Matched Unrelated Donor Group Research Articles

Post-Transplant Cyclophosphamide (PT-Cy) Based Haploidentical Cell Transplantation (Haplo) Versus Rabbit Anti-Thymocyte Globulin (r-ATG) Based HLA Matched Unrelated Donor (MUD) Transplantation in Patients (pts) with Relapsed/Refractory Lymphoma

Background PT-Cy has emerged as an effective strategy for graft-versus-host disease (GVHD) prophylaxis in Haplo. The reported risk of GVHD with non-PT-Cy in pts receiving MUDs varies between centers. In this report, we compared the engraftment rates, survival, risk of GVHD and comorbidities between PT-Cy Haplo and r-ATG-based MUDs approach in pts with relapse/refractory lymphoma receiving an allogeneic transplantation. Method We retrospectively evaluated 160 adult pts with lymphoma who received Haplo (n=35) or r-ATG-MUDs (n=125) at our center between 2012 and 2018. Pts received GVHD prophylaxis of r-ATG (2-4 mg/kg total on days -3 to -1), tacrolimus and methotrexate if MUD, and tacrolimus and mycophenolate mofetil in addition to PT-Cy (50 mg/kg on days+3, +4) if Haplo. Tacrolimus taper was initiated at 6 months after transplantation in pts with no active GVHD. The study was IRB-approved. Results Haplo pts were more likely to be younger (median age 47 vs 55 yrs; P=0.032), have a lower HCT-Comorbidity Index (median 2 vs 3; P=0.048), and to include more diffuse large b-cell lymphoma (31% vs 22%, and Hodgkins disease (29% vs 16%) (P=0.015). Significant differences were also observed in the conditioning intensity and cell source of transplants between the 2 groups. The majority of Haplo pts (80%) received a reduced intensity-conditioning (RIC) of melphalan/fludarabine +/- 2Gy TBI; the remaining received a myeloablative (MA) busulfan-based regimen (9%) or nonmyeloablative (NMA) (11%) conditioning. In comparison, the percentage of MUDs pts receiving RIC, MA and NMA [bendamustine, fludarabine, rituximab or fludarabine, cyclophophamide, rituximab were 31%, 22% and 46%, respectively (P<0.001). The percentage of pts receiving bone marrow as a source of cells in the Haplo and MUDs groups were 74% vs 14%, respectively (P<0.001). There was no difference in the # of prior therapies received (median = 3, in both), the # of pts who failed a prior autologous (37% vs 26%; P=0.21), disease status (CR vs PR vs refractory; P=0.3), IPI >2 (25% vs 19%, P=0.73) or PET-positive status (55% vs 44%, P=0.33) at study entry between the 2 groups. PT-Cy Halplo group had a significantly higher incidence of symptomatic BK- induced hemorrhagic cystitis compared to r-ATG MUD group (49% vs 10%, P< 0.001). Delayed engraftment was noted in PT-Cy Haplo group compared to r-ATG MUD group with median time to achieve ANC > 500 (18 days vs 10 days; P<0.001), and platelets > 20k were 25.5 days vs 10 days (P<0.001), respectively. The median follow-up time for pts treated with PT-Cy Haplo and r-ATG MUD pts was 12.1 and 20.8 months, respectively. Similar survival and non-relapse mortality (NRM) rates were observed between the 2 groups. The 1-year OS rates were 64% vs 67% (P=0.76) and the 1-year PFS rates were 52% vs 58% (P=0.67). The cumulative incidence (CI) of 1-year NRM was 30% vs 26%, respectively (P=0.66). Chemo-sensitivity (Figure 1), NMA conditioning (Figure 2), and HCT-Comorbidity Index of < 4 were associated with a better OS and PFS in univariate and multivariable analyses. Among histologies, pts with follicular lymphomas had the best OS and PFS. T-cell lymphoma had the worse outcomes. In addition, cystitis was associated with a lower survival rate by univariate analysis (P=0.036). The CI of acute 2-4 GVHD (26% vs 33%, P=0.43), acute 3-4 GVHD (14% vs 12%, P=0.66), and 1-year CI of chronic GVHD (6% vs 15%, P=0.19) were not statistically different between PT-Cy Haplo and r-ATG MUD. By univariate analysis, bone marrow source of graft was the only factor that was found to be significantly associated with a lower risk of chronic GVHD (HR 0.34; P=0.041) (Figure 3). Conclusion Our data show similar survival rates and risk of acute and chronic GVHD in pts with lymphoma who received PT-Cy Haplo and r-ATG MUD. The use of bone marrow graft was the only predictor of a lower incidence of chronic GVHD. Considering the statistically significant delayed time to engraftment and the higher risk of hemorrhagic cystitis, a MUD remains the donor of choice in lymphoma pts who have this option. Disclosures Jabbour: Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Kebriaei:Kite: Honoraria; Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Champlin:Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding; Actinium: Consultancy.

Characterization of Viral Infections after Antithymocyte Globulin-Based Conditioning in Adults Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Antithymocyte globulin (ATG) has been shown to reduce the incidence of graft-versus-host-disease (GVHD) after matched related donor (MRD) and matched unrelated donor (MUD) hematopoietic stem cell transplantation (HCT); however, because of increased risks of infection and relapse, this use has not translated into a significant improvement in post-transplant survival. The goal of this single-center, retrospective cohort analysis was to quantify the incidence of viral reactivation and viral end-organ disease (EOD) within the first 100 days after MUD HCT with ATG-based conditioning compared with MRD HCT without ATG. Fifty-nine adult patients underwent ATG-based MUD HCT compared with 64 patients receiving MRD HCT without ATG. Cytomegalovirus reactivation was the most frequent event in both groups (65% MUD versus 61% MRD), followed by BK virus reactivation (26% versus 24%) and Epstein-Barr virus reactivation (20% versus 9%). A higher percentage of MUD patients experienced viral EOD by day +100 when compared with MRD patients (34% versus 16%, P = .022). This was most notable for EOD involving BK virus (15% versus 6%, P = .14) and Epstein-Barr virus (7% versus 0%, P = .050). Correspondingly, more patients in the MUD group experienced virus-related complications, including hospitalization (24% versus 3%, P < .001), intensive care unit admission (10% versus 6%, P = .19), and mortality (8% versus 4%, P = .44). There were no significant differences in either relapse-free survival (RFS; 62% versus 78%, P = .07) or overall survival (OS; 72% versus 86%, P = .07) at 6 months post-HCT. However, when using the final time point of 21 months in the MUD/ATG group and 23 months in the MRD/no ATG group, MUD patients who received ATG had inferior survival (OS: 27% versus 77%, P = .009; RFS: 40% versus 59%, P = .042). Our results add to and further quantify the infectious risks associated with the use of ATG in MUD transplants and promote the implementation of more intensive preemptive viral monitoring practices in patients receiving ATG-based MUD transplants.

