Received Reduced-intensity Conditioning Regimens Research Articles

Infection-related mortality after HLA-identical and haploidentical hematopoietic cell transplantation using reduced-intensity conditioning in an outpatient setting.

Despite the improvements in supportive care for allogeneic-hematopoietic cell transplantation (allo-HCT) recipients, infectious complications and infection-related mortality (IRM) continue to be a major issue for transplantation centers. We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo-HCT) or HLA-identical HCT at a tertiary referral center during 2013-2020. Patients in the haplo-HCT group received post-transplant cyclophosphamide (PT-Cy), and all received reduced-intensity conditioning regimens. More haplo-HCT recipients presented severe infections in the pre-engraftment period (22.4% vs. 6.7%, p=0.003). Viral (14.9% vs. 4.5%, p=0.016) and fungal (12.1% vs. 1.1%, p=0.003) etiologies were more common in this period in this group. The 100-day and 2-year cumulative incidence of IRM was 15% and 21% for the haplo-HCT and 5.6% and 17% for the HLA-identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). No differences in IRM were observed based on allo-HCT type, with more haplo-HCT patients suffering from severe infections in the pre-engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted.

Improved Gvhd and Relapse Free Survival Outcomes in Older Acute Leukemia Patients Receiving Young Haploidentical Donor Vs Older Matched Sibling Donor Reduced Intensity Conditioning Hematopoietic Cell Transplants

Background: Allogeneic hematopoietic cell transplants (alloHCT) from HLA-matched sibling donors (MSD) or matched unrelated donors (MUD) may cure patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndromes (MDS). Older patients with AML benefit from alloHCT, but donor selection may be complicated by the advanced age and comorbidities of HLA-matched siblings. Haploidentical (Haplo) HCT with post-transplant cyclophosphamide (PTCy) is an alternative approach to traditional HLA-matched alloHCT. HaploHCT is associated with reduced graft-versus-host disease (GVHD) risk but reduced overall survival (OS) in some series with older recipients. There are limited published data assessing outcomes using younger Haplo donors versus older MSD for older HCT recipients. The objective of this study is to characterize treatment outcomes and GVHD rates in older HCT recipients of younger HaploHCT compared to older MSD grafts. Methods: This retrospective cohort analysis included patients aged 50 years and older with AML, ALL, or MDS who received reduced intensity conditioning (RIC) and either a young Haplo donor or older MSD graft from 2014 to 2020. Young donors included those <50 years old, and older donors were ≥50 years old. The primary outcome was OS one-year post-HCT. Secondary analyses included aGVHD and cGVHD outcomes, relapse-free survival (RFS), GVHD-RFS (GRFS), non-relapse mortality (NRM), infection incidence, time to neutrophil recovery, and relapse incidence. Kaplan-Meier method with log-rank test was used to assess OS, RFS, and GRFS. All data presented are organized as Haplo versus MSD. Results: Twenty-nine patients received younger donor Haplo grafts and 47 patients received older MSD grafts. Median age for donors was 35.4 years vs 61.6 years in the Haplo and MSD cohort, respectively. The underlying hematologic disorder leading to alloHCT in the two cohorts were AML (83% vs 47%), ALL (3% vs 11%), and MDS (28% vs 43%) (p<0.001). Stratified cytogenetic risk categories for each diagnosis were not significantly different. RIC regimens included Fludarabine (Flu)/Melphalan or Flu/Busulfan for older MSD recipients, whereas the younger donor Haplo cohort received Flu/Cy/TBI (200cGy). PTCy/Tacrolimus (Tac) was the GVHD prophylaxis (ppx) regimen for all Haplo recipients, whereas 96% of MSD cohort got Tac/Methotrexate (MTX) and 4% of MSD cohort got Tac/MTX/MMF. Peripheral blood was the graft source in 62% of HaploHCT and 100% of MSD (p<0.001). Seventy-six percent of donors in the Haplo cohort were recipient offspring. One-year OS was 86% vs 72% (p=0.27), RFS was 69% vs 70% (p=0.76), NRM was 7% vs 9% (p=0.86), and GRFS 89% vs 62% (p=0.005) [Table 1] for Haplo vs MSD cohorts, respectively. Median OS (HR 0.88, p=0.785) and median RFS (HR 1.38, p=0.459) were not reached in either group. Median GRFS was longer in the Haplo cohort (190 vs 148 days, HR 0.52, p=0.021) [Figure 1]. One-year incidence of relapse was not different between cohorts (p=0.14). Incidence of aGVHD (38% vs 32%, p=0.51) was similar in both cohorts, although maximum aGVHD grade was lower in the Haplo group (p=0.04). cGVHD incidence numerically favored HaploHCT (45% vs 66%, p=0.08) [Table 1]. Individuals receiving HaploHCT had a longer median time to neutrophil engraftment (19 vs 14 days, p<0.001) and a shorter median time to full CD3 chimerism (32 vs 76.5 days, p<0.001). They also had a higher incidence of CMV viremia (p=0.014), BK viremia (p=0.05), and fungal infections (p=0.047) [Table 1]. Incidence of HHV6 (p=0.18) and EBV viremia (p=0.89) were not different between cohorts. Discussion: Our results demonstrate similar OS, RFS and incidence of aGVHD and cGVHD between younger donor HaploHCT and older MSD alloHCT for older patients. GRFS was significantly better in the Haplo cohort, which may have been primarily influenced by higher incidence of cGVHD and higher grades of aGVHD observed for recipients of older MSD grafts with Tac/MTX-based GVHD ppx. aGVHD and cGVHD rates may be reduced with the use of HaploHCT and incorporation of PTCy at the expense of more opportunistic infections. Our results suggest that young donor HaploHCT using PTCy may be a reasonable alternative for alloHCT and reduce risks for GVHD for older patients with leukemia even if a MSD is available. These data also suggest MSD alloHCT with PTCy should be explored. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hematopoietic Stem Cell Transplantation in Paroxysmal Nocturnal Hemoglobinuria

