Use Of PBSC Research Articles

Prevention of CMV/EBV Reactivation By Double-Specific T Cells in Patients after Allogeneic Stem Cell Transplantation: Results from the Randomized Phase I/IIa Multivir-01 Study

Allogeneic stem cell transplantation (aSCT) is used to cure hematologic malignancies or deficiencies of the hematopoietic system. It is associated with severe immunodeficiency of the host early after transplant and therefore early reactivation of latent herpesviruses such as CMV and EBV within the first 100 days are frequent. Small studies and case series indicated that application of herpes virus specific T cells can control and prevent disease in this patient population. Study Design: A randomized, controlled, phase I/IIa multi-center study was conducted in 5 centers in Germany between 2013 and 2018 (ClinicalTrials.gov Identifier: NCT02227641). The study aimed at prevention or pre-emptive treatment of reactivation of CMV and EBV post aSCT. Major inclusion criteria were male or female HLA matched (10/10) unrelated or related donor seropositive for CMV and EBV, patient age between 18 and 75, the use of PBSC as stem cell source and the presence of on of the following HLA alleles: A*01:01, A*02:01, B07:02, B*08:01, B*35:01, C*07:02. CMV/EBV specific T cells were generated from a fraction of the allogeneic stem cell graft by stimulation with peptide pools for both viruses developed at the University Hospital Erlangen. Three doses of 5x10E4 CD3+ T cells per kilogram body weight were applied with an interval of at least 30 days without dose escalation starting earliest at day 30 after aSCT. Observation period was 204 days after aSCT. Primary endpoint of the study was toxicity of the T-cell-product assessed as acute transfusion reaction and acute GvHD due to the infusion of activated T cells. Results: 33 patients were screened and 29 patients were randomized. 16 patients were randomized into the treatment group of who 3 patients crossed over to the control arm due to failure of manufacturing the product or due to not meeting release criteria. Four patients were excluded from the study before receiving the first dose due to transplant related toxicity or withdrawal of consent. In total 9 patients were treated with 25 doses of the T cell product (dose range 2.1-4.1x10E4/kg CD3+ T cells). The earliest infusion was on day 30 (range: 30-69) post aSCT. There was no statistical difference between the groups regarding disease, patient age, donor type, performance status and comorbidities. The median follow up for both groups was 930 days. None of the patients treated experienced any acute transfusion reaction. Two patients developed acute GvHD after the second infusion and did not receive the third dose. Overall there was no statistical significant difference regarding survival (A) (treatment: 55.9% vs. control 69.2%, p=0.44), transplant related mortality (B) (22.2% vs. 7.1%, p=0.28), relapse (C) (11.1% vs. 14.3%) and acute GvHD (D,E) (33.3% vs. 46.2%, p=0.44). Number of AE per patient (27.1±24.6 vs. 24.4±11.2, p=0.60) and severity of AE (1.60±0.39 vs. 1.64±0.24) were similar in both groups. The incidence of reactivation of CMV (44.4% vs. 64.3%, p=0.16) and EBV (77.8% vs. 44.4%, p=0.12) was not statistically different and not associated with the treatment as several reactivations of occurred before application of the first dose. Within the treatment group we observed in several cases substantial expansion of CMV and EBV specific T cells in the peripheral blood which could not attributed to the presence viral antigens in case of reactivation. Conclusion: The study met its primary endpoint as there was no toxicity of the T-cell product observed. The cumulative incidence of acute GvHD as the primary endpoint was not statistically different in both groups and there was no acute toxicity related to the product. The study suffered from slow recruitment due to the market approval of Letermovir and low patient numbers did not allow for conclusive analysis of secondary endpoints such as the use of antiviral therapy.

Impact of Covid 19 pandemic on hematopoietic stem cell transplantation activities: Report from a single center

The current COVID-19 pandemic has placed unprecedented stress on the healthcare system, including HSCT. Several international organizations have created guidelines for managing different aspects of HSCT in the context of the pandemic. Comparing 2019 and 2020, our transplant center performed the same number of transplants. In both periods, transplants were mainly for patients with acute leukemia; thus, the urgency criteria was respected in light of pandemic restraints. Transplants by sibling donors and cord blood units remained the same, while transplants by unrelated donors were increased, in particular from European registries, and transplants by haploidentical donors were decreased. This change was made in light of the necessity of cryopreserving all apheresis products. We decided against cryopreserving bone marrow products due to the greater risk of drastic reduction in CD34 + cell count during the process. For urgent cases with only a haploidentical donor available, we opted for the use of PBSC following stimulation with G-CSF. GvHD prophylaxis was performed with PTCY on days + 3 + 5, cyclosporine with tapering from day + 100, and mycophenolic acid until day + 90 post-HSCT. Post-transplant outcomes such as graft failure, sepsis, and GVHD were not affected by the changes implemented. As a result of logistic difficulties, we halted our Car-T program from the start of the lockdown in March 2020 until September 2020. In accord with international guidelines, we were able to continue our HSCT program in the order to ensure a lifesaving treatment for patients with hematologic diseases for whom this procedure cannot be postponed.

Favorable outcomes of allogeneic hematopoietic stem cell transplantation with fludarabine-bendamustine conditioning and posttransplantation cyclophosphamide in classical Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with relapsed and refractory classic Hodgkin lymphoma (rrHL). However, the optimal conditioning regimen and GVHD prophylaxis for rrHL remain undetermined. The aim of this study was to investigate outcomes of allo-HSCT with a fludarabine plus bendamustine (FluBe) conditioning regimen and GVHD prophylaxis with posttransplantation cyclophosphamide (PTCY) in patients with rrHL. Allo-HSCT results in 58 adult patients with rrHL were analyzed retrospectively. Three-year overall survival and event-free survival were 81% (95% CI 65-91) and 55% (95% CI 38-72), respectively. The cumulative incidence of relapse (CIR) at 3years was 33% (95% CI 13-51). The cumulative incidence of aGVHD grade II-IV and severe aGVHD grade III-IV was 36% (95% CI 22-48) and 22% (95% CI 9-33), respectively. The cumulative incidence of cGVHD was 32% (95% CI 17-45), including moderate or severe cGVHD in 17% (95% CI 4-28). Patients who developed aGVHD after allo-HSCT had significantly lower CIR (24% vs 49%, p = 0.004). The use of PBSC as a graft source also significantly reduced CIR (4% vs 61%, p = 0.002). FluBe-PTCY allo-HSCT facilitates favorable outcomes, low toxicity, and mortality in rrHL.

Risk Factors for Adverse Outcomes Following Haploidentical Hematopoietic Cell Transplantation with Posttransplant Cyclophosphamide: A Two-Center Analysis

IntroductionAllogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for several malignant hematologic diseases. As only 30% of patients will have a matched related donor, alternative donors play a significant role in HCT. Luznik et al pioneered the use of posttransplant cyclophosphamide (PTCy) based GVHD prophylaxis in haploidentical transplantation (haplo-HCT), which greatly expanded the pool of donors and nearly revolutionized the field. Despite the increasing use of haplo-HCT with PTCy, some questions remain, namely the selection of the best donor, graft source and conditioning regimen, and risk factors for adverse outcomes.MethodsRetrospective study conducted at two Brazilian centers. All patients with hematologic malignancies who underwent first HCT between 2010 and 2021, haploidentical with posttransplant cyclophosphamide, were included. The objective was to identify risk factors for adverse outcomes following haploidentical HCT with PTCy. Independent variables are detailed in table 1. Acute GVHD was graded according to the MAGIC criteria and chronic GVHD was diagnosed according to the NIH consensus criteria. Survival and cumulative incidence curves were built with the Kaplan-Meier and Gray methods, and compared with the logrank and Gray tests, respectively. Multivariate analyses were carried out with Cox models. GVHD, as an independent variable, was included as a time-dependent covariate.ResultsA total of 103 patients were included (table 1). In brief, median age was 39 y/o and most patients were male (58%); 71 patients had low or intermediate disease risk index, while 29 had high or very high-risk disease. Bone marrow was the preferred stem-cell (72%, followed by peripheral blood stem-cells - 28%) and reduced-intensity, the most frequent conditioning regimen (43%). Median follow-up for the whole cohort was 2.6 years.Overall survival at 2 years was 51.7% (95CI 42.4-63.0%, figure 1). Multivariable analyses are in table 2. Risk factors for death were age at transplant (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.002), high or very high disease risk index (HR = 2.73; 95CI 1.52-4.90; p = 0.0008), and compared with low or intermediate, and mother as the donor (HR = 3.50; 95CI 1.44-8.47; p = 0.006).Progression-free survival at 2 years was 45.8% (95CI 36.6-57.2%). In multivariate analysis (table 2), progression-free survival was significantly poorer for older patients (HR = 1.02; 95CI 1.01-1.04; p = 0.009), high or very high disease risk index (HR = 2.29; 95CI 1.30-4.04; p = 0.004), compared with low or intermediate, and mother as a donor (HR = 3.15; 95CI 1.37-7.22; p = 0.007; figure 2). Two-year relapse rate was 22.2% (95CI 15.2-32.5%). Risk factors for relapse (table 2) were high or very high disease risk index (HR = 3.55; 95CI 1.44-8.74; p = 0.006), compared with low or intermediate, and mother as the donor (HR = 2.85; 95CI 1.12-7.25; p = 0.007). Two-year non-relapse mortality was 32.0% (23.9-42.9%). The only risk factor we found was age at transplantation (HR = 1.03 for each year; 95CI 1.01-1.05; p = 0.02; table 2). We found no effect of GVHD, acute or chronic, on relapse, nor on non-relapse mortality.Rates of grades II-IV and III-IV acute GVHD and 2y-chronic GVHD were 30.4% (95CI 22.7-40.8%), 6.9% (95CI 3.4-14.1%) and 19.8% (95CI 13.2-29.7%), respectively. The only risk factor (table 2) identified for grades II-IV acute GVHD was tacrolimus (HR = 0.36; 95CI 0.14-0.95; p = 0.04) compared with cyclosporine. We have not carried out multivariate analysis for grades III-IV acute GVHD due to the low number of events (only 7). In multivariable analysis (table 2), peripheral blood graft was a risk factor for chronic GVHD (HR = 3.72; 95CI 1.53-9.01; p = 0.004; figure 3), compared with bone marrow, while tacrolimus was protective (HR = 0.27; 95CI 0.11-0.68; p = 0.005), compared with cyclosporine.ConclusionOur results show that mother as the donor was an important risk factor for poorer OS, PFS and relapse, and mothers might not the best choice of donor. Tacrolimus was protective for both grades II-IV aGVHD and for cGVHD, suggesting that tacrolimus may be more effective than cyclosporine in preventing GVHD. PBSC was a risk factor for cGVHD without any impact on relapse, and this result does not support the systematic use of PBSC in detriment of BM. As expected, age at transplant negatively impacted OS, PFS and NRM as well as high/very high DRI led to poorer OS, PFS and relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of mother donor, peripheral blood stem cells and measurable residual disease on outcomes after haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide in children with acute leukaemia.

Haploidentical hematopoietic-cell transplantation using post-transplant cyclophosphamide(Haplo-PTCy) is a feasible procedure in children with haematologic malignancies. However, data of a large series of children with acute leukaemia(AL) in this setting is missing. We analysed 144 AL Haplo-PTCy paediatric recipients; median age was 10 years. Patients had acute lymphoblastic(ALL; n = 86) or myeloblastic leukaemia(AML; n = 58) and were transplanted in remission(CR1: n = 40; CR2: n = 57; CR3+: n = 27) or relapse (n = 20). Bone marrow was the graft source in 57%; donors were father (54%), mother (35%), or sibling (11%). Myeloablative conditioning was used in 87%. Median follow-up was 31 months. At day +100, cumulative incidence (CI) of neutrophil recovery and acute GVHD (II-IV) were 94% and 40%, respectively. At 2-years, CI of chronic GVHD and relapse, were 31%, 40%, and estimated 2-year overall survival (OS), leukaemia-free survival (LFS) and graft-versus-host-relapse-free survival (GRFS) were 52%, 44% and 34% respectively. For patients transplanted in remission, positive measurable residual disease (MRD) prior to transplant was associated with decreased LFS (p = 0.05) and GRFS (p = 0.003) and increased risk of relapse (p = 0.02). Mother donor was associated with increased risk of chronic GVHD (p = 0.001), decreased OS (p = 0.03) and GRFS (p = 0.004). Use of PBSC was associated with increased risk of chronic GVHD (p = 0.04). In conclusion, achieving MRD negativity pre-transplant, avoiding use of mother donors and PBSC as graft source may improve outcomes of Haplo-PTCy in children with AL.

Post-Transplant Cyclophosphamide (PT-Cy) for Graft Versus Host Disease (GVHD) Prophylaxis in Allogeneic Transplantation from HLA Identical Sibling and Matched Unrelated Donor for Patients with Acute Leukemia, on Behalf of ALWP-EBMT

Background: Post-transplant Cyclophosphamide (PT-Cy) is being used successfully in the setting of unmanipulated haploidentical transplant as graft versus host disease (GVHD) prophylaxis. Experience with the application of PT-Cy for prevention of GVHD post allogeneic stem cell transplantation (HSCT) from matched sibling donors (MSD) or unrelated donor (UD) is rather limited and it involves mainly single center experience and small numbers of patients.Methods: Study aim was to evaluate the yield of PT-Cy as GVHD prophylaxis post HSCT from MSD and UD transplants for acute leukemia. We analyzed 423 patients (pts) with acute leukemia who received PT-CY alone or in combination to other drugs as GVHD prophylaxis and reported to the ALWP of the EBMT. 78 pts received PT-Cy alone (group 1); 204 received PT-CY in combination with one immunosuppressive (IS) drug -cyclosporine A (CSA) or and methotrexate (MTX) or mycophenolate mofetil (MMF)(group 2), while 141 pts received PT-Cy in combination with 2 IS drugs- CSA+MTX or CSA+MMF (group 3). Transplants were performed from 2007-2015 and median follow up is 16 months.Results: There were some differences among groups: pts in group 1 were younger (median age 37 years, p<0.001) were transplanted in more recent year (2014, p<0.001), with a MSD (80%, p<0.001), and CMV positive donor (73%, p=0.008), received more frequently a reduced intensity conditioning (RIC) (56%, p<0.001) and bone marrow (BM) as source of stem cells (74%, p<0.001), with no ATG (100%, p<0.001). Probability of OS at 2 year was 50%, 52.2% and 62.4%, for the 3 groups, respectively, p=0.06.Overall the cumulative incidence (CI) of grade II-IV acute GVHD was 27.9%, and the CI of chronic GVHD was 33.4%, and 16.5% the CI of extensive cGVHD. The CI of relapse at 2 years was 33.5% and non-relapse mortality (NRM) 18.5%, disease recurrence and GVHD were the most common causes of death in the whole cohort.At 2 years the probability of leukemia free survival (LFS) and overall survival (OS) was 48% and 55%.In multivariate analysis, the addition of IS to the PT-CY did not impact the risk of acute GVHD. Diagnosis of ALL (HR 0.57, p<0.001), unrelated donor (HR 1.65, p=0.02), RIC regimen (HR 1.72, p=0.01) and donor CMV positive (HR 1.77, p=0.01) were associated with the risk of grade II-IV acute GVHD. The use of PBSC (HR 2.41, p=0.01) and the absence of ATG (HR 1.69, p=0.03) were independently associated with an higher risk of chronic GVHD (p=0.005). In comparison to PT-Cy alone the addition of 1 or 2 IS drugs as GVHD prophylaxis were associated with reduced risk of extensive chronic GVHD (PT Cy+ 1 drug, HR 0.25, p=0.02, PT Cy+ 2 drugs, HR 0.77, p=0.01) as well the use of BM (HR 0.21, p<0.001) and the use of ATG (HR 0.22, p<0.001). Notably, the addition of 1 or 2 IS drugs to PT-CY did not impact the risk of relapse. Advance disease status (HR 2.42, p<0.001), was the only factor associated with increased risk of relapse. As for NRM addition of CSA+MTX or CSA+MMF to the PT-Cy (HR 0.35, p=0.04), diagnosis of AML (HR 0.35, p=0.001), and disease status at transplant (HR 2.94, p<0.001), and patients CMV serology (HR 2.04, p=0.04), influenced the NRM.Factors associated with increased OS were the use of PT-Cy in combination with CSA+MTX or CSA+MMF (HR 0.49, p=0.02), diagnosis of AML (HR 0.59, p=0.001), and disease status at HSCT ((CR1 vs CR2 HR 0.58, p=0.02), (CR1 vs advanced disease (HR 0.40, p<0.001)).Conclusions: PT-CY is effective GVHD prophylaxis in MSD and MUD HSCT for acute leukemia. The addition of IS drugs CSA+MTX or CSA+MMF to the PT-Cy shapes its effect and further decrease the risk of severe chronic GVHD, reducing transplant related mortality and improving overall survival. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

