Incidence Of Extensive Chronic GVHD Research Articles

Unrelated cord blood transplantation vs. HLA-matched sibling transplantation for adults with B-cell acute lymphoblastic leukemia in complete remission: superior OS for patients with long-term survival

BackgroundAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important curative therapy for adult acute lymphoblastic leukemia (ALL). For patients who lack a human leukocyte antigen (HLA)-matched sibling donor, unrelated cord blood (UCB) is an alternative graft option. Previous studies have focused mainly on all T- and B-cell ALL (B-ALL) patients, while data related specifically to adult B-ALL patients after UCB transplantation (UCBT) are scarce.MethodsWe retrospectively compared the outcomes of UCBT and HLA-matched sibling transplantation (MST) in the treatment of adult B-ALL patients in complete remission (CR) at our center. From June 2006 to December 2020, 156 adult B-ALL patients who achieved CR before transplantation were enrolled. The main clinical outcomes of UCBT and MST were analyzed.ResultsHematopoietic recovery was significantly faster in MST recipients than in UCBT recipients. Higher incidences of grades II-IV and III-IV acute graft-versus host disease (aGVHD) were found in UCBT recipients (P < 0.001 and = 0.03), while a lower incidence of extensive chronic GVHD (cGVHD) was found in UCBT recipients (P < 0.001). The cumulative incidences of 2-year non-relapse mortality (NRM), 2-year relapse, 5-year disease-free survival (DFS) and 5-year GVHD-free relapse-free survival (GRFS) were comparable between MST and UCBT recipients. The overall survival (OS) during the first 700 days was similar between the MST and UCBT groups, while the OS of patients with a survival time of more than 700 days in the UCBT group was better than that in the MST group according to multivariate analysis (P = 0.03).ConclusionsOur study shows that when treating adult B-ALL patients in CR, UCBT can achieve comparable effects as MST, may provide superior OS for patients with long-term survival, and should be considered a good alternative.

Posttransplant cyclophosphamide for prevention of graft-versus-host disease: results of the prospective randomized HOVON-96 trial

AbstractGraft-versus-host disease (GVHD) is the most important complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). We performed a prospective randomized, multicenter, phase 3 trial to study whether posttransplant cyclophosphamide (PT-Cy) combined with a short course of cyclosporine A (CsA) would result in a reduction of severe GVHD and improvement of GVHD-free, relapse-free survival (GRFS) as compared with the combination of CsA and mycophenolic acid (MPA) after nonmyeloablative (NMA) matched related and unrelated peripheral blood alloHSCT. Between October 2013 and June 2018, 160 patients diagnosed with a high-risk hematological malignancy and having a matched related or at least 8 out of 8 HLA-matched unrelated donor were randomized and allocated in a 1:2 ratio to CsA/MPA or PT-Cy/CsA; a total of 151 patients were transplanted (52 vs 99 patients, respectively). The cumulative incidence of grade 2 to 4 acute GVHD at 6 months was 48% in recipients of CsA/MPA vs 30% following PT-Cy/CsA (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.82; P = .007). The 2-year cumulative incidence of extensive chronic GVHD was 48% vs 16% (HR, 0.36; 95% CI, 0.21-0.64; P < .001). The 1-year estimate of GRFS was 21% (11% to 32%) vs 45% (35% to 55%), P < .001. With a median follow-up of 56.4 months, relapse incidence, progression-free survival, and overall survival were not significantly different between the 2 treatment arms. PT-Cy combined with a short course of CsA after NMA matched alloHSCT significantly improves GRFS due to a significant reduction in severe acute and chronic GVHD.

Outcomes after Second Allogeneic Transplantation and Donor Lymphocyte Infusion for Relapse after a First Allogeneic Transplant

Outcomes after Second Allogeneic Transplantation and Donor Lymphocyte Infusion for Relapse after a First Allogeneic Transplant

253 - High Incidence of Extensive Chronic Gvhd in Patients with the REG3A Rs7588571 Non-GG Genotype

253 - High Incidence of Extensive Chronic Gvhd in Patients with the REG3A Rs7588571 Non-GG Genotype

REG3A Polymorphism Is Associated with the Incidence of Extensive Chronic Gvhd after Allogeneic BMT