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematological disorder characterized by episodic intravascular hemolysis. Despite newer therapies such as eculizumab, hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. MATERIALS AND METHODS: An observational analytical retrospective study was conducted comprising eight PNH patients who had undergone HSCT at our center. From January 2014 to December 2020, we performed HSCT in 8 PNH patients, 5 female and 3 male, with median age of 32 years (range: 15–38 years). RESULTS: Seven patients had pancytopenia, associated with marrow hypocellularity. One patient presented with a thrombotic episode. Seven had matched sibling donor (MSD) transplant and one underwent haploidentical transplant. The median time from diagnosis to transplant was 7 months (range: 1–38 months). All received reduced intensity conditioning (RIC): Flu-Bu-Cy-A TG for MSD transplants and Flu-A TG-Post Cy in haploidentical transplants. Median CD34+ stem cell dose was 5.5 × 106/kg (range 3.4–5.8 × 106/kg). All had successful engraftment. Acute graft versus host disease (GVHD) Grade I–III occurred in six patients. Chronic GVHD occurred in two patients. One patient succumbed to Grade III liver GVHD. Rest seven patients are alive till date and transfusion independent. The overall survival was 87.5% at a median of 26 months. CONCLUSIONS: HSCT is the only curative therapy for PNH. With the use of RIC, the outcomes of PNH patients can be improved. The incidence of GVHD is high with RIC regimens but can be managed with prompt immunosuppression.

Comparing Single Cord Blood Transplantation and Matched Related Donor Transplantation in Non-Remission Acute Myeloid Leukemia

IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for refractory and relapsed acute myeloid leukemia (R/R AML) in non-remission status. Although human leukocyte antigen (HLA)-matched relatives are the preferred donors for R/R AML patients in non-remission status, their 2-year overall survival following HLA-matched related donor transplantation (MRDT) has only been reported to be 25% due to a high relapse rate of over 50%. Alternatively, cord blood transplantation (CBT) is a donor transplantation procedure that has similar advantages to MRDT in terms of rapid availability, making it possible for urgent HSCT. Moreover, CBT can induce a more potent graft-versus-leukemia (GVL) effect in AML patients under various conditions as compared to other donors. Therefore, this study aimed to investigate the impact of CBT as compared to MRDT using the Transplant Registry Unified Management Program 2 in Japan.MethodThis study included 2451 adult patients with non-remission AML who received CBT (1738 patients) or MRDT (713 patients), including bone marrow transplantation and peripheral blood transplantation, for their first HSCT between January 2009 and December 2018. The primary endpoint was set as 5-year progression-free survival (PFS), and secondary endpoints were set as 5-year overall survival (OS), 5-year cumulative incidence of relapse, 5-year cumulative incidence of non-relapse mortality (NRM), 100-day cumulative incidence of neutrophil engraftment, 1-year cumulative incidence of platelet engraftment, 1-year cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD), and 5-year cumulative incidence of extensive chronic GVHD. The impact of CBT compared to MRDT was then evaluated using propensity score (PS)-matching analysis. In PS calculation, covariates that may influence the selection of the donor and outcomes were selected clinically, and they included the following: age, sex, karyotype risk, disease status, presence of blasts in the peripheral blood, HCT-CI, intensity of conditioning regimen, acute graft versus host disease (GVHD) prophylaxis, and years of HSCT.ResultA total of 2451 patients, comprising 1738 who received CBT and 713 who received MRDT, were enrolled and analyzed. The median age was 55 years (interquartile range, 43-63 years), and 1484 patients (61%) were male. Differences in the clinical characteristics between the two groups were noted. Specifically, the CBT group had older patients, more patients with relapse, blasts in peripheral blood, a higher hematopoietic cell transplant comorbidity index, and had more patients who received reduced-intensity conditioning regimen, tacrolimus-based acute graft-versus-host disease prophylaxis, and transplanted recently. After PS matching, we selected 918 patients among the 2451 patients receiving CBT or MRD, and the patient characteristics were well balanced between the groups.Regarding the primary endpoint, the 5-year PFS was 25.2% (95% CI: 21.1%-25.5%) in the CBT group vs. 18.1% (95% CI: 14.5%-22.0%) in the MRDT group (P=0.009) in the PS-matched cohort (Figure 1). The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.69-1.00, P=0.045).Regarding secondary endpoints, CBT group compared to MRDT group had similar 5-year OS (28.4% in CBT group vs 21.7% in MRDT group, P=0.152), lower 5-year cumulative incidence of relapse (49.3% s 62.8%, P<0.001), higher cumulative incidence of 5-year NRM (25.5% vs 19.1% P=0.0158), lower 100 days neutrophil engraftment (49.5% vs 93.5%, P<0.001), lower one-year platelet engraftment (62.6% vs 79.1%, P<0.001), similar one-year cumulative incidence of grade II-IV acute GVHD (35.5% vs 30.5%, P=0.092), and lower 5-year cumulative incidence of extensive chronic GVHD (8.6% vs 18.5%, P<0.001) in the PS-matched cohort.ConclusionIn this population, CBT was associated with a better 5-year PFS as compared to MRDT after allogeneic HSCT. [Display omitted] DisclosuresKondo: MSD Pharmaceutical: Honoraria; Asahi Kasei Pharmaceutical: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Chugai Pharma: Honoraria; Sumitomo Dainippon Pharma: Honoraria. Kanda: NextGeM Inc: Patents & Royalties; Ono Pharma Inc.: Honoraria; Novartis Pharma K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Sanofi K.K.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; SymBio Pharmaceuticals, Ltd.: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees; Megakaryon Co: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; DAIICHI SANKYO Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees; CHUGAI PHARMACEUTICAL Co., Ltd.: Honoraria; Bristol-Myers Squibb Co: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Amgen Astellas BioPharma: Honoraria; TEIJIN PHARMA LIMITED.: Honoraria. Uchida: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Inc.: Honoraria. Atsuta: Astellas Pharma Inc.: Speakers Bureau; Mochida Pharmaceutical Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; Kyowa Kirin Co., Ltd: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria.

Differential Impact of Conditioning Intensity on Post-Transplant Outcome of FLT3 -Mutated and FLT3 Wild Type AML in First Remission, a Report from Taiwan Bone Marrow Transplant Registry (TBMTR)