Spectrum of Infections with a Protocol of Dual T-Lymphocyte Suppression Using ATG and PTCy for Gvhd Prophylaxis in Allogeneic Transplants for High-Risk Hematological Malignancies

Introduction ATG and PTCy have been individually shown to reduce rates of GVHD in allogeneic transplants. We adopted a combination regimen of ATG and PT-Cy for GVHD prophylaxis in allogenic transplants for high risk hematological malignancies in our centre, to decrease the rates of acute and chronic GVHD. Objectives We analysed the spectrum of infections in patients who received this dual T lymphocyte suppression protocol. Patients and methods Reduced intensity conditioning consisted of iv Fludarabine, iv Busulphan, and low dose TBI. GVHD prophylaxis was with Thymoglobulin 4.5mg/kg total dose, PT-Cy 100 mg/kg total dose and cyclosporine. The stem cell source was G-CSF stimulated PBSCs. Results 197 patients (median age 57 y, range 19-74y) with high-risk hematological malignancies were treated with this protocol. The donor types were as follows-10/10 matched unrelated donor (MUD) in 76, 9/10 mismatched unrelated (MMUD) in 26, 10/10 matched related donor(MRD) in 43 and haplo-identical (HI) donors in 52 patients. The median follow-up in the entire cohort was 12 months. The 1year OS in the MUD, MMUD, MRD and HI groups were 75%, 50%, 63.3% and 56.7% respectively. The overall percentages of proven bacterial, viral, and fungal infections were 49%, 62% and 11% respectively (Table 1). The overall incidence of CMV reactivation was 48% and was significantly different among the 4 donor groups (p=0.00). We also observed high rates of EBV reactivation (33%) and BK cystitis (18%). There were 14 pathologically confirmed cases of post-transplant lympho-proliferative disorder (PTLD), of which 1 responded to discontinuation of immune-suppression and the rest needed treatment with Rituximab. There was one death attributed to PTLD. Infections were the primary cause of death in 18 patients (23% of deaths) and a contributory cause of death in an additional 16 patients (20% deaths). The overall incidence of grade 3-4 acute GVHD in our patients was 10.1 % and of moderate/severe NIH stage chronic GVHD was 11.6% which is low compared to conventional GVHD prophylaxis regimes. Only 10% of deaths were attributable to GVHD. Conclusion Our experience shows that dual T lymphocyte suppression with PT-Cy and ATG for GVHD prophylaxis results in low rates of acute and chronic GVHD, but is associated with high rates of infections, especially viral reactivation and PTLD.

Combination of ATG and Post-Transplant Cyclophosphamide for Gvhd Prophylaxis in Matched and Mismatched Donor Peripheral Blood Stem Cell Transplants for Myeloid Malignancies

Introduction ATG and post-transplant cyclophosphamide (PTCy) have been individually shown to be efficacious in reducing rates of GVHD in HLA matched and mismatched transplants. We adopted a combination regimen of ATG and PTCy for GVHD prophylaxis in HLA matched and mismatched transplants for myeloid malignancies in our centre, to decrease the rates of acute and chronic GVHD. Objectives We assessed the overall and progression free survival, incidence of acute and chronic GVHD, relapse rates and non-relapse mortality with this protocol. Patients and Methods Reduced intensity conditioning protocol consisted of iv Fludarabine, iv Busulphan, and low dose TBI. GVHD prophylaxis was with Thymoglobulin total dose 4.5mg/kg, PTCy total dose 100 mg/kg and cyclosporine. The stem cell source was G-CSF stimulated PBSCs. Results 169 patients (median age 58 y, range 19-74y) with high-risk myeloid malignancies (AML-64.5%, MDS-19%, MPN-12%) were treated with this protocol after obtaining institutional approval. The donor types were as follows-10/10 matched unrelated donor (MUD) in 67, 9/10 mismatched unrelated (MMUD) in 24, 10/10 matched related donor(MRD) in 35 and haplo-identical (HI) donors in 43 patients. The median follow-up in the entire cohort was 12 months. The 1year OS in the MUD, MMUD, MRD and HI groups were 73%, 54%, 74% and 56% respectively and the corresponding 1 year PFS were 66%, 38%, 49% and 51% respectively. The percentage of graft failure (primary and/or secondary) in the 4 groups were 1.5%, 12.5%, 0% and 16.3% respectively. The relapse rates were 21% in MUD, 42% in MMUD, 29% in MRD and 14% in HI groups. The MMUD patients had significantly inferior OS (p=0.03), and PFS (p=0.003), and significantly higher risk of relapse(p=0.009), compared to MUD patients. The overall incidence of grade 3-4 acute GVHD in our patients was 10 % and of moderate/severe NIH stage chronic GVHD was 11.6% which is low compared to conventional GVHD prophylaxis regimes. The percentages for grade 3-4 acute GVHD according to donor type were 16.4% in MUD, 4.2% in MMUD, 5.8% in MRD and 9.3% in HI groups and that of moderate/severe NIH stage chronic GVHD were 7.5%, 8.4%, 11.4% and 16.3% respectively. There were high rates of viral reactivation observed with this dual T lymphocyte suppression strategy. The overall incidences of CMV, and EBV reactivation and BK cystitis were 48%, 33% and 17% respectively. In addition, there were 12 pathologically confirmed cases of post-transplant lympho-proliferative disorder. Conclusion Our experience shows that PT-Cy and ATG can be combined for GVHD prophylaxis in PBSCTs for high risk myeloid malignancies and results in low rates of Gr3-4 acute GVHD and moderate/severe chronic GVHD across different donor types with acceptable relapse rates. High rates of viral re-activation are a concern and need close monitoring.

Comparision of Outcomes According to HLA Disparity in Acute Leukemia Patients: A Single Center Institution Experience