Incidence, Risk Factors and Complications of Ocular Graft-Versus-Host Disease Following Hematopoietic Stem Cell Transplantation

The purpose of this research was to evaluate the incidence, risk factors, and complications of ocular graft-versus-host disease (GVHD) in a large single-center study. Retrospective observational case series. This study included 283 patients who underwent hematopoietic stem cell transplantation (HSCT) between 2005 and 2020. Ocular GVHD was diagnosed according to International Chronic Ocular GVHD Consensus Group criteria. Potential risk factors for ocular GVHD were evaluated using the Cox proportional hazards model. The cumulative incidence of ocular GVHD was 19.7% at 1 year, 29.3% at 2 years, 40.7% at 3 years, 47.2% at 4 years, and 49.7% at 5 years. Ocular GVHD was significantly associated with recipient age (hazard ratio [HR]: 1.228; 95% confidence interval [CI]: 1.033-1.459; P=.020); female sex (HR: 1.797; 95% CI: 1.195-2.703; P=.005); peripheral blood stem cell use (PBSC) (HR: 2.079; 95% CI: 1.268-3.411; P=.004); and previous acute GVHD (HR: 1.276; 95% CI: 1.073-1.518; P=.006). Ocular complications after HSCT included cataract, corneal ulcer, corneal perforation, lacrimal obstruction, herpetic keratitis, and cytomegalovirus retinitis. Half of patients developed ocular GVHD in the 5 years following HSCT. Older age, female sex, use of PBSC, and acute GVHD disease were significant predictors of ocular GVHD. Hematologists and ophthalmologists should be aware of its vision threating complications.

Fevers post infusion of T-cell replete hla mismatched haploidentical hematopoietic stem cells with post-transplant cyclophosphamide: risk factors and impact on transplant outcomes.

Fever is a common early complication after infusion of stem cells in patients undergoing T-replete HLA haploidentical transplantation using post-transplant cyclophosphamide (PTCY). We analyzed the records of 172 haploidentical transplant patients to identify risk factors and to assess the impact of such fevers on transplant morbidity and mortality. One hundred and seventy-two patients received haploidential hematopoietic stem cell transplantation (haplo-HSCT) using PBSC (n = 103) or marrow (n = 69) grafts. One hundred and forty patients (81%) experienced fever (T ≥ 100.5 °F or >38 °C) with median onset on d + 2. Compared to patients who did not develop fevers, patients with fevers received higher median CD34+ cell dose (5.00 vs. 3.08 × 106/kg, p < 0.001), CD3+ cell dose (12.8 vs. 4.5 × 107/kg), were more likely to have received a myeloablative regimen (50% vs. 9%, p < 0.001), and PBSC source (71% vs. 9%, p < 0.001). Cox model showed that fever had no impact on TRM, GVHD, OS, and DFS. In the logistic regression to identify correlation with fevers, higher degree of HLA mismatches and use of PBSC were all predictors of developing fever. Fevers between infusion of the T-Cell replete graft and administration of PTCY are very common in Haplo-HSCT. This complication is transient and had no impact on post-transplant morbidity and mortality.

Therapeutic Cyclosporine Exposure Measured As Area Under the Curve (AUC) Significantly Influences the Outcome after Allogeneic Hematopoetic Stem Cell Transplant (alloHSCT)

Introduction: Prevention of Graft versus host disease (GVHD) forms the mainstay of obstacle in the successful outcome of alloHSCT. Various strategies are employed but combination of calcineurin inhibitors with methotrexate or mycophenolate is the commonest preventative measure used. Cyclosporine is dosed according to trough (C0) levels and the optimum level is defined as between 200 and 300 ng/ml. Daily doses are adjusted to achieve the therapeutic levels. As there can be fluctuations in the daily levels, it was postulated that area under the curve (AUC) extrapolated from daily levels may be more useful to define the optimum cyclosporine exposure for prevention of GVHD. Hence this retrospective analysis was carried out to evaluate if cyclosporine AUC for first 14 days has correlation with the incidence of GVHD.Methods: 549 patients who received allograft and had cyclosporine C0 levels available for first 14 days were included in the analysis. The patient population included 353 males (64.3%) and 196 females (35.7%) with a median age of 44 yr. (range: 16-71). Underlying diagnosis included Ac. Leukaemia (n=319, 58.1%), Chr. Leukaemia (n=42, 7.7%), lymphoma (n=119, 21.7%), myeloma (n=57, 10.4%) or other (n=12, 2.2%).Donor was matched unrelated (n=330, 60.1%), sibling (n=204, 37.2%) or cord (n=15, 2.7%). Stem cell source was PBSC (n=454, 82.7%), BM (n=78, 14.2%), both (n=2, 0.4%) or cord blood (n=15, 2.7%). 415 patients had RIC (75.6%) and 134 had full intensity SCT (24.4%). Alemtuzumab or ATG was used in conditioning in 311 cases (56.6%). The target Cyclosporine AUC with a daily level of 200 was predicted as 2600, 2470 for cyclosporine level of 190 and 2730 for levels of 210.Results: The median AUC for the entire cohort was 3338 (range: 370-6390). Only 56 cases (10.2%) had AUC below 2600. Incidence of AGVHD was significantly higher with use of PBSC (53.7% vs. 21.7%, p<0.001), NHL (66.3% vs. 44.8%, p=0.002) and Alemtuzumab/ATG use (55.9% vs. 40.8%, p<0.001), non-TBI conditioning (57.3% vs. 38.7%, p<0.001) but there was no difference with gender, gender mis-match, intensity of conditioning, CMV match or underlying malignancy. Risk of GVHD was not related to cyclosporine AUC below 2600 (41.2% vs. 50.3%, p=0.2), below 2470 (38.6% vs. 50.3%, p=0.14) or below 2730 (49.4% vs. 49.4%, p=0.99). Similarly incidence of CGVHD was higher with use of PBSC (66.7% vs. 36.6%, p<0.001), Alemtuzumab/ATG (66.2% vs. 53.8%, p=0.003), RIC (64.1% vs. 50.7%, p=0.013) and prior AGVHD (100% vs. 22%, p<0.0001). There was no effect of gender, gender mis-match, underlying malignancy and cyclosporine AUC. AUC did not influence the incidence of AGVHD or CGVHD when the analysis was done separately for full and reduced intensity transplants. The median OS from HSCT was 4.9 yr. (0.01-23.8 yr.). Even though incidence of AGVHD or CGVHD was not influenced by cyclosporine AUC, OS was significantly lower for AUC below 2470 (2.2 vs. 4.9 yr., p=0.0002), below 2600 (2.5 vs. 5.0 yr., p=0.0001) and below 2730 (2.1 vs. 4.6 yr., p<0.0001). By multi-variate analysis, Alemtuzumab/ATG (RR: 1.55, 95% CI: 1.04-2.3, p=0.031) and AUC below 2600 (RR: 1.9, 95% CI: 1.3-2.8, p<0.001) were independently associated with inferior OS. Patients with both the factors had lowest OS (none: 7.5 yr.; one: 5yr., both: 1.1 yr.; p<0.0001).Conclusion: This retrospective analysis had high proportion of cases receiving Alemtuzumab/ATG based GVHD prophylaxis and shows that even though there is no effect of cyclosporine AUC on the incidence of either AGVHD or CGVHD, patients receiving Alemtuzumab/ATG with sub-therapeutic cyclosporine AUC have poor OS. This raises the possibility that in this group of patients it is imperative to have target cyclosporine levels in first 14 days. The duration of target cyclosporine levels before tapering the doses needs to be established to improve OS without increasing the toxicity. DisclosuresSomervaille:Imago Biosciences: Consultancy; Novartis: Consultancy, Honoraria. Bloor:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria; GSK: Consultancy, Speakers Bureau.