AML with FLT3 -internal tandem duplication mutation (FLT3-ITD) has a very high relapse rate when patients were treated with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation (HSCT) as soon as possible once remission is achieved is generally recommended. Nevertheless, the best conditioning regimen, specifically the myeloablative (MAC) or reduced intensity conditioning (RIC), for FLT3-ITD AML remains unknown. Of the two largest series reported so far, vast majority of the patients received myeloablative regimen (100% in EBMT report, 87% in CIBMTR report). In this study, we utilize the Taiwan Bone Marrow Transplant Registry (TBMTR) database to analyze the impact of conditioning intensity on the post-transplant outcome of FLT3 -mutated and FLT3 wild type AML.TBMTR is a research collaboration affiliated to the Taiwan Society of Blood and Bone Marrow Transplantation. It comprises all the 14 transplantation centers in Taiwan that contribute detailed information on HSCT. In this study, only adults aged ≥ 18 years with a diagnosis of de novo AML who received allogeneic peripheral blood stem cell transplantation (PBSCT) at the first complete remission (CR1) and with known FLT-ITD mutation status in the registry were included. Patient characteristics and transplant outcome following MAC or RIC allogeneic PBSCT were compared. Kaplan-Meier estimates were used to calculate the probability of LFS and overall survival (OS). Cumulative incidence of relapse and non-relapse mortality (NRM) was calculated from the time of transplant to the time of event. NRM was considered a competing risk for relapse and vice versa. Multivariable analyses for LFS and OS were performed using Cox proportional hazards model.146 patients who met the eligibility criteria were enrolled for analysis. The median follow-up of survivors was 21 months (range, 1-73 months). Of the 146 patients, 49 (33.6%) were positive and 97 (66.4%) were negative for FLT3-ITD mutation. 32.7% and 35.1% of FLT3-ITD mutated and FLT3 WT AML received RIC regimen respectively. FLT3-ITD mutated patients had significantly higher WBC count (51.7 x 109/L) and more normal (64.9%) karyotype at diagnosis comparing to patients without FLT3 mutation (11.8 x 109/L WBC count and 42% normal karyotype). Patients who received RIC regimen were significantly older than patients who received MAC regimen (53.196±12.107 vs 38.327±11.788, p<0.001, for FLT3-ITD mutated AML; 52.084±12.533 vs 39.181±10.704, p<0.001, for FLT3 WT AML).In multivariable analysis, FLT3 mutation status did not negatively impact the transplant outcome in term of both overall survival (OS) and leukemia free survival (LFS). However, RIC regimen is associated with a significant poor LFS (HR 1.754, p=0.0476) and higher relapse rate (HR 2.184, p=0.015). The impact of conditioning intensity is even more prominent in patients of FLT3 WT AML (Figure 1, left, p=0.0468 for LFS, log rank test). For FLT3-ITD mutated AML, the LFS and relapse rate were almost the same after either MAC or RIC conditioning (Figure 1, right, p=0.768 for LFS, log rank test). For NRM and cumulative incidence of acute and chronic GVHD, the differential impact of conditioning intensity was not seen in FLT3-ITD mutated AML and FLT3 WT AML.In conclusion, conditioning intensity has a differential impact on post-transplant outcome of FLT3-ITD mutated AML and FLT3 WT AML. Reduced intensity conditioning is associated with a lower LFS and higher relapse rate for FLT3 WT AML. For patients of FLT3-ITD mutated AML, RIC is just as good as MAC, even though patients who received RIC were almost 15 years older than patients who received MAC. RIC allogeneic HSCT should be a viable option for elderly or unfit AML with FLT3-ITD mutation. [Display omitted] DisclosuresYao:Celgene International Sàrl: Research Funding. Tang:Celgene International Sàrl: Research Funding.

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

Transplant Outcome for Secondary Acute Myeloid Leukemia Based on Prior Hematological Disease or Solid Malignancy — on Behalf of the ALWP of the EBMT

Safety of Allogeneic Stem Cell Transplantation after PD-1 Blockade for Patients with Relapsed/Refractory Classical Hodgkin Lymphoma: Focus on Immune-Related Adverse Events