Introduction:Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) still remains the only established curative approach for the treatment of acute leukemia (AL). HLA-matched sibling or relative donor (MRD) is considered the optimal donor source but when this is not available, a matched unrelated donor (MUD) is considered the best alternative. Prior studies reported comparable results of Allo-HSCT from MSD versus MUD. In this retrospective, single center review, we aimed to compare the transplantation outcomes after 10/10 or 9/10 HLA-matched related to unrelated donor transplantation in adults with AL.Patients and Methods: We retrospectively analyzed 363 consecutive patients with a diagnosis of AL who underwent their first Allo-HSCT between January 2005 and April 2018, using matched 10/10 MRD (n= 244) and MUD (n=54) or mismatched-UD (mmUD) (n=65) at Ankara University School of Medicine, Bone Marrow Transplantation Unit. Patients transplanted using cord blood or haploidentical donors were excluded to homogenously compare adult full-matched sibling or unrelated donors in the acute leukemia setting. Parameters evaluated included hematopoietic engraftment, disease relapse, transplant related complications, mortality, overall survival (OS) and disease free survival (DFS) from transplantation, and the incidence and severity of acute and chronic GVHD.Results:Baseline characteristics are summarized in Table 1. The median age was similar in all groups at the time of transplantation (p= 0.9). Median follow-up from the transplantation for all patients was 25 months (range, 1- 152.8) but median follow up was longer in the MRD group (33.6 months [range, 1-152.8]) than in the MUD and (13.3 months [range, 1-121.5]and mmUD groups (22.3 months [range, 2.3-129.4]and p=0.011). In the MRD group, 90.9% received a myeloablative conditioning (MAC) regimen, while in the MUD and mmUD groups, 73.1% and 81.3% received a MAC regimen (p=0,001). Cyclosporine and methotrexate were used as the main graft versus host disease (GVHD) prophylaxis in all groups. The proportion of patients who received in vivo T cell depletion significantly differed among the two groups (6.6% in the MRD group, 92.6% in the MUD group and 50.8% in the mmUD group, p=0.000). Peripheral blood stem cell (PBSC) was the main stem cell source in all groups (92.2% in the MRD group vs. 90.7% in the MUD group vs. 95.4% mmUD, p<0.1). Most of the patients (94.3%) achieved hematopoietic engraftment, graft failure occurred in 4.5%, 7.4% and 9.2% in MRD, MUD and mmUD groups, respectively (p>0.1). The median time for neutrophil and platelet engraftments was seen faster in MRD group compared to MUD and mmUD (p<0.0001).According to the type of donor the incidence of grades II-IV acute GVHD were similar among MRD, MUD and mmUD (22.1%, 24.1% and 18.5%, respectively). But lower incidence of chronic GVHD was observed post-HSCT with a mmUD than a MSD; 22.2% for MUD, 32.3% for mmUD and 55.6% for MRD (p>0.1). No statistical significance was observed for transplant related mortality (TRM) in terms of the type of donor (MUD group. mmUD groupand MRD group; 22.2%, 23.1% and 18.0%, p=0.572). Relapse incidence was similar among the groups (MRD vs. MUD vs. mmUD; 33.6% vs. 29.8% vs. 30.8%, p=0.807). Two-year leukemia free- and overall survival were not affected the donor types (Figure-1)..Conclusion:Our results suggest that, when an HLA-identical sibling donor is not available for an adult with AL who is otherwise a candidate for Allo-HSCT, a 10/10 or 9/10 UD may be used with the expectation of similar rates of TRM, LFS and OS at 2 years. DisclosuresCivriz Bozdag:NOVARTIS: Consultancy; MSD: Research Funding; TAKEDA: Consultancy. Özcan:Jazz: Other: Travel support; BMS: Honoraria; MSD: Research Funding; Celgene: Other: Travel support, Research Funding; Abbvie: Other: Travel payment; Roche: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel payment, Research Funding; Novartis: Research Funding; Janssen: Other: Travel Support, Research Funding; Bayer: Research Funding; Archigen: Research Funding; MSD: Other: travel support, Research Funding; Jazz: Other. Ilhan:BMS: Speakers Bureau; Roche: Speakers Bureau; Celgene: Speakers Bureau; Alexion: Speakers Bureau. Beksac:Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen,Janssen-Cilag,Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Impact of the Presence of HLA 1-Locus Mismatch and the Use of Thymoglobulin in Unrelated Bone Marrow Transplantation

Introduction: HLA 1-locus mismatched unrelated donor (1MMUD) has been used in allogeneic hematopoietic stem cell transplantation (HCT) for patients who lack an HLA-matched related or unrelated donor, although its outcome has been shown to be inferior to that of HLA-matched HCT. The use of anti-thymocyte globulin such as thymoglobulin (Thymo) as GVHD prophylaxis may overcome this drawback. The aims of this study were to compare the transplant outcomes between 1MMUD and matched unrelated donor (MUD) and to evaluate the effectiveness of Thymo in unrelated HCT from 1MMUD using the recent cohort.Methods: We retrospectively analyzed 3313 adult patients with acute myeloid leukemia (n=1835), acute lymphoblastic leukemia (n=830), or myelodysplastic syndrome (n=648) who underwent a first bone marrow transplantation from HLA -8/8 allele MUD or 1MMUD between 2009 and 2014. The patients who underwent allo-HCT from MUD with Thymo were excluded in this study. Clinical data for these patients were obtained from the Transplant Registry Unified Management Program (TRUMP), which includes clinical data of HCT performed in Japan. We compared the outcomes of MUD (n=2089) and 1MMUD with Thymo (n=109) with those of 1MMUD without Thymo (n=1115).Results: The median total dose of Thymo was 2.5 mg/kg (range 1.0-11.0 mg/kg) in the 1MMUD with Thymo group. The incidence of grade II-IV and III-IV acute GVHD were 44.5% (95% confidence interval (CI), 41.5- 47.4%) and 13.1% (95% CI, 11.2-15.2%), 33.4% (95% CI, 24.5-42.5%) and 5.8% (95% CI 2.4-11.6%), and 36.1% (95% CI, 34.1-38.2%) and 10.5% (95% CI, 9.2-11.9%) in the 1MMUD without Thymo group, the 1MMUD with Thymo group, and the MUD group, respectively (p<0.001, and p=0.0085). The incidence of non-relapse mortality (NRM) at 3 years was higher in the 1MMUD without Thymo group (26.6%; 95% CI 23.7-29.5%) than that in the 1MMUD with Thymo group (11.9%; 95% CI, 5.9-20.2%) or the MUD group (21.4%; 95% CI 19.5-23.4%, p<0.001, Figure1A), although the incidence of relapse did not differ among 3 groups. The probabilities of GVHD-free, relapse-free survival (GRFS) at 1 year were 38.8% (95% CI, 35.8-41.8%), 48.4% (95% CI, 37.9-58.0%), and 41.8% (95% CI, 39.6-44.0%) in the 1MMUD without Thymo group, the 1MMUD with Thymo group, and the MUD group, respectively (p=0.0012, Figure1B).In multivariate analysis (Table 1), the rates of grade II-IV and III-IV acute GVHD, NRM and overall mortality were significantly lower in the MUD group than in the 1MMUD without Thymo group (hazard ratio (HR) 0.75; 95% CI 0.67-0.84; p<0.001, HR 0.77; 95% CI, 0.63-0.95; p=0.014, HR 0.74; 95% CI, 0.63-0.87; p<0.001, and HR 0.87; 95% CI, 0.78-0.98; p=0.017, respectively). Likewise, the rates of grade II-IV and III-IV acute GVHD and NRM were significantly lower in the 1MMUD with Thymo group than in the 1MMUD without Thymo group (HR 0.69; 95% CI 0.49-0.98; p=0.040, HR 0.42; 95% CI, 0.19-0.94; p=0.035, and HR 0.35; 95% CI, 0.19-0.65; p<0.001, respectively). In addition, the overall mortality rate also tended to be lower in the 1MMUD with Thymo group than in the 1MMUD without Thymo group (HR 0.74; 95% CI 0.53-1.03; p=0.075). On the other hand, there were no statistically significant differences in relapse rates between the 1MMUD without Thymo group and the MUD group (HR 1.09; 95% CI 0.94-1.27; p=0.27), or between the 1MMUD without Thymo group and the 1MMUD with Thymo group (HR 1.28; 95% CI 0.84-1.96; p=0.26). Finally, we divided patients in the 1MMUD with Thymo group into 3 groups according the total dose of Thymo (Thymo<2 mg/kg, 2 mg/kg≤Thymo≤4 mg/kg, Thymo>4 mg/kg), and compared the outcomes of the 3 groups with those of 1MMUD without Thymo. The incidence of NRM at 2 years and the probabilities of GRFS at 1 year were 16.1% (95% CI, 3.7-36.3%) and 33.8% (95% CI, 13.9-55.1%) in the Thymo<2 mg/kg group, 6.4% (95% CI, 1.6-16.0%) and 55.3% (95% CI, 40.6-67.8%) in the 2 mg/kg≤Thymo≤4 mg/kg group, 12.7% (95% CI, 3.0-29.6%) and 44.7% (95% CI, 25.1-62.6%) in the Thymo>4 mg/kg group, and 24.1% (95% CI, 21.5-26.8%) and 38.8% (95% CI, 35.8-41.8%) in the 1MMUD without Thymo group (p=0.014 and p=0.053), respectively.Conclusions: The outcome of HCT from 1MMUD without Thymo was inferior to that of HCT from MUD even in the recent cohort. However, the negative impact of 1MMUD disappeared by the use of relatively low dose of Thymo without increasing the risk of relapse. A large prospective study is warranted to confirm the role of low dose of Thymo in HCT from 1MMUD. [Display omitted] [Display omitted] DisclosuresKanda:Otsuka Pharmaceutical: Honoraria, Research Funding.