Higher Incidence and Risk of Developing Second Solid Cancers (SSC) after Haematopoetic Stem Cell Transplantation (HSCT) As Compared to General Population

Introduction: As the number of long-term survivors following HSCT is increasing, the long-term risks and associated morbidity has become important component of survivorship program. The known risk factors for developing cancer include use of chemotherapy agents, radiation exposure, immune dysfunction, previous malignancy in addition to other factors and as HSCT process involves all these factors, this single centre retrospective analysis was undertaken to evaluate the risk of developing SSC in the patients receiving transplant.Methods: From February 1982 to February 2016, 2231 patients received 2495 transplants (median age: 46yr., range: 14-76 yr.; M: 1586, F: 909) for haematological malignancies (Leuk: 744, lymphoma:767, myeloma:848, solid tumours/other:136). Donor was allogeneic (n=744) or autologous (n=1751) and conditioning was with (n=614) or without TBI (n=1881). Donor was sibling (n=375), matched unrelated (n=355), haploidentical relative (n=3) or umbilical cord blood (n=11). Source of stem cell was marrow (n=367), PBSC (n=2086), both (n=31) or cord blood (n=11). GVH prophylaxis included Campath or ATG in 369 cases. Of all the patients 1985 received single transplant, 231 had two, 13 had 3 and 2 had 4 HSCT procedures. Data was analysed as of 15/04/2016 using competing risk model with death as the competing event. Comparison of incidence to general population was performed by computing standardized incidence rates (SIR). Patients with second haematological malignancy were not included in this analysis.Results: Median follow-up was 5.3 years (range: 0-32 years). Patient follow-up was more than 10 years in 467 cases (19%), between 5 to 10 years in 430 (17%), 2 to 5 years in 607 (24%) and less than 1 year in 997 cases (40%). 36% patients were followed-up for more than 5 years. Second solid cancers developed in 116 patients with the incidence of 1% at 5yr (95% CI: 0.5-2.6), 3% at 10 yr (95% CI: 1.6-5.3), 6% at 15yr (95%CI: 3.6-8.8) and 10% (95% CI: 5.9-15.5) at 20 years. Median time to develop SSC from date of HSCT was 11 yr (range: 0.4-28.1 yr). Primary site for SSC included skin (n=37), breast (n=22), GI (n=15), GU (n=16), H&N (n=10), lung (n=6), CNS (n=4), Endocrine (n=4) & HPB (n=2). There was no difference with type of transplant i.e. auto or allograft. Autograft and allograft groups were analysed separately. In univariate analysis, allograft group showed higher cumulative incidence of SSC with use of PBSC (p<0.0001), campath/ATG (p=0.0002), donor other than sibling (P=0.0004), RIC (p<0.0001), non-TBI conditioning (p=0.007), older age at transplant (0.008), development of agvhd or cgvhd (p=0.023) and transplant year after 2000 (p=0.01). In multivariate analysis age above 50 (RR: 1.8, 95%CI: 1.2-1.8, p=0.046) and RIC (RR: 4.4, 95% CI: 1.2-8.3, p=0.03) were independently associated with higher risk of SSC. In autograft group, there were no independent risk factors in univariate or multivariate analysis. As compared to general population incidence was higher for all cancers (SIR=7.4) and also cancers at every primary site. Risk was highest for breast (SIR=14.3), Head/neck (SIR=25.6), brain (SIR=17.4) and colon (SIR=6.2). Overall survival is significantly shorter in patients who develop SSC (median: 12 yr vs. not reached, p<0.0001). The median time to develop SSC from the date of HSCT has significantly shortened over last three decades (years 1982-1990: 21yr, 1991-2000: 11.1 yr, 2001-2010: 6.34 yr, 2011-2016: 2.2 yr; p=0.0001)Conclusion: This single centre analysis confirms that the risk of developing SSC increases with advancing age, use of RIC allograft, longer follow-up and leads to inferior survival. Since the year 2000, SSC are developing early after transplant and it needs to be evaluated if this is a trend seen at other centers and if so, is it related to increasing use of RIC, increasing number of elderly patients, severity of immune-suppression or higher incidence of GVHD. DisclosuresSomervaille:Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Bloor:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Incidence, Risk Factors and Outcome of Late Onset Noninfectious Pulmonary Complications after Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective Cohort Study

Introduction: Late onset noninfectious pulmonary complications (LONIPCs) occurring beyond the third month following allogeneic hematopoietic stem cell transplantation (HSCT) are various and are associated with a poor outcome. Bronchiolitis obliterans (BO) is the most frequent LONIPC. Available epidemiological data are conflicting and exclusively come from retrospective studies.Methods: We conducted a prospective observational cohort study where all consecutive patients who were scheduled to receive an allogeneic HSCT between January, 31, 2006 and December, 31, 2008 at the university-teaching Saint Louis Hospital (Paris, France) were prospectively screened for inclusion in the study. Those allogeneic HSCT recipients surviving at day 100 were included in the cohort. They were followed-up for at least three years after HSCT. Clinical outcomes were the 3-year incidence and mortality of LONIPC, and the identification of early risk factors for LONIPC and specifically BO. This study is registered with ClinicalTrials.gov, number NCT 01219972.Results: 198 patients were included after a median of 101 [IQR: 99-106] days following HSCT, from a total of 243 screened patients. The actual median follow up of the 198 included patients was 72.3 months [IQR: 15.2-88.5]. 68 patients died within the first 36 months resulting in a 3-year overall survival after inclusion of 65.4% (95%CI: 59.1-72.4%). Fifty five episodes of LONIPC were diagnosed in 43 patients. These 55 LONIPC were diagnosed as BO (n=22), interstitial lung disease (n=12), and others. Ten patients had more than one LONIPC during the follow-up. At 36 months after inclusion, the estimated cumulative incidence of LONIPC was 19.8% (95%CI: 14.2-25.3%). The 36 months cumulative incidence of BOS was 10.7%, (95%CI: 6.3-15.1%). 18 patients with a LONIPC died during the follow up with an estimated median survival of 78.5 months (95%CI: 20.0-not reached) after the diagnosis of LONIPC. The occurrence of LONIPC was associated with an increased hazard of death (HR=2.18, 95%CI= 1.14; 4.15; p= 0.0181). Based on a multivariable Cox model, a chest irradiation prior to HSCT, a history of pneumonia within the 100 days post HSCT and a low FEF 25-75 at day 100 were associated with the development of LONIPC. The use of PBSC was predictive for BOS based on a multivariable Cox model both after multiple imputation and on the complete cases whereas both a history of post transplantation pneumonia and bronchial abnormalities on CT scan at day 100 were also identified as predictive factors after multiple imputation and a 10% FEV1 decline from baseline to day 100 was a predictive factor for BOS on the complete cases.Conclusion: our data give clues to identify high-risk patients for developing LONIPC/BO. These patients should be targeted for close monitoring, and so offer earlier treatment of LONIPC or prophylactic treatment to improve the outcome.Funding: The study was supported by an institutional grant from the French Ministry of Health (CRC 04118). DisclosuresPeffault De La Tour:PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding.