[Introduction] Regenerating islet-derived protein 3 alpha (REG3A), a protein produced by Paneth cells, has been reported as a biomarker of lower gastrointestinal graft-versus-host disease (GVHD). The single nucleotide polymorphism (SNP) rs7588571 is located at the upstream of REG3A gene within 2kb, suggesting that the expression of REG3A might be affected by the SNP. In this study, we analyzed the association between the rs7588571 genotype in recipients and transplant outcomes.[Patients and methods] The study population included 118 adult Japanese patients who had undergone T cell replete allogeneic bone marrow transplantation from an HLA-identical sibling donor with GVHD prophylaxis consisting of short-term methotrexate and cyclosporine between 1987 and 2006. Sixty-eight (58%) male and 50 (42%) female patients, with a median age of 35 years (range 15-56), were included. Eighty-eight (75%) patients were classified as having standard risk disease defined as acute myeloid leukemia in first or second complete remission, acute lymphoblastic leukemia without Philadelphia chromosome in first complete remission, chronic myeloid leukemia in chronic phase, myelodysplastic syndrome without excess of blasts, aplastic anemia and paroxysmal nocturnal hemoglobinuria, while other patients were classified as having high risk disease. Conditioning regimen was myeloablative in 113 (96%) patients and reduced-intensity in other patients. Genomic DNA was extracted from patient’s peripheral blood or bone marrow by standard methods. Genotyping was performed using TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, California, USA) on ABI 7300 Real-Time PCR systems (Applied Biosystems). Multiple logistic regression model was used to identify risk factors associated with acute and chronic GVHD, and multivariate Cox model was created for overall survival (OS), non-relapse mortality (NRM), and relapse. Variables with a P-value < 0.1 in the univariate analysis were entered into the stepwise selection method. All tests were two-sided, and P <0.05 was considered significant. This study was approved by the ethics committees at the Nagoya University Hospital and the Japanese Red Cross Nagoya Daiichi Hospital.[Results] The frequencies of the GG, AG, and AA genotypes were 41%, 43%, and 16%, respectively, which were compatible with those reported in the HapMap-JPT database. There was no significant association between the distribution pattern of the rs7588571 genotypes and each patient characteristic. Grade II-IV acute GVHD developed in 12% of all patients, 14% in those with GG genotype, 14% with AG genotype and 11% with AA genotype, respectively. In univariate analysis, the higher patient age (≥35) was the only significant factor for higher incidence of grade II-IV acute GVHD (OR: 5.4, 95% CI: 1.3-32, P=0.011). Extensive chronic GVHD developed in 38% of all patients, 27% in those with GG genotype, 45% with AG genotype and 50% with AA genotype, respectively. The incidence of extensive chronic GVHD in non-GG genotype (46%) was significantly higher than that in GG genotype (27%) (P=0.05). In multivariate analysis, non-GG genotype (OR: 2.5, 95% CI: 1.0-5.8, P=0.04), female to male transplant (2.8, 1.2-7.0, 0.023), and high risk disease (2.8, 1.1-7.2, 0.038) were significant factors for higher incidence of extensive chronic GVHD. The relapse rates at 4-year were 26% in non-GG and 17% in GG genotype (HR: 1.16, 95% CI: 0.49-2.7, P=0.73). High risk disease was the only significant factor for higher relapse rate. The OS and NRM at 4-year were 57% and 20% in non-GG, and 65% and 17% in GG genotype, respectively. The rs7588571 genotypes affected neither OS nor NRM.[Discussion] REG3A polymorphism was associated with the incidence of extensive chronic GVHD. Given its capacity to control the tissue regeneration and intestinal microbiota, REG3A may not only reflect the intestinal damage caused by GVHD but also have a certain role in the pathogenesis of GVHD. Our findings need to be confirmed in larger cohort, and further investigation is required in order to clarify the biological effect of rs7588571 genotypes and the exact role of REG3A in the pathophysiology of GVHD. DisclosuresKiyoi:MSD K.K.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Eisai Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Alexion Pharmaceuticals: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Celgene Corporation: Consultancy; Chugai Pharmaceutical Co. LTD.: Research Funding.

Risk Factors and Impact of Neurological Complications after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction:A significant source of morbidity and mortality related to allogeneic hematopoietic cell transplantation (HCT) is neurologic complication. We performed a retrospective chart review to determine the incidence, risk factors, timing, and impact of neurologic complications in the first five years after HCT.Methods:We performed a retrospective chart review of patients undergoing allogeneic HCT for hematological disorders at the Massachusetts General Hospital between January 2000 and December 2010, focusing on neurologic complications after HCT. We determined the incidence of central nervous system (CNS) infections, intracranial hemorrhage, thromboembolic events, metabolic encephalopathy, posterior reversal encephalopathy syndrome (PRES), seizures, CNS malignancy, and peripheral neuropathy. We classified neurological events as either early (day -7 to day +100), late (day +101 to 2 years) or very late (2 years to 5 years). Risk factors studied were demographics (age, gender, race), disease-related factors (diagnosis, disease status, prior autologous transplant),transplant factors (myeloablative or reduced-intensity conditioning, use of antithymocyte globulin (ATG), stem cell source and GVHD prophylaxis). Outcome variables were neutrophil and platelet engraftment, progression free survival (PFS) and overall survival (OS).Results:There were 263 consecutive patients (median age 54 years, range 18 to 76 years). The diseases were acute myeloid leukemia n=91 (34.6%), non-Hodgkin lymphoma n=64 (24.3%), myelodysplastic syndrome n=41 (15.6%), acute lymphoblastic leukemia n=21 (8.0%), myeloproliferative neoplasm n=13 (4.9%), chronic lymphocytic leukemia n=12 (4.6%), Hodgkin lymphoma n=11 (4.2%), multiple myeloma n=10 (3.8%). Conditioning was myeloablative n=86 (33%), or reduced-intensity n= 177 patients (67%). Donor source was matched related donor n=153 (58.1%), matched unrelated donor n=52 (19.8%), haploidentical n=35 (13.3%), umbilical cord blood n=20 (7.6%), and mismatched unrelated donor n=3 (1.1%). The median days to ANC > 500x106/L, and platelet count > 20,000 x106/L unsupported were 15 (range 7 to 37 days) and 19 (range 7 to 167 days), respectively. The incidence of acute GVHD grades II-IV was 22% and the 1-year incidence of extensive chronic GVHD was 8.9%. The 5-year overall and progression free survivals were 37% and 29% respectively. The major cause of death was relapsed or progressive malignancy.15 patients (5.7%) experienced 19 clinically active neurologic events without having relapsed or progressed at the time, as follows: CNS infection n=0,CNS hemorrhage n=2, CNS thromboembolic event n=1, metabolic encephalopathy n=4, PRES n=3, seizure n=4, CNS malignancy n=4, and peripheral neuropathy n=5 (Table 1). 4 patients experienced CNS relapse as their first neurologic event post transplant. Patients who relapsed or progressed had a higher incidence of neurologic complications -55 of those patients (38.4% of patients who relapsed) experienced 79 neurologic events: CNS infection n=16,CNS hemorrhage n=14, CNS thromboembolic event n=14, metabolic encephalopathy n=14, PRES n=3, seizure n=9, CNS disease n=7, and peripheral neuropathy n=12(Table 2). After 100 days post transplant, neurologic complications were rare in patients who had not relapsed or progressed (2.2% of patients). In a multivariate analysis, risk factors for neurologic complication were relapsed/progressive disease, grade II-IV acute GVHD and use of sirolimus in GVHD prophylaxis. 4 of 17 patients who received sirolimus had a neurologic event (1 thromboembolic stroke, 1 seizure/PRES, 1 seizure/PRES/metabolic encephalopathy and 1 peripheral neuropathy). Neutrophil and platelet engraftment were not affected by neurologic complications. Neurologic complications negatively impacted OS (Hazard Ratio (HR) 3.5, p<0.001) and PFS (HR 2.2, p<0.0001).In summary, (1) Neurologic complications are uncommon after allogeneic HCT (5.7%); (2) Neurologic complications are more common in patients with relapsed or progressive disease (38.4%); (3) Neurologic complications are more common in patients receiving sirolimus-containing GVHD prophylaxis (23.5%), although limited by small numbers; (4) Neurologic complications are uncommon after 100 days (2.2%); (5) Neurologic complications were associated with decreased PFS and OS. [Display omitted] [Display omitted] DisclosuresChen:Novartis: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Impact of low-dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation.

