Impact of HLA Class I Typing-Resolution and Mismatches on Survival and Graft-Versus-Host Disease in Patients after Hematopoietic Stem Cell Transplantations from Unrelated Donors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2060-2060
Author(s):  
Miroslaw Markiewicz ◽  
Jerzy Wojnar ◽  
Malgorzata Krawczyk-Kulis ◽  
Iwona Wylezol ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
High Resolution ◽  
Relapse Rate ◽  
Graft Failure ◽  
Statistical Significance ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Class I ◽  
Hematopoietic Stem ◽  
Unrelated Donors ◽  
Grade 3

Abstract We analyzed 150 consecutive patients (pts) transplanted from unrelated donors (URD) at single institution- Silesian Medical Academy in Katowice- with use of the same standard operating procedure from February 1997 until December 2004 for CML (74 pts), AML (28), ALL (27), SAA (9), MDS (7), MM (1), NHL (1), PNH (1), OMF (1), bi-phenotypic AL (1). 92 pts were transplanted from matched donors, including 59 with complete 10 alleles (HLA-A,B,C,DRB1,DQB1) high resolution (HR) DNA-typing; and 33 with first class match established on base of low-resolution (LR) (13), serological (7) or un-complete typing without HLA-C (13) and second class HR typing. 58 pts were transplanted from mismatched donors (first class typing was HR in 43, LR in 14 and serological in 1 pt): 22 with single allelic mismatch (2 HLA-A, 7-B, 6-C, 7-DQB1), 33 with single HLA-C antigen mismatch and 3 with double mismatches (2 B+C, 1 C+C). Survival advantage at 4 years, although without statistical significance (p=0.16), was observed in the group of pts transplanted from 10/10 alleles matched donors (36+/− 11%) over those with mismatched donors (24+/− 11%). Oppositely, pts transplanted from matched donors who were not completely typed in HR did not achieve better survival (23+/− 17%). Poorest survival (13+/− 12%, p=0.007) was observed in patients transplanted from mismatched homozygous donors (n=10). The risk of acute GVHD grade 3–4 was increased (p=0.007) in pts with mismatched donors (31+/− 6%) when compared to matched completely typed in HR (10+/− 4%). Also the rate of graft failure tended to be lower in pts with matched than mismatched donors (5.1% versus 10.2%, p=0.25). In contrast, relapse rate was lower in mismatched (23+/− 10%) than in HR matched pts (34+/− 12%, p=0.55) what may reflect better GVL effect in mismatched transplant recipients. Unexpectedly, the rate of chronic GVHD was similar in pts with 10/10 alleles matched and mismatched donors (40+/− 10% versus 42+/− 9%, p=0.75). These results indicate that complete high resolution HLA class I typing is necessary for adequate selection of unrelated donors. Class I HLA-B and -C mismatches influence both survival and serious a-GVHD incidence. 10/10 alleles matched mismatched p survival at 4 years 36+/− 11% 24+/− 11% 0.16 aGVHD grade 3–4 10+/− 4% 31+/− 6% 0.007 graft failure rate 5.1% 10.2% 0.25 relapse rate 34+/− 12% 23+/− 10% 0.55 cGVHD 40+/− 10% 42+/− 9% 0.75 10/10 alleles matched mismatched homozygous donors p survival at 4 years 36+/− 11% 13+/− 12% 0.007

Superior Outcomes with Matched Unrelated Donors Compared with One Human Leukocyte Antigen Mismatched Related Donors In Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 907-907
Author(s):  
Stefan O. Ciurea ◽  
Rima M. Saliba ◽  
Gabriela Rondon ◽  
Poliana A. Patah ◽  
Fleur Aung ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Resolution ◽  
Graft Failure ◽  
Human Leukocyte ◽  
Hla Typing ◽  
Class I ◽  
Hematopoietic Stem ◽  
Leukocyte Antigen ◽  
Unrelated Donors ◽  
Related Donor