Impact of Cytopenia Following Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Using Post-Transplant Cyclophoshamide

IntroductionAllogeneic transplantation from a haploidentical donor (HaploSCT) is an alternative strategy in the treatment of hematologic malignancies in absence of HLA-identical donor. Recent studies reported similar outcome after HaploSCT compared to HLA-identical transplantation in different settings (Bashey, JCO 2013; Wang, Blood 2015; Gosh, JCO 2016). Although survivals seemed promising after HaploSCT, hematopoietic recovery following such a mismatched transplantation could represent a limitation. Thus, our series aims to evaluate hematological recovery after HaploSCT using a post transplantation cyclophosphamide (PT-Cy) platform.MethodsThis retrospective monocentric study included consecutive patients with following criteria: adults with hematological malignancies; bone marrow or peripheral blood T-replete HaploSCT from 2011 to 2015; non-myeloablative (Baltimore approach) or reduced intensity conditioning (busulfan-based) regimen; PT-Cy as part of GVHD prophylaxis. Patients with primary graft failure were excluded. Absolute neutrophil count (ANC), red cells (RCT) or platelet transfusion (PT) requirements on day 30 (D30) and day 100 (D100) were analyzed among disease-free patients. We first separately evaluated the rate of patients with significant cytopenia in each lineage (defined by ANC < 1 G/L, RCT need, PT need) and searched for impact of pre-transplantation factors on cytopenia (multivariate analyses by binary logistic regression). Then, we evaluated outcome by D30- and D100-landmark analyses according to cytopenia.ResultsOne hundred and forty six patients with a median age of 56 years (range: 19-73) were analyzed: 142 and 117 were evaluable at D30 (4 early deaths) and D100 (17 deaths, 11 relapses), respectively. At D30, 20% of patients had ANC<1G/L, 67% needed RCT and 63% needed PT. Corresponding values at D100 were 20%, 42% and 28%, respectively (Figure 1).At D30: the use of PBSC (HR 9.5, p=0.002) was significantly associated with ANC>1G/L at D30; the use of NMAC Baltimore schema (HR 0.3, p=0.012) and CD34+ cell dose > median (HR 0.4, p=0.041) decreased PT needs while hematopoietic cell transplantation comorbidity index (HCT-CI)≥3 (HR 3.3, p=0.004) was associated with PT needs; no factor was found to significantly influence RCT.At D100: Age>60 years (HR 2.4, p=0.045), female to male HaploSCT (HR 3.3, p=0.020) and HCT-CI≥3 (HR 3.7, p=0.006) were significantly associated with higher risk of RCT need; female to male HaploSCT (HR 3.6, p=0.015) and HCT-CI≥3 (HR 6.9, p=0.001) were associated with PT needs; no factor was found to significantly influence ANC.With a median follow up of 25 months (range: 5-55), cox multivariate model with adjustment by age (continuous), disease risk index (low/intermediate vs high/very high), HCT-CI (0-2 vs ≥3), conditioning regimen (baltimore vs. busulfan-based) and graft source (bone marrow vs PBSC) showed that ANC<1 G/L was strongly associated with higher NRM (HR 2.9, p=0.011) and shorter OS (HR 3.4, p<0.001), overcoming the impact of RCT and PT needs (Figure 2A and 2B). In contrast, D100 analysis showed that PT need was the most determinant factor of increased NRM (HR 13.7, p=0.013) and poor OS (HR 7.3, p=0.003), while both D100 ANC and RCT needs did not impact outcome (Figure 2C and 2D).DiscussionWe found that cytopenia remain a concern after HaploSCT, leading to increased NRM and OS. The absence of ANC>1G/L at D30 as well as the need of PT at D100 may be considered as a strong post transplantation factor predicting poor outcome. Some pre-transplantation factors of cytopenia have been identified, such as CD34+ cell dose, sex mismatch and graft source. Among them, some may help for donor selection while the optimal donor for HaploSCT is still unknown. Moreover, better neutrophil recovery at D30 is achieved with the use of PBSC. CD34+ optimal cell dose in this setting remains also to be determined. In addition, post transplantation events such GVHD and/or infections should be evaluate to explore their interactions with such cytopenia, aiming to develop early therapeutic interventions. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

First report of pediatric hematopoietic stem cell transplantation activities in the eastern mediterranean region from 1984 to 2011: on behalf of the pediatric cancer working committee of the eastern mediterranean blood and marrow transplantation group.

To describe the hematopoietic stem cell transplantation (HSCT) activities for children in the Eastern Mediterranean (EM) region, data on transplants performed for children less than 18 years of age between 1984 and 2011 in eight EM countries (Egypt, Iran, Jordan, Lebanon, Oman, Pakistan, Saudi Arabia and Tunisia) were collected. A total of 5187 transplants were performed, of which 4513 (87%) were allogeneic and 674 (13%) were autologous. Overall, the indications for transplantation were malignant diseases in 1736 (38.5%) and non-malignant in 2777 (61.5%) patients. A myeloablative conditioning regimen was used in 88% of the allografts. Bone marrow (BM) was the most frequent source of stem cells (56.2%), although an increasing use of PBSC was observed in the last decade. The stem cell source of autologous HSCT has shifted over time from BM to PBSC, and 80.9% of autologous HSCTs were from PBSCs. The donors for allogeneic transplants were matched-related in 94.5% of the cases, and unrelated transplants, mainly cord blood (99%) in 239 (5.5%) cases. This is the first report to describe the pediatric HSCT activities in EM countries. Non-malignant disorders are the main indication for allogeneic transplantation. Frequency of alternate donor transplantation is low.