We retrospectively evaluated the outcome of administering low-dose rabbit anti-thymocyte globulin (thymoglobulin: ATG-T) to 219 patients (ATG-T group, n = 30; no-ATG-T group, n = 189) who received an initial unrelated hematopoietic stem cell transplantation (uHSCT). The median total dose of ATG-T was 1.5 mg/kg. There was no significant difference in the cumulative incidences of grade II-IV (42 vs. 38 %, P = 0.87) and grade III-IV (5 vs. 7 %, P = 0.52) acute GVHD. In patients who received uHSCT from a donor with at least one HLA allele mismatch, the cumulative incidence of extensive chronic GVHD was significantly lower in the ATG-T group than that in the no-ATG-T group (13 vs. 44 %, P = 0.02). No patient in the ATG-T group developed chronic lung dysfunction. The probabilities of 1-year, GVHD-free/relapse-free survival (GRFS) were 61 % in the ATG-T group and 35 % in the no-ATG-T group (P = 0.02). Patients in the ATG-T group discontinued immunosuppressive drugs significantly earlier than those in the no-ATG-T group (P < 0.01). The use of low-dose ATG-T did not increase the incidence of severe infectious disease. The use of low-dose ATG-T in patients who received uHSCT was associated with a superior GRFS, reflecting the reduced incidence of severe/persistent GVHD without compromising overall survival.

Similar Incidence of Severe Acute Gvhd and Less Extensive Chronic Gvhd in PBSCT from Unmanipulated Haploidentical Donor Compared with That from Matched Sibling Donor for Patients with Hematologic Malignancies

▪Unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HCT) resulted in encouraging outcomes for treatment of hematologic malignancies and become an alternative option in case of lacking HLA matched sibling donor (MSD). Transplantation with G-CSF mobilized peripheral blood stem cell (PBSCT) has been a stable transplant setting with MSD. Unmanipulated haploidentical donor (haplo-PBSCT) has been applied in patients with hematologic malignancies. However, the characteristics of graft-versus-host disease (GVHD) in unmanipulated haplo-PBSCT are not clear. Here, we report the results of a cohort study on the clinical features of acute and chronic GVHD in haplo-PBSCT compared with PBSCT from MSD in patients with hematologic malignancies.PATIENTS AND METHODSBetween July, 2007 and June, 2014, 94 patients with hematologic malignancies received haplo-PBSCT and 100 patients received PBSCT from MSD consecutively at our unit (Table 1). The PBSCs were collected on day 5 and 6 after 4 days of rhG-CSF (5 mg.kg¨C1 °¤day¨C1), then were infused on the day of collection. The conditioning regimen consisted of Bu (9.6 mg.kg-1, iv, days -10~-8), Carmustine, (250 mg.m-2, day -5), cytarabine (8 g.m-2, days -7~-6), CY (120mg kg-1, days -4~-3). Antithymoglobulin (ATG, rabbit; 10 mg.kg-1, days -5~-2) was used for haplo-PBSCT. All recipients received cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis. The endpoint of the last follow-up for all surviving patients was July 15, 2015.RESULTSAmong the patients with acute GVHD, there was no difference of the rate of the involved organs between these two groups (skin: 67.4% vs 68.0%, p=1.000; liver: 15.2% vs 20.0%, p=0.742; gut: 33.3% vs 32%, p=1.000). Haplo-PBSCT was associated with higher incidence of acute GVHD grade 2-4 (HR: 3.04, 95% CI: 1.55-5.98, P =0.001) and lower incidence of extensive chronic GVHD (HR: 0.49, 95% CI: 0.24-0.99, P =0.047) compared with MSD PBSCT. There was no difference of the incidence of acute GVHD grade 3-4 between these two groups (haplo-PBSCT, 9.6% vs MSD PBSCT 8.9%, P =1.000). According to NIH criteria, the incidence of severe chronic GVHD was lower in haploidentical group (13.6%) compared with MSD group (40.5%, p=0.041). There was no difference of those for mild and moderate chronic GVHD (mild: 27.3% vs 13.5%, p=0.189; moderate: 59.1% vs 45.9%, p=0.422).CONCLUSIONIn this cohort study, haplo-PBSCT was associated with similar incidence of severe acute GVHD, lower extensive chronic GVHD and lower severe chronic GVHD compared with MSD-PBSCT. It suggested the potential advantage of ATG in improvement of long-term quality of life of the transplant recipients.Table 1Characteristics of patients and donorsHaploidentical donor, n = 94Matched sibling donor, n = 100P valueGender, n (%)Receipt, male73 (77.7)64 (64.0)0.041Donor, male63 (67.0)60 (60.0)0.371AgePatient, y, median27380.055Donor, y, median38390.364Hematologic malignances, n (%)Acute leukemia72 (76.6)61 (61.0)MDS3 (3.2)21 (21.0)0.000CML5 (5.3)10 (10.0)Lymphoma14 (14.9)8 (8.0)Status of disease, n (%)0.000CR142 (44.7)76 (76)CR214 (14.9)5 (5)NR/beyond CR238 (40.4)19 (19)Time to transplant (d)3612990.946Conditioning Regimen, n (%)0.354BuCy60 (63.8)66 (66.0)TBIcy28 (29.8)23 (23.0)FB6 (6.4)11 (11.0)CD34+ in graft (106/kg)5.864.770.057≥4.6051 (54.3)41 (41.0)0.084 DisclosuresNo relevant conflicts of interest to declare.