Abstract Abstract 907 Most candidates for hematopoietic stem cell transplantation lack a human leukocyte antigen (HLA)-identical sibling donor; however, many patients may have a related donor with whom they are mismatched at one antigen/allele. It is not known whether such a match is preferable to a matched unrelated donor (MUD). We hypothesized that, in transplantation using related donors, adding a single HLA antigen/allele mismatch, identified through high resolution HLA typing at HLA-A, -B, -C, -DRB1 and -DQB1, would be associated with worse outcomes than transplantation using matched unrelated donors. Patients and Methods: To test this hypothesis, we analyzed outcomes (survival, relapse, non-relapse mortality) of 367 patients who received transplants from either a 10/10 MUD (n=318) or a one-antigen/allele mismatched related donor (MRD) by 7/8 HLA typing (n=49) treated during the same period of time (1995-2009) at our institution. All patients had intermediate/high-resolution HLA typing at all 5 loci either prospectively or retrospectively, if treated after or before year 2002. Of the 49 patients treated with mismatched related donors, 28 patients (57%) had one antigen/allele mismatched at HLA class I or II loci (or 9/10), 18 patients (37%) had 2 alleles mismatched (or 8/10), and 3 patients (6%) had 3 alleles mismatched (or 7/10). From the 28 patients with a one-allele mismatch, 24 had class I mismatches at either HLA-A or -B loci, and 4 had class II mismatches at either HLA-DR or -DQ loci. Characteristics between the MUD group and 9/10 MRD group were similar [median age 53 vs. 47 years (p=0.08); AML/MDS diagnosis 84% vs. 82% (p=0.5); active disease at transplant 59% vs. 57% (p=0.9); myeloablatie conditioning 63% vs. 75% (p=0.2); bone marrow stem cells 58% vs. 70% (p=0.2); pentostatin use 14% vs. 11% (p=0.4); median year of transplant 2006 vs. 2004, respectively] except more patients in the MUD group received ATG (96% vs. 68%, p=0.02). Results: Outcomes at 3-years were analyzed for the 28 consecutive patients who had received a transplant from a 9/10 MRD based on 5-loci (including -DQB1) HLA typing. Graft failure was more common in patients treated from 9/10 related donors than from MUD. The incidences of primary and secondary graft failure for the 9/10 MRD were 7% and 14%, respectively, whereas none of the MUD transplant recipients had either primary or secondary graft failure (p= 0.02). Cumulative incidence of progression was 40% vs. 25% (p=0.02, HR 1.9, CI 1.1–3.9), non-relapse mortality 40% vs. 26% (p=0.05, HR 1.9, CI 1.0–3.6) and grade II-IV a GVHD was 27% vs. 38% (p=0.4, HR 0.7, CI 0.3–2.5) for the two groups, respectively. Median survival was 6 months for the 9/10 MRD vs. 18 months for the MUD group. The overall survival and progression-free survival rates were 19% and 45% (p=0.007, HR 1.8, CI 1.2–2.9) and 19% vs. 42% (p=0.006, HR1.8, CI 1.2–2.9), respectively. Outcomes for 9/10 MRD transplant patients with class I mismatches (n=24) were significantly worse than outcomes in those with MUD transplants (n=318). The 2-year actuarial OS rate was 27% for the 9/10 MRD and 48% for the MUD transplant group (HR 1.9; 95% CI 1.1 – 3.1; p=0.01). Conclusion: These results indicate that transplant outcomes for patients treated from a one-antigen/allele mismatch related donor are significantly worse than from a MUD, primarily due to increased non-relapse mortality. Patients receiving transplants form a 9/10 related donors, at least with a class I mismatch, should be treated on investigational protocols. Disclosures: No relevant conflicts of interest to declare.

Impact of HLA High-Resolution Matching on Outcomes of Myeloablative Unrelated Donor Hematopoietic Stem Cell Transplantation in Chinese Population