Improved Outcomes with Allogeneic Stem Cell Transplantation for Aplastic Anaemia Using HLA Identical Sibling Donors: The Indian Stem Cell Transplant Registry (ISCTR) Experience

Introduction: Allogeneic stem cell transplantation (SCT) is the best form of therapy for a young patient (< 50 years) with severe aplastic anaemia. In developing countries, there is a big time interval between diagnosis and SCT leading to increased transfusions and increased risk of infections, both of which adversely affects transplant outcome. This retrospective analysis is aimed at studying the outcomes of SCT among Indian patients with aplastic anaemia.Methodology: The Indian Stem cell transplant registry (ISCTR) is a group of transplant physicians representing about 30 active transplant centres in India. This retrospective analysis was done on data reported on 634 patients by 20 centres who reported outcomes of SCT for aplastic anaemia. Data was collected from individual medical records and databases. Analysis was done using SPSS software version 16.0Results: Six hundred and thirty four patients [445 males and 189 females] with a median age of 21 years (range: 2 - 65) underwent allogeneic SCT between 1990 and March 2015. There were 209 children (age < 15 years). The median time from diagnosis to SCT was 5 months (range: 1 - 120) while the median number of transfusions was 20 (range: 1 - 150). All donors were HLA identical sibling or family donors; matched unrelated and haplo-identical donor transplants were excluded from this analysis.Conditioning regimen was Cyclophosphamide based (Cy/ Cy+ ATG/ Cy+ TBI/TLI) in 78 patients (12.3%) while majority received Fludarabine with Cyclophosphamide (n = 481; 75.8%) and 75 received other conditioning regimens (Flu/TBI, Flu/Bu, Bu/Cy etc). Graft source was bone marrow [BM] in 124 (19.5%) and peripheral blood stem cells in 510 patients (80.5%). Graft versus host disease (GVHD) prophylaxis predominantly consisted of Cyclosporine and methotrexate in 543 patients (85.6%).Engraftment was seen in 572 patients (90.4%) while 19 (2.9%) had primary graft failure and 43 (6.7%) expired prior to engraftment due to infection or bleeding. The median time to neutrophil engraftment was 13 days (range: 8 - 21) while platelet engraftment occurred at 13 days (range: 5 - 37). Grade II - IV acute GVHD occurred in 29.3% while grade III-IV was seen in 14.1%. Chronic GVHD was seen in 41% of evaluable patients which was limited in most patients. At a median follow up of 43 months (range: 1 - 264), 431 patients are alive. The 5 yr OS for the entire group is 66.3 + 2.0%. The OS was higher in children compared to adults (73.4 + 3.3% vs 62.8 + 2.5%; p = 0.006), better for Flu/Cy compared to Cy based conditioning (69.8 + 2.2% vs 57.8 + 5.6%; p = 0.002) and better for PBSC compared to BM (68.9 + 2.2% vs 56.1 + 4.8%; p = 0.020). There has been significant improvement in outcomes over the past 15 years [3 yr OS of 41.9 + 1.3% for 1984-1995, 40.9 + 1.2% for 1996-2000, 70.6 + 5.0% for 2001 -2005, 70.3 + 3.1% for 2006-2010 and 68.8 + 3.0% from 2011 onwards].Conclusion: Outcomes of patients with aplastic anaemia are improving and patients have a 70% chance of getting cured with a HLA identical sibling donor transplant. The use of PBSC as graft source is not associated with inferior outcomes. 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.

Advanced Age at Transplant Increases the Risk of Second Solid Malignancy (SSM) after Haematopoetic Stem Cell Transplantation (HSCT)

Introduction: It is increasingly important to understand the long term risk associated with transplantation because the number of long term survivors is steadily growing. In comparison to other long term risks following transplantation like infertility, cataracts, endocrine dysfunction, etc. the risk of second malignancy is likely to be associated with increased risk of mortality and hence significant impact on survival outcomes. This retrospective, single centre analysis was undertaken to evaluate the risk of second solid malignancy in patients undergoing HSCT.Methods: From February 1973 to November 2013, 1983 patients (median age: 45yr., range: 14-76 yr.; M: 1259, F: 724) received stem cell transplants for haematological malignancies (Ac. Leuk: 507, Chr. Leuk: 97, lymphoma:645, myeloma:621, solid tumours:113). Donor was allogeneic (n=528) or autologous (n=1455) and conditioning was with (n=556) or without TBI (n=1427). Donor was sibling (n=302), matched unrelated (n=220) or cord blood (n=6). Source of stem cell was marrow (n=322), PBSC (n=1627), both (n=28) or cord blood (n=6). GVH prophylaxis included Campath in 203 cases. Of all the patients 1774 received single transplant but 209 received more than one transplant. Data was analysed as of 01/12/2013 using competing risk models with death as the competing event. Patients who developed second haematological malignacy were not included in this analysis.Results: Patient follow-up was more than 10 years in 382 cases (19%), between 5 to 10 years in 328 (17%), 1 to 5 years in 667 (34%) and less than 1 year in 606 cases (31%). Second solid malignancy developed in 70 patients with the incidence of 1% at 5yr (95% CI: 0.5-1.6), 2.2% at 10 yr (95% CI: 1.6-3.3), 4.8% at 15yr (95% CI: 3.6-6.8) and 8% (95% CI: 5.9-10.5) at 20 years. Site of second malignancy was brain (n=2), breast (n=15), cervix (n=3), GIT (n=11), genitourinary (n=9), lung (n=3), skin (n=17), head & neck (n=7), thyroid (n=3) and non EBV related lymphoma (n=3). In univariate analysis 10 yr. probability of developing SSM was not influenced by gender, stage of disease, primary diagnosis, type of HSCT, use of TBI, cranial top-up radiation, type of donor or year of transplant. It was significantly higher with use of PBSC (1.4% vs. 2.6%, p=0.02) and age above 65yr. (1.5% vs. 11%, p=0.001). In multi-variate analysis age above 65yr. (RR: 1.8, 95% CI: 1.1-2.9, p=0.02) and PBSC (RR: 9.4, 95% CI: 1-99, p=0.05) were independently associated with increased risk of SMN. 19 patients have died due to SSM (27%) and survival was significantly shorter with gastrointestinal, genitourinary and lung cancers.Conclusion: This single centre analysis shows that the risk of developing SSM increases with advancing age, longer follow-up and the survival is poor. Long term survivors of stem cell transplants need follow-up probably for life in speciality clinics. Continued vigilance, avoidance of known carcinogens and life style changes are strongly recommended. DisclosuresBloor:GSK: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cavet:Novartis: Research Funding; BMS: Research Funding.

Significant and Rapid Improvement in Survival After Unrelated Donor (URD) Hematopoietic Cell Transplantation (HCT): Analysis of National Marrow Donor Program (NMDP) Facilitated Transplants From 2000 to 2009