Comparable Results with Treosulfan Based Conditioning Regimen in Matched Related and Matched Unrelated Donor Transplants for Beta Thalassemia Major and the Challenges from India: A Single Center Experience

Background: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with thalassemia major. Majority of the patients undergoing transplants in India belongs to advanced Pesaro risk stratification and 2013 data from India using treosulfan based conditioning for matched related donor transplants (MRD) has showed an event free survival of 78.8 ± 6.0 at 3 years (Mathews et al. Plos One 2013). Advanced age and risk stratification is a deterrent in proceeding with matched unrelated donor (MUD) transplant in India. Since only 25-30 % of patients are likely to get a MRD, MUD transplant is a feasible option in the background of limited life expectancy in patients with thalassemia major. However, there is no data comparing MRD and matched unrelated donor (MUD) transplants from India.Method: This is a retrospective analysis to compare the outcomes between MRD and MUD transplants from a single institution. Events were defined as primary graft failure, graft rejection leading to recurrence of transfusion dependence or death.Results: A total of 123 patients with thalassemia major underwent MUD search in DKMS and DATRI registries. Fifteen (12%) and 13 (10%) patients found 10/10 HLA identical donors respectively and 4 (3%) of them had matches in both the registries. Very few patients underwent NMDP search due to cost constraints.Among the 36 patients who underwent stem cell transplantation, MRD group had 27 patients and MUD group has 9 patients. Base line characteristics of age, sex and Pesaro risk stratification were matched. (Table: 1) Majority of patients belonged to high risk category in both the groups. The conditioning regimens used in both the groups were thiotepa, fludarabine, and treosulfan (TreoFluT). All the MRD non-sibling transplants and MUD transplants also received antithymocyte globulin (ATG) as part of the conditioning regimen. All patients received HLA identical (10/10) grafts. In the MRD group, the stem cell source was 24 (89%), 2 (7%) and 1 (4%) from sibling, parent and 1st cousin respectively. The MUD grafts were procured from 3 different registries DKMS (German) 5 (56%), NMDP (US) 2 (22%) and DATRI (Indian) 2 (22%). Cyclosporine and short course methotrexate were used as Graft versus host disease (GVHD) prophylaxis in all the patientsMultiple challenges are involved in the availability and procurement of donor grafts from different registries. A special DCGI (Drug controller General of India) approval needs to be taken for every graft source procured from overseas. The estimated average cost of MRD transplant is 24000 US$ and MUD transplant is 48000 US$ for DKMS and DATRI grafts and 78000 US$ for NMDP grafts. Inspite of lower costs than the western countries, affordability is a major concern even if matched donors are available.Overall survival at 1 year in MRD and MUD groups was 84.3 ± 7.2% and 88.9 ± 10.5% at a median follow up of 20 (0-57) months and 13 (1-31) months respectively (p= 0.799) (Fig:1). The thalassemia free survival at 1 year was 84.3 ± 7.2% and 77.8 ± 13.9% with a median follow up of 20 (0-57) and 12 (1-31) months respectively (p= 0.732). (Fig: 2).Conclusion: Although the incidence of acute GVHD and chronic GVHD incidence are higher in the MUD transplant group, TreoFluT based conditioning for allogeneic stem cell transplantation with both matched related and unrelated donor graft source is a feasible option in beta thalassemia major patients even in high risk category from developing countries.Table 1Patient demographics and transplant characteristicsMRD (n= 27) n(%) Median(range)Mean ± SDMUD n=9 n(%) Median(range)Mean ± SDP-valueAge (yrs)10 (2-18)9 (2-18)0.502Sex: Male19 (70)6 (66)0.835Class I1 (4)2 (22)0.135Class II6 (22)3 (33)Class III20 (74)4 (44)Class III Vellore high risk11 (55)3 (75)0.693Stem cell sourcePBSC BM BM + CB BM + PBSC + CB23 (85) 2 (7) 1 (4) 1 (4)7 (78) 2 (22) 0 00.599Cell doseMNC/TNC x 108/Kg CD34 x 106/Kg8.04 (3.49 -14.6) 5.91 (0.23 -27.75)7.2 (2.83 -10.47) 8.47 (0.49 -21.6)0.782 0.381Acute GVHD6 (22)6 (66)0.014Grades I and II5 (19)4 (44)0.505Grades III and IV1 (4)2 (22)Classic acute GVHD5 (18)3 (33)0.287Persistent00Recurrent03 (33)Late onset1 (4)0Chronic GVHD6 (22)6 (67)0.014Classic Chronic GVH5 (18)3 (33)0.545Overlap syndrome1 (4)3 (33) [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Survival after T-Cell Replete Haploidentical Related Donor Transplant Using Post-Transplant Cyclophosphamide Compared with Matched Unrelated Donor (MUD) Transplant for Lymphoid Malignancies