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4361-4361
Author(s):  
He Huang ◽  
Yi Luo ◽  
Jimin Shi ◽  
Yamin Tan ◽  
Xiaoyan Han ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Resolution ◽  
Chinese Population ◽  
Hla Class I ◽  
Class Ii ◽  
Hla Class Ii ◽  
Class I ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Unrelated donor hematopoietic stem cell transplantation (URD-HSCT) is more frequently associated with severe graft-versus-host disease (GVHD) or graft rejection, and the success of URD-HSCT is influenced by the degree of HLA compatibility between the donor and patient. However, HLA mismatched unrelated donors should to be considerable for patients awaiting allogeneic HSCT who lack a suitable related donor or matched unrelated donor. The purpose of the study was to observed the impact of HLA-A, -B, -DRB1/B3 high-resolution matching on outcomes of URD-HSCT in Chinese population. Patients and methods: 182 patients with hematological malignancies received URD-HSCT (bone marrow, n=130; peripheral blood stem cell, n=52) in our center between Nov. 1998 and May. 2008, and donors were from Chinese Marrow Donor Program (Chinese Mainland) and Tzu Chi Stem Cells Center (Chinese Taiwan), and the median age of all patients was 26 years (range 8–52 years). The selection of unrelated donor relied on donor-recipient HLA-A, -B, -DRB1/B3 matching by high-resolution molecular typing by PCR-SSP or PCR-SSO, with 121 cases of HLA 6/6 alleles matched, 51 cases of 1/6 allele mismatched and 10 cases of 2/6 alleles mismatched. The distribution of single HLA class I or class II mismatching was as follows: 37 HLA class I mismatching with 21 HLA-A and 16 HLA-B, and 14 HLA class II mismatching with 12 HLA-DRB1 and 2 HLA-DRB3. All of the patients were received Bu/Cy or Bu/Cy modified myeloablative conditionging regimen. MMF combined with CsA and short course MTX were performed as aGVHD prophylaxis, while other 18 patients received additional anti-CD25 monoclonal antibody to prevent severe aGVHD. Results: After a median follow-up of 14.9 months, 170 patients achieved sustained engraftment with the engraft failure of 6.6%, early treatment-related mortality (TRM) of all patients was 14.4% at 100 days after transplant, and clinical relapse was observed in 8 patients (16.5%). aGVHD developed in 106 (58.2%) patients of all with grade I–II 82 (45.1%) and grade III–IV 24 (13.1%). By Kaplan-Meier method, the accumulative probability of 5-year overall survival (OS) and disease free survival (DFS) of all patients was 51.65±4.15% and 47.38±4.05%, respectively. The incidences of aGVHD was a little higher in HLA 1–2 alleles mismatched group (n=61) compared to HLA matched group (n=121) (67.2% vs 53.7%, p>0.05), and the incidences of grades I–II and III–IV aGVHD in HLA mismatched transplants were 45.9% and 21.3% respectively, while those in HLA matched transplants were 44.6% and 9.1% respectively. Comparing the outcomes between HLA 1–2 alleles mismatched and HLA matched transplants, the engraft failure were 9.8% and 5.0% (P>0.05), and early TRM were 18.0% and 12.4% (P>0.05), respectively. The Kaplan-Meier probability OS at 5 years were 44.31±6.86% and 55.66±5.11% in HLA mismatched and matched group (P>0.05) respectively. In HLA 2 alleles mismatched URD-HSCT, the incidence of engraft failure and aGVHD were 30.0% and 80.0%, and the outcomes were really inferior to HLA matched transplants. The impact of single HLA class I (n=37) or HLA class II mismatched (n=14) on the results of URD-HSCT had been also studied, and incidences of aGVHD in HLA class I or class II mismatched transplants was not significantly different compared with HLA matched transplants. In HLA class I and class II mismatched URD-HSCT, the engraft failure were 5.4% and 7.1% (p>0.05), and early TRM were 13.5% and 35.7% (p>0.05), respectively. The probability OS at 5 years in single HLA class II mismatched transplants was significantly lower compared with HLA matched transplants (23.81±12.94% vs 55.66±5.11%, p<0.01). Conclusion: URD-HSCT could be optimized by comprehensive and precise donor-recipient alleles matching, however, HLA mismatching was associated with the risk of URD-HSCT. Moreover, HLA 2 alleles mismatches of donor-recipient HLA-A, B, DRB high-resolution matching was correlated with an inferior clinical outcome. For patients with high-risk diseases without a suitable matched unrelated donor, alternative methods to URD-HSCT with a single HLA mismatch may permit early treatment before disease progression. In our study, it also demonstrated that HLA class I mismatching was correlated with a high incidence of aGVHD, and HLA class II mismatching was associated with an inferior overall survival in Chinese population, however, larger studies would have to dissect out the magnitude of the risk incurred with specific mismatches more clearly owing to small patient numbers in each group.

DynaChip Anti-HLA Antibody Analysis In Sera of Patients Following Allo-HSCT From HLA-Mismatched Unrelated Donors.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4575-4575
Author(s):  
Miroslaw Markiewicz ◽  
Urszula Siekiera ◽  
Tomasz Kruzel ◽  
Monika Dzierzak-Mietla ◽  
Patrycja Zielinska ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Hla Class I ◽  
Class I ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Study Results ◽  
Reactive Groups ◽  
Unrelated Donors ◽  
Class Ii Antigens

Abstract Abstract 4575 Introduction: Anti-HLA antibodies constitute potentially important factor that may influence outcomes of HLA-mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT). The rationale of this study was to detect presence of anti-HLA antibodies in recipients of allo-HSCT from HLA-mismatched unrelated donors. Patients and Methods: Anti-HLA-A,B,C,DR,DQ,DP antibodies were identified in sera collected from 46 recipients of allo-HSCT from HLA-mismatched unrelated donors. Sera were collected between 1 month and 5.5 years after allo-HSCT, and additionally before allo-HSCT in 17 pts. We have used microchips spotted with purified HLA class I and HLA class II antigens to allow binding of anti-HLA antibodies present in tested sera to the surface of the microchip, pre-optimised reagents and DynaChip Processor (Dynal Invitrogen Corporation) for assay processing, data acquisition and analysis. Results: Antibodies against HLA class I, II or I and II were detected in 15%, 11% and 35% of pts whereas no antibodies were detected in 39% of patients. Antibodies were directed against HLA-A, B, C, DR and DQ in 37%, 46%, 35%, 48% and 35% of pts, respectively. Pre-transplant anti-HLA antibodies have been detected in 7 pts (41%) out of 17 tested before allo-HSCT. In this group percent of Panel Reactive Antibodies (% PRA) increased following allo-HSCT in 3 pts and decreased in 4. In 5 out of 10 remaining pts without pre-transplant antibodies, %PRA increased post-transplant. DynaChip software allowed to define specificities of HLA-A,B,C,DR and DQ antibodies on low and high resolution levels. The specificity of antigens that masked results of antibody identification has been also defined in 2 pts. At this stage we did not define exactly whether detected anti-HLA antibodies were donor-specific. Cross-reactive groups (CREG's) analysis has been also used to compare antibodies’ reactivity. Anti-HLA-DP antibodies were not detected in the examined group of transplanted patients. Conclusions: Presented preliminary study results indicate, that anti-HLA antibodies can appear post-transplant in mismatched allo-HSCT recipients. Further analysis aiming to evaluate their influence on transplant outcomes is ongoing. We intend to extend the search for anti-HLA antibodies with use of Luminex LabScreen method. Disclosures: No relevant conflicts of interest to declare.