AbstractAbstract 234Allogeneic HCT using an URD can be curative therapy for patients with high-risk hematologic diseases. Over the past few decades, changes in practice have led to steady improvements in HCT outcomes, but patients and physicians may forgo URD HCT due to safety and efficacy concerns. To determine if outcomes have improved in the current era, we conducted an analysis of 15,509 patients undergoing first URD HCT using either peripheral blood stem cells or bone marrow facilitated by the NMDP from 2000 to 2009. Recipients of myeloablative (MA) and reduced intensity conditioning (RIC) were included. Two time periods were studied (2000–04 and 2005–09) and analysis was stratified by age at HCT: <18 years (y) (N=1255 and 1600), 18–59y (N=3951 and 6035) and ≥ 60y (N=412 and 1806). Acute leukemia was the most common indication for HCT for both time periods (53% and 47% for <18y, 53% and 56% for 18–59y and 53% and 53% for ≥ 60y). Notable changes in practice from 2000–04 to 2005–09 for all age groups included HCT for earlier stage disease, shorter time from diagnosis to HCT, increased use of PBSC as a graft source, decreased use of total body irradiation based conditioning and increased use of HLA 8/8 matched donors. Overall survival (OS) was 12–13% better at 1y for patients transplanted in the more recent era for all three age groups, a highly significant finding (see Table). The large improvement in 1y survival rates was mostly sustained through 3y of follow-up. Survival gains were due to across-the-board reductions in transplant related mortality (TRM) and, in children and the elderly, fewer post-HCT relapses. One contributor to reduced TRM was a significant decline in the incidence of grade 3–4 acute graft-versus-host disease (GVHD) for <18y (21 vs 15%, P <0.001) and 18–59y groups (23 vs 19%, P<0.001) although there was no change for patients ≥ 60y (17 vs 16%, P=0.58). To partially control for variables that routinely affect URD HCT outcomes such as relapse risk, conditioning intensity and HLA match, we conducted additional subset analyses in more homogenous populations when sufficient numbers of patients permitted. In children with malignant diseases, the major contributor to improvement in 1y OS in patients with both standard risk (63 vs 74%, P=<0.001) and advanced malignancies (47 vs 54%, P=0.08) was a significant reduction in TRM (23 vs 15%, P=0.002 and 27 vs 18%, P=0.01); small improvements in relapse rates did not meet statistical significance in the subset analyses. There were sufficient numbers of adults 18–59y for analysis by both disease risk and conditioning intensity. One year OS improvements for MA HCT for standard risk malignancies (55 vs 66%, P<0.001) were accompanied by significant decreases in both TRM and relapse. Improved OS for adults with advanced malignancies receiving either MA (35 vs 46%, P<0.001) or RIC HCT (44 vs 59%, P<0.001) was mainly due to reduced TRM. Adults receiving RIC HCT for standard risk diseases did not have improved OS (58 vs 60%, P=0.54). The large number of adult HCT also permitted subset analyses by HLA match status, which was restricted to patients with myeloid leukemia and MDS to minimize other variables. Better 1y OS in recipients of HLA 8/8 matched donors (52 vs 59%, p<0.001) and 7/8 matched donors (43% vs 50%, P=0.009), was accompanied by significant reduction in TRM in both HLA match groups. There were too few patients ≥ 60y in the earlier period to permit subset analyses. In summary, survival following URD HCT has improved significantly and rapidly over the last decade for all age groups. Reduced early TRM and, in certain populations, fewer relapses were important contributors to survival improvements. Increased availability of better matched donors contributes to but does not completely explain better survival in the most recent era. Multivariate analyses to better understand the practice changes associated with improved outcomes are ongoing.TableOutcomes at 1 and 3y for all patients stratified by age groupAge group1y3y2000-042005-09P value2000-042005-09P valueProb % (95% CI)Prob % (95% CI)Prob % (95% CI)Prob % (95% CI)<18yOS60 ± 272 ± 2<0.00150 ± 362 ± 2<0.001TRM24 ± 316 ± 2<0.00127 ± 221 ± 2<0.001Relapse26 ± 322 ± 30.0733 ± 327 ± 30.00718-59yOS47 ± 259 ± 2<0.00136 ± 243 ± 2<0.001TRM33 ± 221 ± 1<0.00137 ± 228 ± 1<0.001Relapse28 ± 229 ± 10.6132 ± 235 ± 20.03≥ 60yOS40 ± 453 ± 2<0.00125 ± 435 ± 3<0.001TRM31 ± 423 ± 20.00334 ± 431 ± 20.20Relapse42 ± 534 ± 30.00346 ± 539 ± 20.01 Disclosures:Majhail:National Marrow Donor Program: Employment. Chitphakdithai:National Marrow Donor Program: Employment. Shan:National Marrow Donor Program: Employment. King:National Marrow Donor Program: Employment. Anton:National Marrow Donor Program: Employment. Bakken:National Marrow Donor Program: Employment. Braem:National Marrow Donor Program: Employment. Navarro:National Marrow Donor Program: Employment. Miller:National Marrow Donor Program: Employment. Confer:National Marrow Donor Program: Employment.

Improved Clinical Outcomes of High Risk β Thalassemia Major Patients Under Going a HLA Matched Related Allogeneic Stem Cell Transplant with the Use of a Treosulphan Based Conditioning Regimen and Peripheral Blood Stem Cell Grafts

Abstract 1017▪▪This icon denotes a clinically relevant abstractAllogeneic stem cell transplant (SCT) remains the only curative option for patients with β thalassemia major (TM). However, the clinical outcome following SCT in patients with TM who belong to the Class III and the Class III high risk (HR) group remains poor. (Class III HR = age≥7 years and liver size≥5 cms: defined by us previously; BBMT 2007;13:889).From October, 1991 to June, 2011, 332 HLA matched related transplants for TM were done at our center. In an attempt to improve the clinical outcomes we used a Fludarabine (Flu) with intensity reduced Bu/Cy conditioning regimen, for a short period in 2006 and from August, 2009 a treosulphan based conditioning regimen (thiotepa: 8 mg/kg on day-6, treosulphan: 14gm/m2 for 3 days from day −5 to −3 and fludarabine 40mg/m2 for 4 days from day -5 to -2). We undertook a retrospective analysis to compare the impact of these alterations on the clinical outcome, especially in the high risk groups.A total of 178 (53.6%) Class III underwent SCT and 76 (42% of Class III) of these were Class III HR. Of the Class III patients, 135 received a conventional oral busulphan based conditioning regimen, 13 the Flu/Bu/Cy regimen and 30 the treosulphan based regimen (baseline characteristics of three groups summarized in Table 1). The treosulphan based regimen was associated with a significant reduction on the incidence of sinusoidal obstruction syndrome (SOS), TRM and rejections (table 1). The 2 year Kaplan-Meier estimate of EFS for these three groups was 59.6 ± 4.3, 23.1 ± 11.7 and 89.1 ± 6.0) respectively (P=0.000). Among those conditioned with a treosulphan based regimen DAH occurred in 4 and two of them (who also had features of SOS) succumbed to subsequent complications. With the treosulphan based regimen, initially bone marrow was the stem cell source (n=12) and this was associated with a delay in engraftment (median time to ANC>1000/mm3 was 19 days: range: 15–21), greater morbidity and a higher incidence of mixed chimerism on day 28 post transplant (50%) compared to PBSC (n=18, median time to ANC>1000/mm3= 15 days; range: 12–28, day 28 mixed chimerism in 12%). Use of PBSC was not associated with a significant increased risk of acute or chronic GVHD. It was noted that these favorable observations were retained in the Class III HR subset and the 2 year Kaplan-Meier estimate of EFS in this subset, with a treosulphan based conditioning regimen (n=19), was 89.5 ± 7.0% (Figure 1).In conclusion a treosulphan based conditioning regimen with a peripheral blood stem cell graft is well tolerated in high risk patients with TM and significantly improves the clinical outcome.Table 1:Baseline characteristics and clinical outcomes of Class III patients conditioned with different conditioning regimens.Busulphan based N (%)/ Mean ± SD/ Median(Range)Fludarabine based N (%)/ Mean ± SD/ Median(Range)Treosulphan based N (%)/ Mean ± SD/ Median(Range)P-valueN1351330Age9 (2–24)11 (4–14)11 (4–21)0.102Sex: M85 (63)8 (61.5)19 (63.3)0.994Class III HR*53 (39.3)4 (30.8)19 (63.3)0.036Live size4 (2–11)4 (3–7)5 (2–10)0.066F>M#49 (36.3)5 (38.5)7 (23.3)0.379Splenectomy30 (22.2)1 (7.7)7 (23.3)0.455HbsAg5 (3.7)000.441HCV28 (20.7)1 (7.7)4 (13.3)0.371Stem cell source$———0.000BM125 (92.6)13 (100)12 (40)GBM9 (6.7)——PBSC1 (0.7)—18 (60)CD34 dose6.4 (2.64–15.8)7.1 (2.80–12.7)11.4 (4.1–24.4)0.001ANC>0.5 × 109/Lt (days)16.88 ± 4.1419.12 ± 2.7516.03 ± 2.910.047Platelet>20 × 109/Lt (days)30 (10–137)32 (22–49)16.5 (9–44)0.000SOS@89 (65.9)4 (30.8)4 (13.8)0.000Treatment related mortality40 (31.7)5 (41.7)2 (6.7)0.012Rejections———0.034Primary graft failure4 (2.9)6 (46.2)1 (3.3)Secondary graft rejection12 (8.9)12 (15.4)0 (0)Ac GVHD55 (45.8)2 (20.0)11 (37.9)0.240Ch GVHD17 (18.1)03 (13)0.4122 yr KM estimate of EFS59.6 ± 4.323.1 ± 11.789.1 ± 6.00.0002 yr KM estimate of OS65.8 ± 4.253.8 ± 13.893.3 ± 4.60.028*HR high risk#F>M female donor to male recipient$Stem cell source. BM=bone marrow, GBM=G-CSF primed BM, PBSC=peripheral blood stem cells@SOS sinusoidal obstruction syndrome [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation for Acquired Aplastic Anemia: Better Outcome with Bone Marrow as Compared to Peripheral Blood in HLA-Matched Sibling Donor Transplantation and Improved Outcome Over Time After Matched Unrelated Donor Transplantation. A Retrospective Analysis of Transplants Reported to the German Registry for Stem Cell Transplantation (DRST).