Randomized Trial on GvHD Prophylaxis with or without Anti-Human T-Lymphocyte Immunoglobulin ATG-Fresenius (ATG-F) in Allogeneic Hematopoietic Cell Transplantation from Matched Unrelated Donors: Final Long-Term Results after 8.6 Years Median Follow-up

Background:Previously, in 201 adult patients with allogeneic hematopoietic cell transplantation from matched unrelated donors, we demonstrated that the addition of ATG-F to standard cyclosporine, methotrexate GvHD prophylaxis (control) significantly reduces acute and chronic GvHD without negatively affecting relapse and survival [1,2,3].Methods:Now, we present final results after an extended follow-up (median 8.6, Q1 8.0, Q3 9.3 years) with regard to chronic GvHD, non-relapse mortality (NRM), relapse, relapse mortality, disease-free survival (DFS) and overall survival (OS). Additionally, we analyse the effect of ATG-F vs control on the composite endpoint severe GvHD (acute GvHD III-IV, extensive chronic GvHD) and relapse-free survival, and on time under immunosuppressive therapy. Since mortality within the first year after transplantation is usually high, we also analyse conditional survival, i.e. the OS probability after having survived 1 and 2 years after transplantation.Results:The incidence of extensive chronic GvHD after 8 years was 13.5% in the ATG-F group vs 51.8% in the control group (p<0.0001). The 8-year rates with respect to outcome were: NRM 20.5% vs 34.0% (p=0.15), relapse 35.2% vs 29.9% (p=0.54), relapse mortality 30.8% vs 28.8% (p=0.90), DFS 44.3% vs 36.1% (p=0.60), and OS 48.7% vs 36.8% (p=0.31), ATG-F vs control, respectively.ATG-F substantially increased the combined severe GvHD/relapse-free survival rate. The rates were 48.5% vs 20.4% after 1 year and 33.6% vs 13.0% after 8 years (p=0.0003), ATG-F vs control, respectively (see figure).The probability of being alive and free of immunosuppressive therapy was 46.8% in the ATG-F group and 11.2% in the control group at 8 years (p=0.0002).The survival probabilities increased when patients had survived the first year. The conditional 8 years-survival probability increased in the ATG-F group from 48.7% (unconditional) to 70.6% and 80.9% (conditional on having survived 1 and 2 years after transplantation), and in the control group from 36.8% (unconditional) to 58.5% and 71.7% (conditional on having survived 1 and 2 years after transplantation).Conclusion:The long-term follow-up of 8.6 years shows that ATG-F GvHD prophylaxis provides a sustained protective effect without increasing relapse and compromising survival. ATG-F in addition to standard cyclosporine, methotrexate as GvHD prophylaxis results in significantly improved severe GvHD/relapse-free survival. Furthermore, the stable results from our prospective trial after an extended long-term follow-up demonstrate that the choice to use ATG-F in unrelated donor transplantation after myeloablative conditioning substantially increases the probability of surviving free of immunosuppressive therapy, and thus reduces the risk associated with long-term immunosuppression.

Thymoglobulin Does Not Impact Relapse or Survival after Matched Unrelated Transplantation for AML/MDS Compared to Matched Related Donor Transplantation without Thymoglobulin Use