▪Background: The use of haploidentical hematopoietic cell transplantation (HCT) using post- transplant cyclophosphamide (PT-Cy), calcineurin inhibitors (CNI) and mycophenolate as graft-versus-host disease (GVHD) prophylaxis is rapidly increasing in patients (pts) lacking suitable HLA-matched donors. Herein we compare outcomes of haploidentical HCT using this GVHD prophylaxis with 8/8 allele-level MUD HCT.Methods: Included are 917 adult (>18) lymphoma pts who underwent allogeneic HCT between 2008 and 2013. All pts received non-myeloablative or reduced-intensity conditioning regimens. The study cohort was divided into 3 groups; haploidentical (n=185), MUD without (w/o) antithymocyte globulin (ATG; n=491) and MUD with (w/) ATG (n=291). The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence (Cum-Inc) of acute GVHD, chronic GVHD, non-relapse mortality (NRM), relapse/progression (rel/prog) and progression-free survival (PFS). The study had an 83% power to detect an 11% difference in OS.Results: The baseline characteristics are shown in Table 1. Pts in the haploidentical group received conditioning with Flu/CY/2Gy TBI and PT-Cy + CNI and mycophenolate as GVHD prophylaxis, while the two MUD cohorts received fludarabine-based (+ an alkylator or 2GyTBI) conditioning and CNI-based GVHD prophylaxis. Graft source was bone marrow in 93% of the haploidentical pts and peripheral blood in 94% and 91% of MUD w/o ATG and MUD w/ ATG pts, respectively.The 28-day neutrophil recovery and platelet recovery were 94%, 97%, 97% (p=0.32) and 63%, 89%, 84% (p<0.001) in the haploidentical, MUD w/o ATG and MUD w/ ATG groups respectively. Cum-Inc of grade II-IV acute GVHD at day100 and chronic GVHD at 1 year was 27%, 40% and 49% (p=0.07) and 13%, 51% and 33% (p<0.001) in the haploidentical, MUD w/o ATG and MUD w/ ATG groups, respectively. On multivariate analysis (MVA) higher risk of chronic GVHD was seen in MUD w/o ATG (RR=5.85, 95%CI 3.96-8.64; p<0.0001) and MUD w/ ATG (RR=3.64, 95%CI 2.37-5.59; p<0.0001) groups relative to the haploidentical cohort. The 3 year NRM was 17%, 22% and 26% in the haploidentical, MUD w/o ATG and MUD w/ ATG groups (p=0.08), respectively. On MVA a trend towards higher NRM was noted in MUD w/ ATG cohort, RR 1.54 (95%CI 0.98 - 2.41, p=0.06), relative to the haploidentical group. Among the haploidentical, MUD w/o ATG and MUD w/ ATG cohorts the 3 year Cum-Inc of rel/prog was 36% vs. 28% vs. 36%, PFS was 47% vs. 49% vs. 38% and OS was 60%, 62% and 50% (Figure), respectively. MVA demonstrated no significant difference between the three groups in terms of rel/prog (p=0.27) and PFS (p=0.07). Compared to the haploidentical group, the two MUD groups did not have a significantly different mortality risk (inverse of OS; p>0.05), but compared to MUD w/ ATG, the MUD w/o ATG pts had a reduced mortality risk (RR=0.67; p=0.001). We tested for a transplant center effect on survival and found none.Conclusion: With lower-intensity conditioning regimens the early (up to 3 years) survival outcomes are comparable between conventional MUD transplants (w/ or w/o ATG) and haploidentical HCT with PT-Cy approach. Chronic GVHD was significantly lower with haploidentical HCT. Prospective, randomized confirmation of these findings is necessary before wide spread adoption of haploidentical HCT over MUD transplants in lymphomas. Table 1Haploidentical N=185 (%)MUD w/o ATG N=491 (%)MUD w/ ATG N=241 (%)p-valueAge @ HCT, median (range)55 (18-75)55 (19-74)55 (20-73)0.13Male sex118 (64)301 (61)163 (68)0.25White race149 (81)469 (96)227 (94)<0.001KPS ≥ 90145 (78)311 (63)153 (63)<0.001HCT-CI≥355 (30)175 (36)88 (37)<0.001Histology NHL Hodgkin139 (75) 46 (25)386 (79) 105 (21)193 (80) 48 (20)<0.001Months from diagnosis to HCT, median (range)31 (<1-255)34 (<1-342)32 (4-460)0.19High LDH @ HCT16 (31)31 (33)11 (27)<0.001BM +ve @ HCT6 (12)5 (5)2 (5)0.35Extranodal disease @ HCT18 (35)20 (21)6 (15)0.11Prior lines of therapy, median (range)3 (1-7)3 (1-12)3 (1-8)0.41Remission @ HCT CR PR Refractory Untreated / missing72 (39) 99 (54) 10 (5) 4 (2)215 (44) 215 (44) 55 (11) 6 (1)100 (41) 96 (40) 40 (17) 5 (2)0.02Disease Risk Index Low Intermediate High45 (24) 126 (68) 13 (7)199 (41) 263 (49) 48 (10)75 (31) 129 (54) 37 (15)<0.001Median follow-up, months (range)36 (5-73)35 (4-74)35 (<1-75) [Display omitted] DisclosuresArmand:Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS: Research Funding; Sequenta, Inc.: Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Sureda:Seattle Genetics Inc.: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.

Single Cord Blood Combined with HLA-Mismatched Third Party Donor Cells: Comparable Results to Matched Unrelated Donor Transplantation in High-Risk Patients with Hematologic Disorders

Matched unrelated donor (MUD) transplantation is the first alternative in the absence of a matched sibling donor. For patients without a suitable adult donor, we have adopted the dual stem cell transplantation protocol consisting of cord blood (CB) in combination with CD34+ cells from a third party HLA-mismatched donor. We analyzed the outcomes of patients undergoing both procedures in a single center. Starting in 2004, a total of 20 patients with high-risk disease underwent 22 dual transplants and 25 patients underwent myeloablative MUD transplantation. The 30-day cumulative incidence of neutrophil engraftment was similar in both groups (91% and 95%), with a median time to engraftment of 14 and 16 days, respectively. Grade II-IV acute graft-versus-host disease was more frequent in the MUD group (40% versus 5%). Except for a tendency toward a higher incidence of viral hemorrhagic cystitis in the dual transplantation group, posttransplantation infectious events were comparable in the 2 groups. The 3-year cumulative incidence rates of relapse (41% versus 44%) and nonrelapse mortality (30% versus 25%) were similar in the MUD and dual transplantation cohorts. Estimated 3-year overall survival and disease-free survival were 47% and 41%, respectively, with no survival advantage for either group. In our experience, dual transplantation offers survival rates comparable to those from myeloablative MUD transplantation with similar nonrelapse mortality rates.

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

AbstractAbstract 907Most 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. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Partially Matched Related Hematopoietic Stem Cell Transplantation without Ex Vivo T Cell Depletion Compared with Matched Unrelated Transplantation in Adult Patients with Hematologic Malignancies

The optimal alternative donor for adult hematopoietic stem cell transplantation (HSCT) candidates who lack an ideal histocompatible sibling remains controversial. We studied the clinical outcomes of 88 adult patients with hematologic malignancies who received a partially matched related donor (PMRD) transplant (n=36) or a matched unrelated donor (MUD) transplant (n=52) with a uniform myeloablative protocol without ex vivo T cell depletion. Age and other characteristics were comparable in the 2 groups, except that the PMRD group had a higher proportion of bone marrow (BM) grafts. Primary engraftment was achieved in nearly 98% of the whole cohort. The incidences of acute grade III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 15% and 16% in the PMRD group and 16% and 14% in the MUD group. Although treatment-related mortality (TRM) was 42% in the PMRD group and 31% in the MUD group (P=.29), the relapse rate was<11% for the whole cohort. With a median follow-up of 30 months, no statistically significant difference was observed in 3-year overall survival (OS) and event-free survival (EFS) between the PMRD group (45% and 38%) and the MUD group (54% and 50%). These data demonstrate that HSCT performed with PMRD can be an alternative option for treating adult patients with hematologic malignancies.

Features of Herpesviruses (CMV, EBV, HHV6) Infections and Immune Reconstitution after Allogeneic Stem Cell Transplantation (allo-SCT) Using Alternative Donors: Comparison Between Matched Unrelated Donors (MUD) and Cord Blood (CB) as Stem Cell Source.