The Influence Of Anti-HLA Antibodies On Engraftment and Donor’s Chimerism Following Allogeneic Hematopoietic Stem Cell Transplantation From HLA-Mismatched Unrelated Donors

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4542-4542
Author(s):  
Miroslaw Markiewicz ◽  
Anna Koclega ◽  
Sylwia Mizia ◽  
Urszula Siekiera ◽  
Alicja Dobrowolska ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Graft Failure ◽  
Hla Antigens ◽  
Class I ◽  
Hla Antibodies ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Unrelated Donors

Introduction Although anti-HLA Antibodies (Abs) are considered an important factor of graft failure in solid organ transplants, their role in allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still undiscovered. Large polymorphism and immunogenicity of HLA-antigens and heterogeneity of anti-HLA Abs warrant the need of such investigation. The purpose of this study was to define the presence of anti-HLA Abs before allo-HSCT from HLA-mismatched unrelated donors and their impact on engraftment and post-transplant full donor’s chimerism. Material and Methods 70 HLA-mismatched donor/recipient pairs entered the study. Indication for allo-HSCT was: ALL, AML, CML, SAA, PNH, MDS and CLL. Preparative regimen was myeloablative in 68pts (97%) and reduced in 2pts (2.3%). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (69pts) or Alemtuzumab (1pt). HLA A,B,C,DR,DQ alleles were PCR-typed. Single HLA-antigen was mismatched in 46pts, single HLA-allele in 16pts, double antigens or alleles in 2 pts and another 2 pts had combined antigenic/allelic HLA mismatch. Anti-HLA A,B,C,DR,DQ,DP Abs were identified in sera collected prior to the conditioning treatment with use of automated DynaChip assay utilizing microchips bearing purified class I and class II HLA antigens. Post-transplant chimerism was analyzed using STR-PCR method at 30, 100-days and 1-year after allo-HSCT. Results Anti-HLA Abs pre-formed before allo-HSCT were detected in 32pts: against class I, II or both in 13(18.6%), 7(10%) and 12(17.1%) pts. Anti-HLA Abs were detected after allo-HSCT in 49pts: against class I, II or both in 22(32.4%), 7(10.3%) and 20(29.4%) pts, respectively. Anti-HLA Abs directed against the mismatched HLA antigens were observed in 4 pts before allo-HSCT. Although no Abs specific to mismatched HLA alleles were detected, Abs belonging to the same Cross-Reactive Groups (CREGs) were present in 5pts. No graft failure has been observed (graft failure was defined as absence of neutrophil recovery by day 30 after allo-HSCT or loss of donor’s chimerism). The detection of anti-HLA Abs before allo-HSCT was associated with decrease of post-transplant donor’s chimerism (18/31 vs 11/35, p=0.03). Anti-HLA Abs had no significant impact on engraftment of platelets and neutrophils. The median time to neutrophils engraftment was 16.9 days (range 7-31 days) in pts with and 18.9 days (range 13-30 days) in pts without anti-HLA Abs (p=0.188). The median time to platelets engraftment was 16.9 days (range 9-31 days) in patients with and 18.3 days (range 10-32 days) in pts without anti-HLA Abs (p=0.274). Conclusions Our preliminary results indicate, that anti-HLA Abs are present before transplantation in mismatched allo-HSCT recipients. They influence the post-transplant full donor’s chimerism, but they did not influence engraftment and graft failure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Leucovorin Following Methotrexate Graft-Vs-Host Disease Prophylaxis in Myeloablative Allogeneic Hematopoietic Transplantation Shortens the Duration of Mucositis and Hospitalization