▪Thymoglobulin does not impact relapse or survival after matched unrelated transplantation for AML/MDS compared to matched related donor transplantation without Thymoglobulin use.Background: Thymoglobulin has been used customarily after matched related (RD) and unrelated (MUD) hematopoietic stem cell transplantation (HCT) to decrease risk of GVHD and graft rejection. However, its use has been implicated in increasing the risk of relapse. As matched sibling related donors considered the best available donor source for patients with AML /MDS, we hypothesized that production of outcomes (Relapse/Survival) after MUD transplant with use of thymoglobulin similar to RD transplantation without the use of thymoglobulin, would justify the use of thymoglobulin after MUD HCT in AML/MDS.Method: We compared the outcomes of 98 (29 matched RD/ 69 matched MUD) consecutive patients with AML/MDS who underwent HCT with Fludarabine/ Busulfan based conditioning between 7/2009-12/2014. Patients Characteristics are shown in Table-1. Patients received full intensity conditioning (FIC) with Fludarabine 40 mg/m2 for 4 days and Busulfan 3.2 mg/Kg single daily dose for 4 days (AUC 4200-5000). GVHD prophylaxis for FIC was Tacrolimus/mini Methotrexate and Tacrolimus/Mycophenolate for RIC. Thymoglobulin was added at dose of 1.5 mg/Kg for 3 days for MUD patients only regardless the conditioning intensity.Results: With median follow up 696 days (RD 746 days, MUD 676 days), the overall survival at 1 year was 75% +/- 8% and 74% +/- 5% for RD and MUD respectively, P=0.66. All patient engrafted except two patients in FIC MUD group. The cumulative incidence of relapse at 1 year was 31% +/- 8% and 23% +/- 5% for RD & MUD respectively, while the treatment related mortality (TRM) was 3.5% +/- 3% and 10% +/- 3% for RD and MUD HCT recipients. Cumulative Incidence acute GVHD grade II-1V was 29% in RD and 49% in MUD. Grade III-IV acute GVHD was 14% in Both RD and MUD recipients. Higher cumulative incidence of extensive chronic GVHD was observed in MUD recipients of 28% vs 20% in RD recipients.Conclusion: The addition of thymoglobulin to MUD HCT did not increase the cumulative incidence of relapse compared to RD HCT patients who did not receive thymoglobulin. RD HCT remained associated with lower TRM than MUD HCT despite the addition of thymoglobulin. MUD HCT with thymoglobulin produced similar overall survival to RD HCT without thymoglobulin. Our data suggest continued use of low dose thymoglobulin with MUD HCT while avoiding its use with matched RD HCT. Table 1PatientsRelated DonorUnrelated DonorNumber2969AML2261MDS78Graft Failure02Age (Range)53 (35-71)56 (25-73)Reduced Intensity825Full Intensity2144CR11747CR245Relapsed/Refractory817 DisclosuresNo relevant conflicts of interest to declare.

Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning Improves Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

Background: Bendamustine is a novel active agent in CLL with favorable safety profile. We recently reported the preliminary results of allogeneic stem cell transplantation (alloSCT) in lymphoma/CLL patients (pts) after BFR conditioning (Khouri et al. Blood 2014; 124:2306). Herein, we report more mature outcomes in CLL pts. Results and safety were compared with a previous regimen using FCR (fludarabine, cyclophosphamide, rituximab).Patients and Methods: We studied 89 CLL pts treated on 3 trials (one includes FCR later changed to BFR) at our center. Twenty-six (29%) pts received BFR and 63 (71%) received FCR. The BFR regimen consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m2 IV daily on days -5 to -3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant.Results: Patient characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), % pts with β2-microglobulin >3 mg/L at study entry, refractory disease (38% in BFR vs. 48% in FCR, P=0.4), presence of 17p deletion [27% in BFR vs. (8/33) 24% in FCR], unmutated status [19/21 (90%) of BFR vs 22/24 (92%) in FCR] and peripheral blood stem cell source (92% in BFR vs. 87% in FCR). Donor/recipient CMV and sex-mismatched distributions were not significantly different between the groups. However, more patients received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 32%, P=0.05). Ten (38%) BFR pts vs 2 (3%) FCR pts did not experience severe neutropenia (P <0.001) and 21 (81%) vs 39 (63%), respectively, did not require platelet transfusions (P=0.08). Median follow-up times for BFR and FCR groups were 29 (range 19-60), and 104 (range, 34-195) months. The 3-year overall survival (OS) estimates in the BFR and FCR groups were 82% vs. 51% (P=0.03) and the 3-year progression-free survival estimates were 63% vs. 27% (P=0.001). The 3-year OS improvements were seen across the prognostic factors studied for BFR and FCR respectively: MUD (93% vs 30%), presence of 17p deletion (86% vs 50%), and age >50 years (79% vs 50%), β2-microglobulin >3 mg/L (73% vs 45%), >3 prior lines of therapy (70% vs 43%) and recent years of transplant (82% vs 47%). Treatment-related mortality was 11% and 27% (P=0.05) at 2-year. The incidence of acute grade 3 GVHD was 4% and 10% in the BFR and FCR groups, respectively, despite the higher % of MUD transplants in BFR. Grade 4 acute GVHD was not observed in either group. The 3-year incidence of extensive chronic GVHD in BFR vs FCR was 45% vs 58% (P=0.01). This difference in GVHD incidence may in part be explained by a lower absolute blood level of CD8+ T cells in BFR patients compared to the FCR group at 6 months (median 343 vs 538, respectively) and 9 months (median 208 vs 406, respectively) post alloSCT.Conclusions: This is the first study to show that conditioning in alloSCT for CLL impacts outcomes with an improved survival after BFR when compared to the FCR regimen. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning.

We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B cell lymphoma [n=19], T-cell NHL [n=6], mantle cell lymphoma [n= 4], or other B-cell subtypes [n=3]), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1–11.9) years. The cumulative incidence of grade II–IV acute GVHD at day +100 was 12%, and the cumulative incidence of extensive chronic GVHD at 1 year was 36%. The 3-year cumulative incidences of overall survival, progression-free survival (PFS), and non-relapse mortality (NRM) were 81%, 44%, and 7%, respectively. Fifteen patients died (relapse, n=10; NRM, n=5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (>1 year) complete remissions following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n=24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GVHD, durable disease control, and excellent overall survival (81% at 3 years).

Impact of ABO blood group mismatch in alemtuzumab-based reduced-intensity conditioned haematopoietic SCT.