Features of herpesvirus infections (CMV, EBV, HHV6) and immune reconstitution after CB transplantation (CBT) has been little studied thus far. Here, we report a retrospective comparison between 15 consecutive adult CBT recipients (CBT group) and 40 patients who received allo-SCT using MUD (MUD group).The 2 groups had no significant differences in terms of gender, age, disease features, transplant characteristics (CB: meloablative conditioning 46% vs. MUD: 35%; P=NS). However, in vivo T-cell depletion was more frequently used in the MUD group (62.5% vs 6%, P=0.0002). As expected, median number of CD34+ stem cells infused was significantly lower in the CBT group (0.15 10*6/Kg vs 8.2 10*6/Kg, P<0.0001). Both groups were stringently monitored through CMV, EBV, and HHV6 DNA quantifications in the blood prior to allo-SCT, and then monthly up to 9 months after allo-SCT. An active infection was defined by the presence of at least one positive PCR during the follow-up period (detection limit at 2 Log/mL blood). Of note, both groups experienced similar incidences of acute grade 2–4 GVHD, chronic GVHD and disease relapses. Immune reconstitution (T4, T8, B and NK lymphocytes ) at 3, 6 and 9 months post transplant was investigated and compared between the two groups. In this cohort, 22, 29 and 29 patients experienced at least one positive PCR for CMV, EBV and HHV6 respectively, with the % of positive samples for CMV, EBV and HHV6 being 14%, 16% and 27% respectively. No correlation in term of incidence could be found between the 3 viruses. The incidence of CMV infection did not differ between the two groups, and the univariate analysis could not identify a significant risk factor for CMV infection. However, HHV6 positivity was significantly higher in the CBT group as compared to the MUD group (CBT: 80%; MUD: 42.5%; P <0.0001). HHV6 viral loads were also significantly higher in the CBT group (mean, 3.98±0.86 Log/mL, vs. 3.19±0.82 Log/ mL, P<0.0001). In multivariate analysis, the use of CB cells as stem cell source in combination with a myeloablative conditioning regimen appeared to be independent parameters associated with an increased risk of HHV6 infection (OR=5.4, 95%CI, 1.2- 23.0; P=0.02 and OR=3.5, 95%CI, 1.03–12.05, P= 0.04, respectively). Interestingly, the occurrence of HHV6 infection translated towards delayed engraftment (median time to neutrophils and platelets recovery: 37 vs 16 d.; P=0.03; and 98 vs. 12 d.; P=0.0001). In sharp contrast with HHV6, EBV infections were less frequent in the CBT group as compared to the MUD group (27% vs. 62%; P<0.0001). In multivariate analysis, the use of a MUD for allo-SCT, was the strongest risk factor associated with an increased EBV infection (OR=0.31, 95%CI, 0.07–1.37; P=0.04). At 3, 6 and 9 months post transplant, median B lymphocytes count in the CBT group was significantly higher (P=0.03; P=0.003; P=0.01) whereas median T8 lymphocytes count was significantly lower (P=0.05; P=0.01; P=0.09). We also noticed that median NK lymphocytes count in the CBT group was significantly higher at 3 months (P=0.0006) but this was not linked to HHV6 infections. Overall, these results show that after allo-SCT, the pattern of HHV6 and EBV infections is dependant on the source of stem cells. A specific relationship is suggested between HHV6 PCR positivity and the use of CB cells. In addition to a potential delayed engraftment, the clinical implications of the latter finding need to be refined and prospective screening and antiviral prophylaxis approaches are warranted in the context of CBT.

Outcome of haematopoietic stem cell transplantation in patients transplanted with matched unrelated donors vs allele‐mismatched donors: a single centre study

We studied the importance of human leucocyte antigen (HLA)-A, -B and -DRB1 high-resolution matching on the outcome of haematopoietic stem cell transplantation (HSCT) with matched unrelated donors (MUDs) vs single allele-mismatched unrelated donors. Fifty consecutive HSCT patients receiving an HLA-A, -B or -DR allele-level-mismatched unrelated graft (mmUD) were compared with a matched cohort of 100 patients with an HLA-A, -B and -DR-MUD. Rejection occurred in seven patients (14%) in the mmUD group and in four patients (4%) in the MUD group (P = 0.04), but this was mainly an effect of HLA-C mismatch. The cumulative incidence of acute graft vs host disease (GVHD) grades II-IV were 61%, 26% and 33% in the class I mmUD, class II mmUD and MUD groups, respectively. In multivariate analysis, HLA class I mismatch was associated with an increased risk of acute GVHD grades II-IV (2.09, P = 0.007) and transplant-related mortality (TRM) (1.99, P = 0.06). The 5-year overall survival was 81% in patients with a class II allele-mismatched donor compared with 52% (P = 0.025) and 50% (P = 0.017) in patients with a class I mismatch and a MUD. In multivariate analysis, HLA class II allele mismatch was associated with improved survival (3.38, P = 0.019). Relapse-free survival were 53%, 37% and 42% in patients with a class II mmUD, class I mmUD and a MUD, respectively (not significant). An HLA-C or -DQ mismatch had no significant impact on survival, TRM and relapse. In conclusion, compared with MUD, HLA class I allele mmUD had an increased risk of acute GVHD and TRM.

Slow platelet recovery after PBPC transplantation from unrelated donors

The effects of the composition of PBPC grafts from matched related donors (MRDs) and matched unrelated donors (MUDs) have not been compared. In a single-center study, the compositions of 55 MRD PBPC grafts and 33 MUD grafts were studied for their effect on the rate of engraftment in patients who had evidence of donor cell engraftment on day +28. The MUD grafts came more frequently from young male donors and contained more CD34(+) cells but similar numbers of colony-forming units granulocyte-macrophage (CFU-GM) and burst forming units-erythroid. The recovery of neutrophils to >500/mm(3) was equally fast in both groups, but recovery of platelets to >20,000/mm(3) was significantly delayed in the MUD group (P<0.001). The MUD group also required more transfusions of platelets and red cells. Patients receiving grafts containing low numbers of CFU-GM had markedly delayed platelet recovery. The patients with the slowest engraftment tended to have prolonged transportation times. Storage experiments suggested a major loss of viable CD34(+) cells and CFU-GM when undiluted PBPC products are stored at room temperature. The data suggest that a fraction of the MUD grafts suffer during transportation. In vitro proliferation assays should be part of the validation and auditing of transportation of MUD grafts.

Genomic tissue typing and optimal antithymocyte globuline dose using unrelated donors results in similar survival and relapse as HLA‐identical siblings in haematopoietic stem‐cell transplantation for leukaemia

Sixty-one leukaemia patients treated with haematopoietic stem cell transplantation (HSCT) from a genomic human leucocyte antigen (HLA)-A, -B and -DRbeta1 matched unrelated donor (MUD) were compared with 121 patients with an HLA-identical sibling donor. All patients received conventional conditioning. We selected all patients with unrelated donors who received optimal antithymocyte globuline (ATG) dose, 6 mg/kg. One hundred and seven patients received stem cells from peripheral blood and 75 patients received bone marrow (BM) cells. The incidences of acute graft-versus-host disease (GVHD) grades II-IV were 33.4% and 34.7% in the MUD and sibling group, respectively. After year 2001, the incidence of chronic GVHD was similar in the two groups (27.8% vs. 25.8%). There was no difference in overall survival (60% vs. 60%), transplant-related mortality (18.6% vs. 16.6%) and relapse (23% vs. 26.4%) between the two groups. Haematopoietic stem cell transplantation with unrelated donors results in similar GVHD, relapse and survival as compared to using sibling donors. Reasons for this may be improved tissue-typing techniques and supportive care and optimisation of the ATG dose.