Introduction: Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with relapsed and refractory Hodgkin lymphoma (rrHL). However, there is a question of applicability of allo-HSCT for patients previously treated with immune checkpoint inhibitors (ICIs). Initial reports indicate that allo-HSCT in this setting may be associated with increased risk of early transplant-related toxicity, graft versus host disease (GVHD), immune-related adverse events. But subsequently some studies demonstrated acceptable rates of both acute GVHD (aGVHD) and chronic GVHD (cGVHD) after prophylaxis with posttransplantation cyclophosphamide (PTCy). The aim of this study was to define safety and toxicity of allo-HSCT after ICIs for patients with rrHL. Patients and methods: We conducted a retrospective analysis of allo-HSCT results in 23 adult patients with rrHL performed between 2017 and 2019 in RM Gorbacheva Research Institute, Pavlov University. All patients were treated with ICIs before the transplantation (single-agent nivolumab, n=13; nivolumab and brentuximab vedotin, n=5; nivolumab and chemotherapy, n=5). The median time from the last dose of ICIs to allo-HSCT was 83 days (range, 50-350 days) and the median number of cycles was 20 (range, 6-32). Objective response to PD-1 therapy before allo-HSCT was documented in 15 patients (65%) including CR (n=9, 39%) and PR (n=6, 26%). Five patients (22%) had stable disease/disease progression and 3 patients (13%) were transplanted in indeterminate response according to LYRIC criteria. Three (13%) patients had matched HLA-related siblings, 12 patients (52%) had unrelated donors and 8 patients (35%) had haploidentical donors. All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and PTCy-based GvHD prophylaxis. Bone marrow and peripheral blood stem cells was the graft source in 14 (61%) and 9 patients (39%), respectively. All analyses were performed using R 3.6.1 software. Results: At the time of analysis, median follow-up was 14 months (range, 1-26). Engraftment rate was 87%. Two patients had primary graft failure and there was 1 early death due to severe cytokine release syndrome after haploidentical HSCT. The 1-year OS and EFS were 83% (95% CI, 58-93) and 74% (95% CI, 49-87) respectively, whereas the 1-year cumulative incidences of relapse and NRM were 13% (95% CI, 5-39) and 13% (95% CI, 5-38) respectively.Out of the 20 patients with engraftment 15 patients developed acute GVHD including severe (grade III-IV) in 9 patients. All patients had skin aGVHD (stages 1, 2, and 3), 3 patients had gastrointestinal GVHD (stages 2, 3, and 4) and 2 patients had liver GVHD (stages 1 and 2). Four patients with steroid-refractory aGVHD received single-agent ruxolitinib (n=2) or combination of ruxolitinib with extracorporeal photopheresis (ECP) and steroids (n=2). All patients achieved complete response. Ten patients had chronic GVHD including 6 patients with moderate or severe disease. Most commonly skin (90%), mucosa (60%), gastrointestinal tract (30%), liver (20%), lung (10%) and eyes (20%) were involved. Four patients with steroid-refractory cGVHD achieved CR receiving combined immunosuppressive therapy (ruxolitinib and steroids, n=2; combination of steroids, cyclosporine A and ECP, n=2). One patient with severe skin cGVHD (score 3) achieved PR on combination of steroids and ECP, another patient with a severe refractory cGVHD (skin score 3, mucosa score 2 and lungs score 1) achieved stabilization only with third line of therapy (combination of ruxolitinib and imatinib). No cases of GVHD-related mortality were observed. There were no other immune-related adverse events. Conclusions: Our study showed the trend to higher incidence of aGVHD and cGHVD including steroid refractory form after ICIs, however this did not lead to GVHD-related mortality. Introduction of target agents for srGVHD might ameliorate GVHD-related mortality and morbidity in rrHL patients after ICIs. The optimal timing of allo-HSCT and regimen of GVHD prophylaxis are likely to be important in the successful outcome of the transplantation. Disclosures No relevant conflicts of interest to declare.

Safety and efficacy of allogeneic stem cell transplantation after nivolumab therapy for patients with relapsed/refractory classical Hodgkin lymphoma