The impact of ABO incompatibility on clinical outcomes following haematopoietic SCT (HSCT) remains controversial. This retrospective study assessed the effect of ABO mismatch on transplant outcomes and transfusion requirements in 594 patients undergoing reduced-intensity conditioned (RIC) HSCT with alemtuzumab in three UK transplant centres. We found no significant effects of minor, major or bidirectional ABO mismatch on overall survival, relapse-free survival, nonrelapse mortality or relapse incidence. Although the rate of acute GVHD was unaffected by ABO mismatch, the incidence of extensive chronic GVHD was higher in patients with minor and major mismatch compared with those who were ABO matched (hazard ratio (HR) 1.74, P=0.032 for minor, HR 1.69 P=0.0036 for major mismatch). Red cell and platelet transfusion requirements in the first 100 days post transplant did not differ by ABO mismatch. In this large UK series, ABO mismatch in RIC HSCT has no clinically significant effect on survival outcomes but appears to modify susceptibility to extensive chronic GVHD.

HLA-E polymorphism and clinical outcome after allogeneic hematopoietic stem cell transplantation in Egyptian patients

Human leukocyte antigen-E (HLA)-E in a non-classical major histocompatibility complex (MHC) class I (Ib) molecule. HLA-E-peptide complex acts as a ligand for natural killer (NK) cells and CD8+ T lymphocytes playing a dual role in natural and acquired immune responses. The difference in expression levels between HLA-E alleles was suggested to have impact on transplantation outcome. The aim of the study is to evaluate the clinical effect of HLA-E alleles on transplantation in a group of Egyptian patients. HLA-E genotyping was analyzed in eighty-eight recipients of stem cell transplantation using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). HLA-E*01:03 allele showed a trend towards lower cumulative incidence of relapse at 2years compared to homozygous HLA-E*01:01 genotype (8% versus 21.5%, p=0.09, HR: 0.30, 95% CI: 0.91–1.69). HLA-E was the only factor showing near significant association with relapse incidence. HLA-E polymorphism did not affect the cumulative incidence of acute GVHD grades II-IV at 100days, the 2-year cumulative incidence of extensive chronic GVHD, transplant related mortality (TRM) or overall survival (OS). Conclusion: the suggested association of HLA-E polymorphism with reduced risk of relapse needs verification in a larger cohort. However, its proposed role in GVL helps better understanding of alloreactivity of T cells and NK cells and their implication in immunotherapy post allogeneic hematopoietic stem cell transplantation.

Outcomes Following Allogeneic Stem Cell Transplantation (AlloSCT) in Patients with Primary Mediastinal (PMBL), Germinal Center B (GCB) and Non-GCB Cell-like Diffuse Large B Cell Lymphomas (DLBCL)

Background: Primary mediastinal (PMBL), GCB and non-GCB B-cell lymphoma are three major subtypes of DLBCL with distinct clinical outcomes. PMBL and DLBCL of GCB immunophenotype have a higher chance of cure than patients with non-GCB DLBCL when treated with conventional chemotherapy. In the relapsed/refractory setting, there is paucity of data regarding the impact of histological classification of DLBCL on survival following alloSCT in patients who were not eligible for or who have failed a prior autologous SCT (ASCT). Herein, we compare outcomes of alloSCT in these patients.Methods and Patients: We identified 101 de novo DLBCL patients who were treated at our center from January 1, 1998 to December 31, 2011. Seventeen (17%) tumors were PMBL. We determined the cell-of-origin in the remaining patients, based upon the Visco/Young and Choi immunohistochemical algorithms, and classified 62 (61%) as GCB and 22 (22%) as non-GCB tumors. GCB patients were older than non-GCB [median (range): 54 (21-70) vs 48(24-58) years, p=0.003)] and PMBL [26(19-48), P <0.001)]. Patients with PMBL, however, were more likely to have bulky disease at study entry (SE) than other subtypes [24% (PMBL) vs 5% (GCB) and 5% (non-GCB); P= 0.04]. Stage III-IV at SE in GCB, non-GCB and PMBL was present in 42%, 45% (P=0.8) and 35% (P=0.6), respectively; the number of prior chemotherapies received was 4 in both GCB and non-GCB and 5 in PMBL (P=0.3). The proportion of patients who have failed a prior ASCT was comparable in all three groups (32%, 32% and 47%, P=0.2). Refractory disease was present in 35% of GCB and PMBL patients at SE compared to 14% in non-GCB patients (P=0.03). Distribution of IPI, LDH, and proportion of PET+ patients (47%, 45% and 47%) were not statistically different in all 3 groups. A larger proportion of GCB patients (44%, reference) received non-myeloablative conditioning than non-GCB (23%, P=0.07), or PMBL (12%, P=0.3); the remaining patients received reduced-intensity conditioning (RIC). The proportion of patients who received a matched sibling donor in GCB, non-GCB and PML were 69% (reference), 64% (P=0.6) and 41% (P=0.03), respectively. The remaining patients received matched unrelated donors. More GCB patients received peripheral blood as stem cell source than non-GCB (89% vs 73%, P=0.08) or PMBL (47%, P=0.001) patients. Median year of transplant was 2006 in both GCB and non-GCB and 2004 in PMBL.Results: Median (range) follow-up months in surviving GCB, non-GCB and PML patients were 63 (5-157), 29 (7-117) and 52 (10-133) months respectively. The 3-year cumulative OS were 52% (reference), 18% (P=0.09) and 46% (P=0.6). The 3-year cumulative PFS were 39%, 12% (P=0.1) and 41% (P=0.9) (Figure). When we restricted the comparison to patients who had chemosensitive disease and received RIC, the 3-year OS rates for GCB, non-GCB and PMBL were 47%, 25% (HR=0.6, P=0.3) and 44% (HR=0.9, P=0.9), respectively. The 3-year PFS rates were 37%, 10% (HR=0.6, P=0.2) and 44% (HR=0.7, P=0.8). Non-relapse mortality at 3-years was 29% (reference), 47% (P=0.1), and 35% (P=0.6). The incidence of acute II-IV GVHD was 24%, 27% and 29%. The incidence of extensive chronic GVHD was 34%, 54% (P=0.07) and 41% (P=0.5). The major cause of death in all 3 subgroups was disease progression (38%, 38%, and 33%), followed by acute GVHD 14%, 13%, and 33%.Conclusions: Our results suggest a tendency for inferior survival after alloSCT in non-GCB when compared to GCB and PMBL subtypes of DLBCL. This occurred despite the younger age in the non-GCB versus GCB group. Innovative approaches are needed to improve outcomes in non-GCB patients after alloSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Non-Myeloablative Allogeneic Transplantation Resulting in Clinical and Molecular Remission with Low Non-Relapse Mortality (NRM) in Patients with Advanced Stage Mycosis Fungoides (MF) and Sézary Syndrome (SS)