A Comparison of 1 Antigen-Mismatched Related and Matched Unrelated Transplants.

It is unclear how related donor transplants in which the donor-recipient pair is mismatched in one locus (1AgMM) compare to transplants performed using a fully matched unrelated donor (MUD), matching at HLA-A, B, C, DRB1 and DQB1. Here, we performed such a comparison.Methods: We studied 83 consecutive patients (pts) with acute leukemias and myeloproliferative/myelodysplasia syndromes receiving grafts considered to be “1-antigen mismatched related” (1AgMM) and compared their outcomes to that of 134 MUD HSCT performed from 1992 to 2006. Among 83 1AgMM transplants, 40 had prospectively or retrospectively performed high-resolution HLA typing (Hires), of which 6 pts were 8/10 matched, and 43 had only low resolution (Lowres) typing. 8/10 Hires pts were excluded from this analysis. All MUD donor-recipient pairs were typed by Hires. Median age, gender, cytogenetic risk, disease status at transplant and stem cell source were similar. Diagnosis were ALL in 5% of the Hires group, 28% of the Lowres and 0 in the MUD group; AML/MDS cases were 76%, 60% and 87%, respectively; and CML cases were 19%, 12% and 13%, respectively(p< 0.001). Preparative regimens were of reduced intensity for 22% of Hires, 21% of Lowres patients and 40% of MUD patients (p=0.02). High-resolution typing was performed for HLA-A, B, DRB1, DQB1 and DPB1, and SBT/SSOP for HLA-C. Cumulative incidence of NRM, acute and chronic GVHD was estimated accounting for death in the absence of event as a competing risk. The Cox's proportional hazards model was used to compare outcomes beteween groups.Results: With a median follow-up of 15 mo for MUD pts, 27 mo for Hires patients and 33 mo for Lowres pts, OS at 18 mo is 52%, 46% and 22% (p= 0.002 for the comparison of MUD vs Lowres; P=NS for the comparison of MUD vs Hires); NRM is 23%, 26% and 54%(p=0.001 for the comparison of MUD vs Lowres; P=NS for the comparison of MUD vs Hires). Primary graft failure occurred in 1% of MUD, 5% of MOL and 12% of SER (p=0.003). Cumulative incidence of grade II-IV aGVHD is 34% for MUD pts, 48% for Hires and 49% for Lowres(p= 0.07); cGVHD: 34%, 40% and 54%(p=0.01 for the comparison of MUD vs Lowres). We divided the Hires related group according to presence of Class I or Class II mismatches, and compared their outcomes to the MUD group (Table). 23 pts had Class I and 11 pts had Class II mismatches; median follow-up is 26 and 62 mo, respectively. Distribution of gender, diagnosis, cytogenetic risk, dis. status at transplant, ablative/RIC regimens and stem cell source was similar between the 2 groups. Pts with class I mismatches had the worse survival.Conclusion: Cumulative incidence of grade II-IV aGVHD and cGVHD, non-relapse mortality and overall survival of 1AgMM (allele level typing) patients was similar to that observed in a cohort of recipients of molecularly matched, HLA 10/10 MUD transplants.OS at 18 moHR (95%CI) PC. Incid. gd II-IV aGVHDHR (95% CI) PC. Incid. chronic GVHDHR (95% CI) PMUD n=13452%Reference34%Reference34%ReferenceClass I n=2334%1.8 (1–3.1) P=0.0540%1.3 (0.6–2.9) P=0.435%1.1 (0.5–2.5) P=0.7Class II n=1173%0.6 (0.2–1.9) P=0.464%2.8 (1.3–6.3) P=0.0148%2.3 (0.9–5.7) P=0.08C. Incid= cumulative incidence

Graft-versus-leukemia effect in hematopoietic stem cell transplantation for pediatric acute lymphoblastic leukemia: significantly lower relapse rate in unrelated transplantations

To determine graft-versus-leukemia (GVL) effect after hematopoietic stem cell transplantation (HSCT), we studied the outcome of consecutive children with acute lymphoblastic leukemia (ALL) who received fully matched marrow allografts comparing relapse rate post HSCT between matched sibling donor (MSD) and matched unrelated donor (MUD) recipients. Furthermore, we estimated event-free survival (EFS) on the basis of the occurrence of acute graft-versus-host disease (aGVHD). Between 1998 and 2006 we performed 37 fully MSD and 36 fully MUD HSCTs. All patients received identical conditioning regimens with cyclophosphamide/total body irradiation and dual GVHD prophylaxis with cyclosporine (CSA) and methotrexate (MTX). Three-year cumulative incidence of relapse for the MSD and MUD groups were 55.6+/-12.3 and 22.0+/-8.1%, respectively (P=0.03). Three-year EFS according to aGVHD was 32.7+/-12.2% for no aGVHD, 61.2+/-10.0% for grade I-II aGVHD and 66.7+/-11.1% for grade III-IV aGVHD. Three-year EFS and overall survival (OS) were 40.5+/-11.6, 49.1+/-9.5% for the MSD group, and 60.5+/-8.7, 62.3+/-8.4% for the MUD group. In children with ALL receiving dual GVHD prophylaxis, relapse rate is significantly higher among recipients of MSD compared to MUD transplantation, which may in part be attributed to a better GVL effect with the unrelated graft.

Comparative Analysis of Matched Related Donor (MRD) and Matched Unrelated Donor (MUD) Hematopoietic Stem Cell Transplantation in Treatment of Patients with Chronic Myeloid Leukemia.