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5696-5696
Author(s):  
Craig W. Freyer ◽  
Alex Ganetsky ◽  
Colleen Timlin ◽  
Daria V. Babushok ◽  
Noelle V. Frey ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Graft Failure ◽  
Statistical Significance ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Hematopoietic Transplantation ◽  
Duration Of Hospitalization ◽  
Grade 3 ◽  
Allogeneic Hematopoietic Transplantation

Abstract Introduction: Grade 2-4 mucositis is a major complication after myeloablative (MAC) allogeneic hematopoietic transplantation (HCT) in about 90% of patients. Graft-vs-host-disease (GVHD) prophylaxis with methotrexate (MTX) exacerbates mucositis and delays engraftment. Severe mucositis precludes administration of all 4 MTX doses which increases the risk of GVHD and can prolong hospitalization due to infection, pain control, and the use of total parenteral nutrition (TPN). Leucovorin (LCV) prophylaxis following MTX is advised by the EBMT-ELN adult working group, but not universally accepted given the absence of prospective trials. Our group implemented routine LCV prophylaxis following MAC alloHCT with MTX GVHD prophylaxis in 8/2017. We compared the outcomes of these patients with historical controls. Methods: We treated 22 consecutive adults receiving MAC alloHCT with MTX GVHD prophylaxis with LCV 15 mg PO q6h x 4 doses, starting 12 h after the d +3, +6, and +11 MTX doses. Twenty-nine consecutive patients undergoing similar MAC conditioning and MTX GVHD prophylaxis were retrospectively identified as the control. Routine LCV was not given to control patients, but could have been added following d +6 or +11 MTX to limit toxicity at physician discretion. The primary endpoint was the incidence of grade 2-4 mucositis. Secondary endpoints included the duration of grade 2-4 mucositis, time to engraftment, incidence of neutropenic fever (NF) and bacteremia pre-engraftment, duration of antibacterials for NF, ability to receive all MTX doses, incidence and duration of TPN and patient-controlled analgesia (PCA) use, duration of hospitalization, incidence of acute and chronic GVHD, graft failure, and relapse. Results: Baseline characteristics between the two groups were similar (table 1). All patients received tacrolimus and MTX GVHD prophylaxis with the majority receiving Cy/TBI conditioning. Approximately 30% of controls received ≥ 1 dose of LCV (most following d +11 MTX) to limit toxicity. Although the incidence of grade 2-4 mucositis was similar with between groups (82% vs 91%, p = 0.38), a lower incidence of grade 3-4 mucositis was observed with LCV, although this did not reach statistical significance (32% vs. 55%, p = 0.16). The LCV group had a significantly shorter duration of grade 2-4 mucositis (5.6 vs. 9.7 d, p = 0.01) and less frequent PCA use (32% vs. 62%, p = 0.048). The LCV group needed TPN less often (18% vs. 38%, p = 0.21) and when needed, had a shorter duration of TPN (10 vs. 21 d, p = 0.15), although these findings did not reach statistical significance. The LCV group had a significantly shorter duration of hospitalization (28 d vs. 33.7 d, p = 0.03). Platelet engraftment seemed to be more rapid (16.5 vs 22.2 d, p = 0.097) without reaching statistical significance. The addition of LCV did not appear to impact the incidence of acute GVHD (grade 2-4: 23% vs. 14%, p = 0.47; grade 3-4 14 % vs 3%, p = 0.3) by d +100 or chronic GVHD at 1 year (14% vs. 21%, p = 0.44). No differences were observed in the time to neutrophil engraftment, or in the incidence of nephrotoxicity, hepatotoxicity, graft failure, or relapse between the arms. No other obvious practice change was implemented during the study period that would have been anticipated to impact any of these endpoints. Conclusions: The addition of LCV to MAC alloHCT with MTX GVHD prophylaxis resulted in significant reductions in the duration of grade 2-4 mucositis, frequency of PCA use, and duration of hospitalization compared to a similar historical control. We also observed less frequent grade 3-4 mucositis, more rapid platelet engraftment and less TPN use with LCV, but these findings did not reach statistical significance. Our sample size was small, which may have limited our power to detect small differences between the groups. In addition, about 30% of controls received at least 1 dose of LCV which could have biased our results toward the null. There was no increase in acute or chronic GVHD, graft failure, or relapse risk with the addition of LCV; however follow up remains relatively short. LCV prophylaxis following MTX GVHD prophylaxis warrants prospective evaluation to more definitely assess effects on mucositis, engraftment, GVHD and relapse, as well as to clearly determine the impact on resource utilization such as use of TPN, PCA, and length of hospitalization. Disclosures Frey: Novartis: Consultancy; Servier Consultancy: Consultancy. Gill:Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership; Novartis: Research Funding. Perl:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Porter:Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board; Genentech: Other: Spouse employment.

