotyped patients and were adjusted for tumor thickness, method of nodal staging, sex, ulceration, and primary tumor site. RESULTS: HLA typing was performed on 553 (80%) of the 689 enrolled patients (294 vaccinated and 259 observed). Expression of ≥ two M5 antigens was associated with a superior vaccine treatment effect. Among patients who matched ≥ two of the M5, the 97 vaccine-treated patients had improved RFS compared with the 78 observation patients (5-year relapse-free survival, 83% v 59%; P = .0002). The major components of this effect were contributed by HLA-A2 and HLA-C3. Among those who were HLA-A2–positive and/or HLA-C3–positive, the 5-year RFS for vaccinated patients was 77%, compared with 64% for observation (P = .004). There was no impact of HLA-A2 and/or HLA-C3 expression among observation patients. CONCLUSION: This prospective analysis indicates a highly significant benefit of adjuvant therapy with Melacine among patients expressing ≥ two of the M5 class I antigens, validating a prior observation in stage IV disease. HLA-A2 and HLA-C3 contributed most to this effect. Processed melanoma peptides found in Melacine may be presented by HLA-A2 and HLA-C3 and play a role in preventing relapse in vaccinated patients.

scholarly journals Impact of KIR/HLA Incompatibilities after Posttransplant Cyclophosphamide Based T Cell-Replete Haploidentical Hematopoietic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3340-3340
Author(s):  
Sarah Lindner ◽  
Tobias Berg ◽  
Christian Seidel ◽  
Franziska Kalensee ◽  
Michael A. Rieger ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
The Impact

Introduction: Posttransplantation cyclophosphamide (PTCy) based T cell-replete haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) is a valid option for patients with indication for allogeneic HSCT without a human leucocyte antigen (HLA) matched donor. However, selection criteria to determine the optimal among several available haplo donors are still a matter of debate. Especially, the impact of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA) incompatibilities (inc) in the setting of PTCy T cell-replete haplo HSCT is unclear. PTCy has been reported to eliminate most mature donor NK cells infused with the graft, including single KIR+ NK cells, thereby blunting NK cell alloreactivity in this setting (Russo et al., Blood 2018). Willem et al. (J Immunol 2019) reported (i) a significant loss of KIR2DL2/3+ NK cells at day +30 in patients with inhibitory KIR/HLA incompatibility (inc.) suggesting that PTCy might target responsive KIR NK cells and (ii) a correlation of genetic KIR2DL/HLA inc. with less relapse, but more graft-versus-host-disease (GvHD). Similarly, NK alloreactivity defined as KIR receptor-ligand mismatch or group B KIR haplotype with the presence of KIR2DS2 has been correlated with improved survival (Salomon et al., BBMT 2018). Aims of our study were to evaluate the impact of (i) HLA/KIR inc, (ii) donor KIR genotype and (iii) HLA-DP mismatch status on survival and incidence of relapse, acute and chronic GvHD in our homogeneously treated, independent patient cohort. Patients and methods: We retrospectively analyzed the outcome of 51 consecutively transplanted patients (AML/MDS (n=28/5), ALL (n=9), HD (n=2), NHL (n=5), CML (n=1), PMF (n=1)) receiving a PTCy based T cell-replete haplo HSCT between 01/2011-12/2018. All patients received a myeloablative conditioning regimen (fludarabine/total body irradiation (FTBI) or thiotepa/busulfan/fludarabine (TBF)) with unmanipulated bone marrow (98%) as the preferred graft (median CD34+ cells: 3.02 x 106/kg (range, 1.50-6.90) and median CD3+ T cells: 3.54 x 107/kg (range 1.52-43.74)). GvHD prophylaxis with ciclosporin A started on day 0, mycophenolate-mofetil on day +1, PTCy was applied on day +3 and +5. Results: Patient, donor and transplant characteristics as detailed in table 1 were well balanced between the inh. KIR/HLA inc. group (n=29) vs. no inh. KIR/HLA inc. group (n=22) with the exception of the median donor age (41.7 (range, 23.4-73.7) vs. 33.6 years (range, 19.0-56.2), resp. All patients engrafted. At day +28 (range, 20-29; n=26) CD3+ cells were 88.5/nL (range, 3-665), CD3+CD4+ cells 22.5/nL (range, 0-277.0), CD3+CD8+ cells 117.0/nL (range, 7-478), CD19+ cells 1.0/nL (range, 0-12), CD56bright cells 74.4/nL (range11.1-93.4), CD56dim cells 25.5/nL (range, 6.4-88.9) measured by flow cytometry and without differences between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. Cytomegalovirus (CMV) reactivation occurred in 73.3% of patients at risk and median time of occurrence was 32 days (range, 12-97) without difference between groups. Median follow-up for surviving patients was 26.1 months (range, 2.8-92.8) and we found no significant differences in 2-year overall survival (OS; 65.3±10.3 vs. 89.6±7.0, p=0.311), 2-year relapse-free survival (RFS; 66.0±9.4 vs 77.8±10.2, p=0.235), GvHD- and relapse-free survival (GRFS; 48.4±9.8 vs 60.5±12.0, p=0.182) as well as cumulative incidence (CI) of relapse (23.3% vs 16.2%, p= 0.283), acute GvHD grade 2-4 (27.6% vs 31.8, p=0.563), moderate-severe chronic GvHD (22.2% vs. 9.9%, p=0.227) and NRM (16.3% vs 5.3%, p=0.283) between the inh. KIR/HLA inc. group vs. no inh. KIR/HLA inc. group. This was also the case for donor KIR genotype AA vs AB (n=46; 2-y OS: 74.9±13.0% vs. 73.0±9.9%, p=0.844; 2-y RFS: 60.0±14.8% vs 74.5±8.4%, p=0.645) and HLA-DP-identical/permissive mismatch (MM) vs non permissive MM (n=45; 2-y OS: 70.7±10.0% vs 72.7±13.4%, p=0.945; 2-y RFS: 73.2±8.2% vs 63.6.0±14.5%, p=0.798) Conclusion: Our outcome data support the hypothesis of PTCy eliminating mature donor NK cells infused with the graft and thereby reducing the impact of alloreactivity in this setting. However, our patient number is quite small and the findings need to be validated in larger cohorts and preferably prospective studies. Disclosures Lindner: Celegene, Sanofi, Neovii: Honoraria, Research Funding. Berg:Riemser Pharma GmbH: Consultancy, Honoraria; Incyte, Abbvie, Astellas, Alexion and Celgene: Other: travel support. Bug:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants. Schwaeble:Uniqure BV: Research Funding. Ullrich:CellGenix: Honoraria, Research Funding; Novartis: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document