Introduction: The majority of patients with refractory, advanced stage MF or SS have a life expectancy less than 5 years. Currently, there is no curative therapy and none of the available therapies provides a long-term remission. We have performed allogeneic transplant in 29 patients as a prospective clinical study using a novel non-myeloablative preparative regimen to provide prolonged disease control.Patient and Transplant Regimen: This cohort included 11 patients with MF and 18 patients with SS. The median age was 62 years (range 20-75). These patients were heavily treated with a median number of prior systemic therapies of 5 (range 2-13). The median time from diagnosis to transplant was 33 months (range 9-147). Five patients had stage IIB disease and 24 patients (83%) had stage IV disease (21 with IVA and 3 with IVB). All 11 patients with MF had evidence of large cell transformation. All patients had active disease at the time of preparative regimen (skin: 100%, blood: 62%, lymph node: 62%). The patients received total skin electron beam therapy (TSEBT, 24-36 Gy) as part of preparative regimen for skin disease control, immediately followed by total lymphoid irradiation (TLI, 8 Gy) and rabbit anti-thymocyte globulin (ATG). All patients received G-CSF mobilized peripheral blood hematopoietic cells from either an HLA-matched related (n=11), HLA-matched unrelated (n=13) or HLA-mismatched unrelated (n=5) donor. Cyclosporine or tacrolimus and mycophenolate mofetil were used for GVHD prophylaxis. The entire protocol required only a 5-day inpatient stay during the infusion of ATG.Results: As planned, all patients received their allograft infusion as outpatient. Patients tolerated the immediate post-transplant period extremely well. Fifteen patients required hospital admission within 100 days after transplant, with a median length of hospital stay of 4 days. The most common cause for admission was delayed ATG reaction. At day +90, full donor chimerism (donor CD3+ > 95%) was achieved in 10 patients (34%) and mixed chimerism was found in 14 patients (48%). Of these 14 patients, 9 of them subsequently achieved full donor chimerism and 1 had secondary graft rejection. Five patients (17%) had primary graft rejection (donor < 5%). Three of the 6 with graft rejection received a second transplant after experiencing disease progression. The incidence of GVHD in our study was considerably lower than reported in other studies using reduced intensity regimens. The cumulative incidence of grade II-IV acute GVHD was 21%. Five patients had grade II acute GVHD (4 skin, 1 GI) and 1 had fatal grade IV acute GVHD (GI). The cumulative incidence of extensive chronic GVHD at 1 and 2 years was 13% and 23%, respectively. One death was attributed to complications of chronic GVHD.At 3-month post transplant, 19 patients achieved a complete response and 7 had a partial response (ORR 90%). Two patients experienced disease progression immediately after transplant, and 1 patient had stable disease. The median post-transplant follow-up for the entire cohort was 22.2 months and for the surviving patients was 24.5 months. The 2-year OS and PFS were 76% (95% CI, 54–88%) and 50% (95% CI, 28–68%), respectively. Among the surviving 21 patients, 81% (n=17) were in CR at last follow-up (16 with durable CR lasting >1 year). Of the 8 deaths in this study cohort, 3 were from NRM, each due to acute GVHD, complications related to chronic GVHD, or secondary malignancy (B-cell acute lymphoblastic leukemia). The 1-year cumulative NRM was 3%. High-throughput sequencing (HTS) of TCRß CDR3 was used for minimal residual disease (MRD) monitoring (Sci. Transl. Med.5:214ra171, 2013) (ImmunoSEQ, Adaptive Biotech). Of the 24 patients assessed, 11 patients (46%) achieved molecular remission in the blood after transplant. The median time to achieve molecular remission in the blood was 60 days (range 30-540). Of these 11 patients, 10 of them also achieved molecular remission in the skin. The 2-year OS and PFS for patients who achieved molecular remission were 86% (95% CI, 34–98%) and 71% (95% CI, 26–92%), respectively.Conclusion: We have developed an effective novel preparatory regimen with low transplant related mortality for non-myeloablative allogeneic transplant in patients with advanced stage MF and SS. Using the utmost sensitive TCRß HTS method to assess MRD, we were able to demonstrate a potentially curative therapy with molecular remission in this patient population. DisclosuresNo relevant conflicts of interest to declare.