Abstract Background The programmed-death 1 (PD-1) blockade with nivolumab has demonstrated high efficiency in patients with relapsed and refractory Hodgkin lymphoma (rrHL) with an acceptable toxicity profile. However, most patients treated with immune checkpoint inhibitors (CPIs) will eventually progress on these therapies. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with rrHL. There are concerns that CPIs before allo- HSCT may increase the incidence of graft-versus-host disease, immune-related adverse events, and nonrelapse mortality (NRM). At present, there is no consensus regarding the optimal transplant strategy for patients previously treated with immune checkpoint blockade. The aim of this study was to evaluate outcomes in patients with rrHL who received CPIs as a bridge to allo-HSCT. Methods We evaluated the results of allo-HSCT in 20 patients who had been transplanted after prior PD-1 blockade between 2017 and 2019. All patients received reduced-intensity conditioning regimen and post-transplant cyclophosphamide (PTCy)-based GvHD prophylaxis. The best response to PD-1 therapy was a complete response in 9 patients, partial response in 4; 5 patients received transplant during the disease progression and 2 patients were transplanted in indetermined response. Results At the time of analysis, median follow-up was 14 months (range, 1-26 months). The 1-year OS and EFS were 95% and 85% respectively, whereas the 1-year cumulative incidences of relapse and NRM were 10% and 5% respectively. Two patients with relapse after allo-HSCT were treated with donor lymphocyte infusion (DLI) in combination with chemotherapy. At the median follow up of 30 days all patients remain alive. 4/20 patients developed severe grade 3-4 GvHD and only 1 patient responded to steroids. The cumulative incidence of chronic GVHD (cGVHD) was 35%. Conclusion Our study demonstrates that HSCT after PD-1 blockade is feasible and not associated with higher mortality. The rate of severe acute and chronic GvHD was relatively higher than previously reported for PTCy-based prophylaxis, but was manageable in the majority of cases. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Reduced Intensity Conditioning and Dual T-Cell Modulation Improves Gvhd Free, Relapse Free Survival in AML Patients Compared with Myeloablative Conditioning

BACKGROUND The efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute myeloid leukemia (AML) relies on the antileukemic effect of the conditioning regimen and the graft-versus leukemia (GVL) effect mediated by donor T-cells. Leveraging the GVL effect while reducing toxicity enables reduced intensity conditioning (RIC) to be used to older or frail patients, but may lead to higher rates of graft-versus-host disease (GVHD), impairing later quality of life. Novel T-cell modulation strategies may limit the incidence of GVHD while preserving antileukemic activity leading to better outcomes. Herein, we compare the outcomes of AML patients treated with myeloablative (MAC) and RIC regimens including patients receiving dual T-cell depletion using Anti-Thymocyte Globulin (ATG) and Post-Transplant Cyclophosphamide (PTCy). METHODS Between 2013 and 2018, 362 adults with AML in complete remission underwent allo-HSCT and were included in the study. Overall, 112 (31%) patients received MAC and 250 (69%) received RIC regimens. MAC consisted of Flu(4), Bu (4mg) and 400cGy of total body irradiation (TBI). RIC regimen consisted on Flu (4), Bu (2) and 200cGy TBI in 249 recipients and one received clofarabine/busulfan. One hundred seventy-one (68.4%) the recipients who received RIC regimen, received a novel dual T-cell depletion strategy using ATG (total dose of 4.5mg/kg in 130 patients and 2mg/kg in 41 recipients), PTCy, and cyclosporine for GVHD prophylaxis. Peripheral blood stem cell (PBSC) grafts were used in 98.9% of the recipients. Data was collected retrospectively and updated on April 2019. The cumulative incidence of GVHD was assessed accounting relapse and death as competing events. A multivariate analysis for overall survival (OS), relapse-free survival (RFS) and GVHD-Free/RFS (GFRFS) was conducted controlled by those variables found to be significant in univariate analysis. RESULTS Baseline information is summarized in Table 1. The incidence of grade II-IV and III-IV acute GVHD at day +100, and moderate/severe chronic GVHD at 1 year was respectively: 28.6%, 10.5%, and 18.4%. RIC was associated with a significantly lower cumulative incidence of clinically relevant acute and chronic GVHD (P&lt;0.05). Main outcome information is summarized in tables 1 and 2, and displayed graphically in figures A-F. With a median follow-up of 3.7 years, 68 (18.8%) recipients relapsed and 160 (44.2%) died. The 2-years OS, RFS, and GRFS were 53.8%, 50.8%, and 33.8%, respectively. OS, RFS, non-relapse mortality, and cumulative incidence of relapse were not significantly affected by regimen intensity (P&gt;0.05). However, RIC regimens were associated with superior GRFS. Forty-three (12.7%) recipients had a high Disease Risk Index (DRI). Conditioning intensity was not a significant risk factor for OS (HR 0.9; P=0.931) or RFS (HR 1; P=0.902) in this group of patients. Tables 3 and 4 show the results from multivariate analysis for OS, RFS, and GFRFS. Older patients, those with high DRI, or recipients of 9/10 matched unrelated donor (MUD) grafts had significantly worse OS and RFS. GVHD prophylaxis with dual T-cell modulation (ATG-PTCy-CsA) was the only protective parameter for a better GRFS (HR 0.5; P=0.005). CONCLUSION In AML patients, RIC with PBSC allografts and dual T-cell modulation with ATG and PTCy led to superior GRFS when compared with MAC regimens. Reduction in the cumulative incidence of clinically significant acute and chronic GVHD may be possible without compromising on the efficacy of the GVL effect. The use of this GVHD prophylaxis strategy, along with mitigation of conditioning toxicity by using RIC, may result in better quality of life. Further investigations would be done with the use of this novel GVHD prophylaxis in the setting of MAC regiments. Dual T-cell suppression leads to increased infectious complications including viral reactivations. The use of lower doses of ATG, or individualized dosing strategies based on lymphocyte count may help to further optimize this strategy. Disclosures Michelis: CSL Behring: Other: Financial Support. Mattsson:Celgene: Honoraria; Therakos: Honoraria; Gilead: Honoraria.