Human-Leukocyte-Histocompatibility Antigens Predict Response to Rituximab and Donor Lymphocyte Infusion (DLI) After Non-Myeloablative Allogeneic Stem Transplantation (NST) for Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2548-2548
Author(s):  
Issa F. Khouri ◽  
Roland Bassett ◽  
Pedro Cano ◽  
Susan O'Brien ◽  
Yvonne Hsu ◽  
...  
Keyword(s):  
T Cell ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Median Number ◽  
Class I ◽  
Hematopoietic Stem ◽  
Hla Alleles ◽  
Cell Counts ◽  
Significant Difference

Abstract Abstract 2548 Background: The effectiveness of allogeneic NST in CLL has been attributed to a graft-versus-leukemia effect due to elimination of tumor cells by alloimmune effector lymphocytes. In a previous study (Khouri et al, Exp Hematol 2004), we found that when patients with CLL develop relapse after NST, immunomanipulation (IMM) via withdrawal of immunosuppression and DLI with rituximab can induce sustained remissions in some patients. The underlying mechanism of this GVL effect is unknown. The simultaneous presence of the killer-immunoglobulin-like receptor (KIR) 3DL1 and its corresponding human leucocyte antigen (HLA) class I ligands bearing the Bw4 epitope has been described in CLL (Verheyden S, Leukemia 2006). Purpose: Considering that the HLA class I molecules may act as restriction elements for GVL targets after NST in CLL, we investigated the potential association of certain common class I HLA alleles and response to IMM. Methods: We studied all 43 CLL pts who required IMM after NST in sequential phase II protocols at the U.T. MD Anderson Cancer Center from February 1996 to August 2007 because of persistent disease or because of progression. In our analysis, we examined the most common alleles and serotypes expressed in the patients studied. This included HLA-A1, A2, A3, A24, B7, B8, B35, B44, B60, B62, BW4, BW6, CW7. These allele groups are known to be common in most world populations. Rituximab was given at a dose of 375 mg/m2 intravenously followed by 3 weekly doses of 1000 mg/m2. A DLI of 1 × 107 CD3-positive T cells/kg was given after the first two doses of rituximab if no GVHD occurred. An escalated DLI dose was given at 6-week intervals if there was persistent active disease and no GVHD. Results: Median age (range) was 55 years (39-73) and the median Hematopoietic Stem Cell Comorbidity Index was 3 (range, 0–8). The median number of prior chemotherapies was 3. At their transplant, 48% of pts had refractory disease, 90% had Binet stage B/C, and 60% had a beta-2 microglobulin of =/> 3. P53 deletion was detected in 11 of 35 pts (31%) tested. Mixed T-cell chimerism was observed in 60 % of pts at day 90. The median number of DLI infused was 2 (range, 1–6); their median maximal dose was 43.6 (range, 1–200) × 106 CD3+/Kg. In these 43 pts, 20 (47%) experienced complete remission (CR), by CT scans, marrow and flow analysis. Pts characteristics at time of study entry (described above) for NST, and at the time of initiation of IMM (this included white blood cell counts, LDH, % lymphocyte in marrow, % CD5-CD19, lymph node size by computed tomography, maximum dose DLI, number of DLIs, GVHD prior IMM and grade, T-cell chimerism), as well as HLA subtypes were assessed. The major determinants to achieve CR following IMM included receipt of a PBSC graft and achievement of a good (> 90%) donor T-cell chimerism at day 90 (p = 0.035), and having a combination of HLA-A1-positive, HLA-A2-negative, and HLA-B44-negative (p= 0.0009). The rate of CR to IMM was 9%, 36%, 50%, 91% respectively in patients who had none of the HLA factors described, I, 2, and all 3 respectively. There was no statistically significant difference in pts and disease characteristics between HLA-A1-positive or negative, HLA-A2 positive or negative nor between HLA-B44-positive or negative pts. In addition the risks of acute II-IV [Cumulative incidence (CI)=23%) and chronic GVHD (CI=69%) were not different between the respective subtypes. With a median follow-up in surviving pts of 37.2 months (range, 11.4–131.1), the progression-free survival rates at 5-year for patients with HLA-A1+/A2-/B44- vs those who had none of those HLA types were 68% vs 15%, respectively, (p<0.0001). Conclusions: Our results represent the first report showing certain HLA alleles might be predictive for response to GVL and achieving long-term remission in CLL. Verification of our findings in a larger cohort of pts is highly warranted for better selecting pts for IMM for the treatment of recurrent malignancy in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy of HLA-Matched PLT Transfusions for Platelet Transfusion Refractoriness in HSCT Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1265-1265
Author(s):  
Keisuke Seike ◽  
Nobuharu Fujii ◽  
Keiko Fujii ◽  
Yasuhisa Sando ◽  
Makoto Nakamura ◽  
...  
Keyword(s):  
Thrombotic Microangiopathy ◽  
Platelet Transfusion ◽  
Hla Class I ◽  
Hla Typing ◽  
Class I ◽  
Red Cross ◽  
Similar Response ◽  
Hematopoietic Stem ◽  
Immune Mediated ◽  
Grade 3