Chronic GVHD Is Not Increased with the Use of PBSC Instead of Bone Marrow for T-Replete HLA-Haploidentical Transplanation Using Post-Transplant Cyclophosphamide : A Multivartiate Analysis of 116 Consecutive Transplants from a Single Center

HLA-haploidentical related donors (HID) are a potential option for patients who need an allogeneic haploidentical transplant but lack an optimally matched conventional donor (HLA-identical sibling or 8 of 8 HLA-A, B, C, DRB1 matched unrelated donor) (MRD and MUD respectively). The Baltimore approach to HID transplantation that uses T-replete grafts and post-transplant cyclophosphamide to control alloreactivity (HIDT-ptCy) has demonstrated promising outcomes and appears to be safe and effective. Bone marrow (BM) grafts have almost exclusively been used for HIDT-ptCy in Baltimore. Early studies from other centers have demonstrated that G-CSF mobilized PBSC may be safely used for HIDT-ptCy (Castagna et al BBMT 2014, Raj et al BBMT 2014). HIDT-ptCy using BM grafts has been associated with relatively low rates and severity of chronic GVHD. However, it is unclear whether the use of PBSC for HIDT-ptCy will be associated with higher rates of chronic GVHD than with BM grafts as has been demonstrated for MRD and MUD transplants. We analyzed 116 consecutive HIDT-ptCy first transplants (BM=64, PBSC=52) performed for hematologic malignancies at our center. Identical supportive care measures were utilized for BM and PBSC patients. GVHD was prospectively documented using established criteria by a single dedicated nurse. NIH consensus criteria were used for chronic GVHD. Gray’s test was used to compare the cumulative incidences of GVHD. A Cox model was used in multivariate analysis of GVHD outcomes. Characteristics of the patients are demonstrated in Table 1. Patients undergoing HIDT-ptCy using PBSC were significantly more likely to receive myeloablative conditioning, were younger, were less likely to have been transplanted prior to 2007. Although the frequency of diagnoses differed, the Dana-Farber/CIBMTR Disease Risk Index (DRI) was not significantly different between the two groups. Median follow-up for BM and PBSC patients was 44 m and 25 m. Six month cumulative incidences of acute GVHD grades 2-4 were 39% and 42% and grades 3-4 were 14% and 21% for BM and PBSC grafts respectively. The two year cumulative incidences of extensive chronic GVHD were 38% and 45% and for severe chronic GVHD were 8% and 6% respectively (p=NS for all BM vs PBSC comparisons). In a multivariate analysis assessing effects of patient, disease and transplant variables on GVHD outcomes, graft type i.e. PBSC vs BM was not a significant predictive factor for acute or chronic GVHD.These data demonstrate that unlike the case following MRDT and MUDT, G-CSF mobilized PBSC grafts are not associated with an increased risk of chronic GVHD than BM grafts following HIDT-ptCy. Severe chronic GVHD is very uncommon with both types of graft following HIDT-ptCy and is an indication of the effectiveness of ptCy in controlling alloreactivity in this setting. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Stable long-term pulmonary function after fludarabine, antithymocyte globulin and i.v. BU for reduced-intensity conditioning allogeneic SCT

Lung function decline is a well-recognized complication following allogeneic SCT (allo-SCT). Reduced-intensity conditioning (RIC) and in vivo T-cell depletion by administration of antithymocyte globulin (ATG) may have a protective role in the occurrence of late pulmonary complications. This retrospective study reported the evolution of lung function parameters within the first 2 years after allo-SCT in a population receiving the same RIC regimen that included fludarabine and i.v. BU in combination with low-dose ATG. The median follow-up was 35.2 months. With a median age of 59 years at the time of transplant, at 2 years, the cumulative incidences of non-relapse mortality was as low as 9.7%. The cumulative incidence of relapse was 33%. At 2 years, the cumulative incidences of extensive chronic GVHD (cGVHD) and of pulmonary cGVHD were 23.1% and 1.9%, respectively. The cumulative incidences of airflow obstruction and restrictive pattern were 3.8% and 9.6%, respectively. Moreover, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio remained stable from baseline up to 2 years post transplantation (P=0.26, P=0.27 and P=0.07, respectively). These results correspond favorably with the results obtained with other RIC regimens not incorporating ATG, and suggest that ATG may have a protective pulmonary role after allo-SCT.

Impact of sex incompatibility on the outcome of single-unit cord blood transplantation for adult patients with hematological malignancies

Donor-recipient sex incompatibility has been associated with transplant outcomes in allogeneic hematopoietic SCT. Such outcomes might be because mHA encoded by Y chromosome genes could be immunological targets for allogeneic T cells and B cells to induce GVHD, GVL effect and graft failure. However, its effect on the outcome of cord blood transplantation (CBT) is yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. In multivariate analysis, male recipients with female donors had a higher incidence of extensive chronic GVHD (hazard ratio (HR) 2.97, P=0.02), and female recipients with male donors had a lower incidence of platelet engraftment (HR 0.56, P=0.02) compared with female recipients with female donors as the reference. Nevertheless, there was no increase in mortality following sex-incompatible CBT. These data suggested that donor-recipient sex compatibility does not have a significant impact on survival after myeloablative CBT for hematological malignancies.

Risk factors and organ involvement of chronic GVHD in Japan

Few studies have evaluated the risk factors for chronic GVHD and organ involvement associated with different graft types, including unrelated cord blood (U-CB). We retrospectively studied 4818 adult patients who received their first allogeneic transplantation and survived for at least 100 days. The incidence of chronic GVHD at 2 years was 37%. The following factors were associated with the development of chronic GVHD: female donor/male recipient, CMV-Ab seropositivity, matched related peripheral blood grafts vs matched related BM grafts, no in vivo T-cell depletion and the occurrence of grade II-IV acute GVHD. Among these factors, the association with acute GVHD occurrence was consistently significant across donor subtypes. The use of U-CB was not associated with chronic GVHD, but was associated with a low incidence of extensive chronic GVHD. Chronic GVHD patients who had received U-CB transplants showed less frequent involvement of the oral cavity (28% vs 55%), eye (12% vs 26%), liver (20% vs 44%), lung (11% vs 25%) and joint (0% vs 6%) than those with matched related BM grafts. In conclusion, we found that U-CB transplants were associated with a low incidence of extensive chronic GVHD and less frequent involvement of the oral cavity, eye, liver, lung and joints.