Abstract 876 Background:Transplantation of bone marrow (BM) from a HLA-matched sibling donor is an effective treatment for severe aplastic anemia (AA) with long-term survival in excess of 80%. In the recent years there were two trends in allogeneic stem cell transplantation (SCT) for AA: (1) increasing proportion of transplants performed from matched unrelated donors (MUD) and (2) increasing proportion of transplants using peripheral blood progenitor cells (PBSC) as stem cell source instead of BM. A similar switch to PBSC over BM grafts is reported in leukemia transplants. PBSC grafts for leukemia are associated with higher rates of chronic graft-versus-host disease (cGVHD). This adverse consequence may be offset by lower rates of leukemia relapse in some settings. In contrast, there is no perceived benefit of cGVHD for AA. A recent retrospective analysis of EBMT/CIBMTR reported worse outcome after PBSCT compared to BMT in young patients after HLA-matched sibling (sib) transplantation. The impact of stem cell source on outcome after MUD transplants has not been studied in detail so far.Some reports on favourable results after MUD SCT prompted the discussion whether MUD SCT should be performed earlier in the treatment algorithm in AA instead of considering it as salvage treatment after failure of immunosuppressive treatment. Therefore we performed a retrospective study on the dataset of the German Registry of Stem Cell Transplantations (DRST) to (1) analyze outcome after MUD compared to sib SCT and (2) to study impact of stem cell source (PBSC vs BM) on both sibling and MUD SCT and (3) to analyze impact of transplant period (1998-2002 vs. 2003-2008). Results:We analyzed 182 sib SCT and 114 MUD SCT (first transplants only). The interval between diagnosis and transplant was significantly longer for MUD SCT as compared to sib SCT (median 98.5 days vs. 511.5 days; p<0.001 ) suggesting that the majority of sib SCT were performed upfront whereas MUD SCT in the majority of cases was performed after failure of other treatments. Median age was 28.5 years (sib SCT) and 30 years (MUD) years (p=0.41). PBSC were used as stem cell source in 50.5% of sib SCT and 61.4% of MUD (p=0.097). 5-year probability of survival was 84.6% (95%-CI: 79.3-90.3%) after sib SCT and 70.1% (95%-CI. 61.8-79.6%) after MUD (p<0.003). In univariate comparison age at transplant has significant impact on survival: After sib SCT 5-year probability of survival in patients ≤ 30 years vs. > 30 years was 94.5% (95%-CI: 90.0-99.3%) vs. 73.5% (95%-CI: 64.3-84.1%)(p<0.001) . 5-year probability of survival after MUD SCT in patients ≤ 30 years vs. > 30 years was 77.7% (95%-CI: 67.3-89.7%) and 60.6 (95%-CI: 48.2-76.2%) (p=0.044). In the most recent period (2003-2008) 2-year probability of survival was 81.6% (95%-CI: 72.9-91.3%) after sib SCT (n=80) and 75.6 (66.1 – 86.5%) after MUD SCT (n=73) (p=0.34). After sib SCT survival was significantly better with BM as compared to PBSCT (5-yr. prob. 95.3%; 95%-CI: 90.9-99.9%; n=89 vs. 74.1%, 95%-CI: 65.1-84.2%; n=92; p<0.001) and cumulative incidence of chronic GvHD was significantly higher with PBSCT as compared to BM (47.0% vs. 18.4%; p<0.01). Cumulative incidence of acute GvHD II-IV did not differ significantly between BM and PBSC. In contrast, stem cells source did neither significantly affect overall survival nor cumulative incidence of acute or chronic GvHD after MUD. In multivariate analysis of the sib SCT older age (>30 years) and use of PBSC were significant risk factors for mortality (Hazard Ratio (HR) 3.4 (1.2-9.3) and HR 4.0 (1.3-12.2). Other variables in the model (conditioning regimen; GvHD prophylaxis; sex match; time diagnosis to transplant and transplant period) were not significant. For MUD SCT none of these variables were significant in a multivariate model. Conclusion:These results indicate that BM grafts should be preferred to PBSC in patients undergoing HLA-identical sib SCT for AA. In contrast, no negative impact of stem cell source on outcome after MUD SCT could be demonstrated. Results of MUD SCT substantially improved over time. In the most recent period from 2003- 2008 the probability of survival after MUD and HLA-identical sib SCT was no longer different. So far majority of MUD transplants were performed late after diagnosis, mostly after failure of immunosuppression. Re-assessment of both the indication of MUD SCT for AA and the timing of MUD SCT is warranted.Supported by the Deutsche José Carreras Leukämie-Stiftung. Disclosures:No relevant conflicts of interest to declare.

Long-Term Immune Deficiency (ID) after Allogeneic Stem Cell Transplantation (allo-SCT) Following a Myeloablative (MA) Conditioning Regimen.

Background; although numerous studies have described ID in the short-term post transplant, few include data on long-term ID following allo-SCT.Aim; describe longitudinally the evolution of T-, B-, and NK-cells in a cohort of 140 consecutive pts following allo-SCT and to correlate this evolution with the advent of late clinical infections.Patients & Methods; 140 pts with a median follow-up of 38 months (mo) were studied [median age 27 (39 less than 16) & 77% with malignancies]. Bone marrow (81%) from sibling (66%) was used before MA conditioning regimen (TBI 42%). 51% had grade II–IV acute- and 30% extensive-GvHD. All pts were monitored before and at 3, 6, 12, & 24 mo post transplant for both CD4 & CD8 subsets [CD45RA (naïve), 45RA+62L- (terminally differentiated), 45RO+ (memory), 28+ (competent), and Dr+ (activated)],NK cells (CD3-, 16+56+), and B cells CD19+/5+, 19+/27- (naives) and 19+27+ (memory).Results; we observed; for both CD4 CD8 a 1- year ID of the naive, memory and competent and above limits value for competent subsets; NK normalization at 6 mo; expansion of CD19+/5+ after 3 mo and persisting (till 24 mo) ID of memory B cells. Chronic GvHD did not influence significantly those parameters for CD8 subsets while strongly affecting the naïve and competent CD4 subsets, but the most profound defect was on B cell subsets especially on memory B. Contrasting this profound ID the cumulative incidence of late severe infections (LSE) was rather low (14% at 4 years). The only clinical factor that was marginally statistically linked to these was the use of PBSC instead of marrow. We then finally constructed Cox models to search for putative clinical or immunological risk factors for these LSE. Only low B cell counts at 6 (p=.05) & 24 mo (p=.016) were associated with the hazard of developing SLE, in particular if patients did not developed chronic GvHD (see Figure) [Display omitted] Conclusion; despite a long lasting ID post transplant following MA conditioning the rate of LSI remains low with modern antimicrobial prophylaxis; only B cell defect correlated with LSI despite immunoglobulin supplementation in pts with low Ig level.