Abstract Introduction: Cross-matched platelet (cross-matched PLT) transfusions are effective for immune-mediated platelet transfusion refractoriness (PTR). However, cross-matched PLT is more costly and takes more effort to cross match than a standard PLT unit. Recently, the utility of virtual HLA cross-matched PLT (HLA-matched PLT) has been reported. HLA-matched PLT is defined as HLA-A/B matched or cross-reactive groups excluded. Cross-matched　PLTs are　collected　from　donors　selected　based　on　patient's HLA　class　I　antibody and HLA typing of the donor. The products are supplied after confirmation of cross-matched negative. Hematopoietic stem cell transplantation (HSCT) patients frequently receive many transfusions before HSCT. Therefore, HLA antibody is often detected, which causes PTR. After HSCT, many complications, such as infection, bleeding, and thrombotic microangiopathy, may occur, which can cause PTR. Inadequate post-transfusion PLT increment occurs in more than 50% of PLT transfusions in patients undergoing HSCT. Here, we evaluated the effect of HLA-matched PLT for PTR in post-HSCT recipients. Methods: The records of all patients who underwent HSCT at Okayama University Hospital between 2010 and 2017 were reviewed to identify patients who received either cross-matched or HLA-matched PLT products after HSCT for hematologic malignancy. All patients had HLA Class I antibody and immune-mediated PLT transfusion refractoriness (PTR). An analysis of the initial episode of the PLT transfusion refractoriness was conducted for each patient. The following data were recorded for each patient: disease, age, sex, body surface area, HSCT donor source, HLA typing (Class I), HLA Class I antibody screen, WHO Grade 3 to 4 bleeding episodes, complications, death, and platelet-corrected count increment (CCI). Non-immune mediated causes were defined as an episode of fever (≥38 °C), bleeding (Grade 3 to 4), DIC, infection, thrombotic microangiopathy, sinusoidal obstructive syndrome, and splenomegaly. PLT products (cross-matched and HLA-matched units) were supplied by the Japanese Red Cross Society. The exact PLT content of each unit was obtained from the Japanese Red Cross Society. The 24-hour corrected count increments (CCI-24) were calculated to evaluate the effect of PLT transfusions. A CCI-24 more than 4500/μL was considered a successful transfusion. Results: Sixteen patients received a total of 241 PLT transfusions; 139 PLT transfusions were cross-matched, and 102 PLT transfusions were HLA-matched. The median CCI-24 for cross-matched PLT transfusions and HLA-matched transfusions was 2626/μL and 6137/μL, respectively, (p<0.001). The percentage of successful transfusions was 38.1% for cross-matched PLT and 57.8% for HLA-matched PLT, respectively, (p<0.001). Eighty-four PLT transfusions were used under situations without cause for non-immune mediated PTR. The percentage of successful transfusions (median CCI-24) was 62.8% (6684/μL) for cross-matched PLT and 65.1% (7108/μL) for HLA-matched PLT(p=0.825). Of the 241 transfusions, 157 (65.1%) transfusions were used under situations with cause for non-immune mediated PTR. When patients had non-immune mediated PTR, the percentage of successful transfusions was only 28.1% for cross-matched PLT and 51.1% for HLA-matched PLT (p=0.001). The median CCI-24 was 1856/μL for cross-matched PLT and 5824/μL for HLA-matched PLT (p<0.001). HLA-matched PLT resulted in a higher response, and episodes of bleeding and splenomegaly were lower by multiple linear regression analysis (Table 1). Conclusions: HLA-matched PLT was not inferior to cross-matched PLT for post-HSCT PTR. Both cross-matched PLT and HLA-matched PLT resulted in a similar response for immune-mediated PTR, but HLA-matched PLT was superior for non-immune mediated PTR. The difference of selection method between cross-matched PLT and HLA-matched PLT may influence the effectiveness of the transfusion. The reasons of superior CCI-24 result in HLA-matched PLT are currently under investigation. Disclosures No relevant conflicts of interest to declare.