Allogeneic HSCT offers a long term remission for CML patients. We compared results of MRD and MUD HSCT in 82 pts with CML, treated between 1999 and 2005. In MRD group, 61 pts (median age 39, range 8–54 yrs) were conditioned with BuCy2 regimen. 50 pts were in chronic, 7 in acceleration and 4 in 2nd chronic phase. 38 pts received peripheral blood (PB) and 23 bone marrow (BM) cells. Prophylaxis of graft versus host disease (GVHD) consisted of cyclosporin (CsA) and methotrexate (MTX). 21 pts (median age 31, range 11–51 yrs) transplanted from MUD were conditioned with BuCy2 (n=13) or TBI-based regimen (n=8). All MUD patients received thymoglobulin. This group comprised of 14 pts in chronic and 3 with accelerated, 1 in blastic phase and 3 in 2nd chronic phase. 10 pts received PB and 11 BM cells. CsA+MTX was given as GVHD prophylaxis. MUD group differed from MRD group by following factors: younger age (p=0.020), longer time to HSCT (p<0.001), use of imatinib before HSCT (p=0.039), and higher pre-transplant (Gratwohl) risk score (p<0.001). Results: Hematopoietic recovery occurred in all pts in MRD group, and in 95% in MUD group. Probability of overall survival for all pts was OS=0.72±0.05. 42 pts developed acute GVHD >2 grade (26 in MFD and 16 in MUD) and 27 pts extensive chronic GVHD (23 in MFD and 4 in MUD). Mean survival, estimated 5-yrs OS, probabilities of GVHD incidence, relapse and non-relapse mortality (Kaplan-Meier method) with respect to transplantation method, are shown in Table.TABLE:Results of transplantation in MRD and MUD groupsProbabilityMRD-HSCT (n=61)MUD-HSCT (n=21)PMean survival (years)5.6 (95%CI=4.9–6.3)3.6 (95%CI=2.4–4.7)0.0020Overall survival0.75±0.050.60±0.110.0759Relapse incidence0.12±0.040.25±0.120.1950Non-relapse mortality0.22±0.050.41±0.110.0311Acute GVHD≥20.45±0.060.79±0.100.0175Chronic extensive GVHD0.47±0.07 (n=57)0.35±0.14 (n=15)0.3103Factors predicting negative outcome by multivariate analysis were: acute GVHD≥2 (p=0.0097, HR=1.81, 95%CI=1.12−2.94), and pre-transplant risk score >2 (p=0.0280, HR=1.61, 95%CI=1.06−2.00). MUD-HSCT or use of imatinib before HSCT did not predict for OS. Conclusion: In the era of tyrosine kinase inhibitors, results of MRD− and MUD-HSCT show that HSCT still remains an important therapeutic option for CML patients.

Does Early Myeloid Recovery Predict Superior Survival in Children and Young Adults Undergoing Hematopoietic Stem Cell Transplantation?.

Introduction: Slow rate of myeloid recovery at the end of induction chemotherapy reflected by a low absolute neutrophil count (ANC) is highly predictive of relapse in children with ALL (Laughton et al, 2005). Whether rate of myeloid recovery is predictive of outcome post-hematopoietic stem cell transplantation (HSCT) in children and young adults has not been studied.Objective: To explore the association between early ANC recovery and survival in children and young adults undergoing allogeneic and autologous HSCT for leukemia or lymphoma.Methods: Retrospective chart review was performed for all consecutive patients (age 6 months to 21 years) undergoing first HSCT for hematologic malignancies and lymphomas at Mayo Clinic, Division of Pediatric Hematology/Oncology from 1995 to 2004. Day 15 and day 28 ANC were calculated for all patients. The primary end point was 1-year relapse free (RFS) and overall survival (OS). To explore the association between ANC and primary outcome, patients were stratified in 2 groups: ≥ or < than median ANC and Kaplan Meier survival curves were generated for both the groups and compared with the log-rank test. Matched related donor (MRD), matched unrelated donor (MUD) and haploidentical (as one group) and autologous transplantations were analyzed separately.Results: There were a total of 50 patients. 28 received MRD, 2 MUD, 10 haploidentical and 10 autologous. The underlying malignancies were (AML n =25, Biphenotypic Leukemia n=1, ALL n =7, NHL n=3, HD n=7, JMML n=5, CML n=2, CLL n=1). No patient was lost to follow up during that time and data was available for all except (day 28 ANC) for one patient. The 1-year RFS and OS rate was the same; 81% for the MRD, 50% for MUD and haploidentical and 70% for autologous transplant populations, respectively. In patients receiving MRD transplants, higher ANC at either day 15 or day 28 post transplantation was associated with better, albeit statistically non-significant, RFS/OS rates at 1 year (86% for ≥ median (0.68) vs. 76% for < median p=0.44 and 92% for ≥ median (2.2) vs. 72% for < median p= 0.18 respectively). Opposite results were observed for MUD and Haploidentical transplantation group (33% for ANC ≥ median (0.47) at day 15 vs. 66% for < median p=0.28, 43% for ANC ≥ median (1.9) at day 28 vs. 60% for < median p=0.48). For autologous transplant group, higher ANC at day 15 was associated with better, albeit statistically non-significant, RFS/OS rates at 1 year (80% for ANC ≥ median (0.42) vs. 60% for < median p=0.60) while opposite results were observed on day 28 (60% for ANC ≥ median (0.46) vs. 75% for < median p=0.54).Conclusions: Our data generated conflicting findings of the association between ANC and RFS/OS in different patient populations undergoing HSCT. However, our results are limited by the small sample size. Further collaborative studies are needed to explore this association.

Does Early Lymphocyte Recovery Predict Superior Survival in Children and Young Adults Undergoing Hematopoietic Stem Cell Transplantation?.

Introduction: Early lymphocyte recovery predicts outcome in adults undergoing high dose chemotherapy followed by autologous stem cell transplantation for a variety of malignancies (Porrata et al; 2001, 2002, 2005). Whether rate of lymphoid recovery is predictive of outcome post-hematopoietic stem cell transplantation (HSCT) in children and young adults has not been studied.Objective: To explore the association between early ALC recovery and survival in children and young adults undergoing allogeneic and autologous (HSCT) for leukemia or lymphoma.Methods: Retrospective chart review was performed for all consecutive patients (age 6 months to 21 years) undergoing first HSCT for hematologic malignancies and lymphomas at Mayo Clinic, Division of Pediatric Hematology/Oncology from 1995 to 2004. Day 15 and day 28 ALC were calculated for all patients. The primary end point was 1-year relapse free (RFS) and overall survival (OS). To explore the association between ALC and primary outcome, patients were stratified in 2 groups: ≥ or < than median ALC and Kaplan Meier survival curves were generated for both the groups and compared with the log-rank test. Matched related donor (MRD), matched unrelated donor (MUD) and haploidentical (as one group) and autologous transplantations were analyzed separately.Results: There were a total of 50 patients. 28 received MRD, 2 MUD, 10 haploidentical and 10 autologous transplant. The underlying malignancies were AML n =25, Biphenotypic Leukemia n=1, ALL n =7, NHL n=3, HD n=7, JMML n=5, CML n=2, CLL n=1). No patient was lost to follow up during that time and data was available for all except (day 28 ALC) for one patient. The 1-year RFS and OS rate was the same; 81% for the MRD, 50% for MUD and haploidentical and 70% for autologous transplant populations, respectively. In patients receiving MRD transplants, higher ALC at either day 15 or day 28 post transplantation was associated with better, albeit statistically non-significant, RFS/OS rates at 1 year (85% for ≥ median (0.23) vs. 78% for < median p=0.69 and 86% for ≥ median (0.47) vs. 77% for < median p= 0.59 respectively). Opposite results were observed for MUD and Haploidentical transplantation group (33% for ALC ≥ median (0.05) at day 15 vs. 67% for < median p=0.2, 33% for ALC ≥ median (0.35) at day 28 vs. 66% for < median p=0.28) and for autologous transplantations (67% for ALC ≥ median (0.23) at day 15 vs. 75% for < median p=0.68, 40% for ALC ≥ median (0.48) at day 28 vs. 100% for < median p=0.07).Conclusions: Our data generated conflicting findings of the association between ALC and RFS/OS in different patient populations undergoing HSCT. However, our results are limited by the small sample size. Further collaborative studies are needed to explore this association.