Comparison of 200 cGy vs. 400 cGy Total Body Irradiation (TBI) When Used with Fludarabine for Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (RIC AHSCT).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2003-2003
Author(s):  
Ronald Sobecks ◽  
Robert Dean ◽  
Lisa Rybicki ◽  
Josephine Chan ◽  
Karl Theil ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Disease Relapse ◽  
Hematopoietic Stem ◽  
Diagnostic Categories ◽  
Unrelated Donors ◽  
Matched Sibling ◽  
Total Body

Abstract Fludarabine(FLU) and 200cGy TBI is commonly used for RIC AHSCT, but we observed 12% graft rejections and a 43% incidence of disease relapse when used at our institution. We hypothesized that this might be improved with dose escalation of TBI to 400cGy. From 12/03–4/07 40 pts with hematologic malignancies received RIC AHSCT using FLU 30 mg/m2/d on days -5, -4 and -3 and then TBI 200cGy on days -1 and 0. Our analysis compared outcomes with 42 historical control pts who received 200cGy TBI from 1/00–11/03. Matched sibling donors (MSD) were used for 32(76%) pts in the 200cGy group and 26 (65%) in the 400cGy group (p=0.27); other pts had 8/8 HLA matched unrelated donors (MUD). MSD pts received cyclosporine/mycophenolate and MUD pts received tacrolimus/mycophenolate. There were no differences in diagnostic categories between the 200cGy and 400cGy groups, which included 19(45%) and 22(56%) pts with myeloid (MY) diseases, respectively, (AML most common for both) while the remaining pts with lymphoid (LY) diseases had NHL most commonly. No other baseline characteristics differed between the groups. 200cGy pts received a higher median CD34+ cell dose (6.77 vs 4.93 × 106/kg, p&lt;0.001), more often required 2nd transplants (5 vs 0; p=0.033) and donor lymphocyte infusions (5 vs 1; p=0.08) post RIC AHSCT. There were no differences in incidence or severity of acute/chronic GVHD, time to platelet and neutrophil engraftment, CMV, other infections or non-infectious toxicities. Although fewer 400cGy pts had graft rejection (2 vs 5), this did not reach statistical significance. Achievement of T cell complete donor chimerism (CDC) was similar between the 200cGy and 400cGy pts (85% vs 87%; p=0.61) as was the median time to achieve CDC (57 vs 40 days, respectively; p=0.80). Median times to achieve CDC for LY vs. MY pts were: 41 vs. 77 days (200cGy; p=0.26); and 30 vs. 61 days (400 cGy pts; p=0.29), respectively. Relapse rates for 200cGy and 400cGy groups were 43% vs. 30%; MY pts 42% vs 27% and LY pts 44% vs 29%, respectively. 12(29%) of the 200cGy pts and 23(58%) of 400cGy pts are alive at median follow-ups of 52 vs 16 mos, respectively. There was a trend toward higher 100 day mortality in the 400cGy pts with 7(18%) deaths (3 disease relapse, 2 cardiac, 1 GVHD, 1 graft failure) vs 2(5%) in the 200cGy pts (2 GVHD) (p=0.06). At current follow-up there are no significant differences in overall(OS) and relapse-free survival(RFS) between the groups. However, in the 200cGy group LY pts’ OS was superior to MY pts (p=0.047, Figure) but this difference was no longer observed upon escalating to 400cGy. This may be due to more comparable RFS between MY and LY pts in the 400cGy pts (p=0.56) than in the 200cGy group (p=0.07). We conclude that 400cGy TBI with FLU for RIC AHSCT is well tolerated and further follow-up is needed to determine if outcomes are superior to those with 200cGy TBI. Future investigation of strategies to further intensify RIC may be appropriate, particularly for pts with MY disease. Figure Figure

Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 725-731 ◽  
Author(s):  
Jochen Casper ◽  
Wolfgang Knauf ◽  
Thomas Kiefer ◽  
Daniel Wolff ◽  
Beate Steiner ◽  
...  
Keyword(s):  
Survival Rate ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Conditioning Regimen ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Unrelated Donors ◽  
Conditioning Regimens ◽  
Grade 3

Abstract New conditioning regimens are being explored to reduce toxicity and enable allogeneic bone marrow transplantation in patients not eligible for conventional transplantation. We have investigated treosulfan, an alkylating agent, with the aim of developing an efficient and reliable but less-toxic conditioning regimen. A series of 30 patients who were not eligible for standard conditioning therapy received transplants from HLA-matched related (n = 14) or unrelated (n = 16) donors after administration of treosulfan 10 g/m2 intravenously daily for 3 days and fludarabine 30 mg/m2 intravenously daily for 5 days. Patients receiving grafts from unrelated donors also were given rabbit antithymocyte globulin 10 mg/kg intravenously daily for 3 days. All patients achieved prompt neutrophil and platelet recovery. Extramedullary toxicity was generally mild with Common Toxicity Criteria (CTC) grade 3 or 4 attributable to the conditioning seen only with transaminases. Complete donor chimerism was achieved by 90% of the patients. Acute graft-versus-host disease (GVHD) grade III or IV developed in 14% of the patients and chronic GVHD in 39%. An estimated overall survival rate of 73% and an event-free survival rate of 49% have been reached after a median of 22 months (range, 7.4-33.4 months). In summary, the combination of treosulfan and fludarabine is a safe and efficient conditioning regimen.

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