Safety and Efficacy of Allogeneic Stem Cell Transplantation after PD-1 Blockade for Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: The programmed-death 1 blockade with nivolumab demonstrated high efficiency in patients with relapsed and refractory Hodgkin lymphoma (rrHL) with acceptable toxicity profile. However, most of the patients treated with immune checkpoint inhibitor (CPIs) will eventually progress on this therapy. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) is a potentially curative option for patients with rrHL. Therefore, allo-HSCT is a consideration for selected patients with HL after treatment with CPIs. There are concerns that CPIs before allo- HSCT may increase the incidence of graft-versus-host disease, immune-related adverse events, and nonrelapse mortality (NRM). At present, there is no consensus regarding the optimal transplant strategy for patients previously treated with immune checkpoint blockade. The aim of this study was to evaluate outcomes in patients with rrHL who received CPIs as a bridge to allo-HSCT. Patients and methods: We retrospectively evaluated the results of allo-HSCT in 22 patients who had been transplanted after prior PD-1 blockade between 2017 and 2019 at the R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology at the First St. Petersburg State Pavlov Medical University (CIC 725). All patients received reduced-intensity conditioning regimen (fludarabine 30 mg/m2, bendamustine 130 mg /m2 per day for 3 days (FluBe)) and post-transplant cyclophosphamide-based GvHD prophylaxis (PTCy). Patients received immune checkpoint inhibitors before allo-HSCT as a single-agent nivolumab or in combination with brentuximab vedotin or chemotherapy. The best response to PD-1 therapy was a complete response (CR) in 9 patients, partial response in 5 patients, 5 patients received transplant during the disease progression and 3 patients were transplanted in indetermined response according to the LYRIC. Patients received a median of 20 (range, 6-32) cycles of a PD-1 inhibitor. The median time from the last dose of anti-PD-1 therapy to HSCT was 83 days (range, 50-350). Results: At the time of analysis, median follow-up was 14 months (range, 1-26 months). Ninety one percent of patients engrafted. One patient had primary graft failure and one died on the day of the haploidentical graft transfusion due to cytokine release syndrome. The 1-year OS and EFS were 91% and 78% respectively, whereas the 1-year cumulative incidences of relapse and NRM were 9% and 9% respectively.Two patients with relapse after allo-HSCT were treated with donor lymphocyte infusion (DLI) in combination with chemotherapy. Both patients remain alive. 4/20 of the engrafted patients developed grade 2 GvHD and all responded to steroids. 4/20 patients developed severe grade 3-4 GvHD and only 1 patient responded to steroids. The cumulative incidence of chronic GVHD (cGVHD) was 35%, including 3 patients with severe, steroid-refractory cGVHD. There were no other immune-related adverse events. No cases sinusoidal obstruction syndrome was observed Conclusions: Our study demonstrates that HSCT after PD-1 blockade is feasible and not associated with higher mortality. We suggest that prior PD-1 blockade should not be considered a contraindication to HSCT in patients with relapsed and refractory Hodgkin lymphoma. severe The rate of severe acute and chronic GvHD was relatively higher than previously reported for PTCy-based prophylaxis, but was manageable in the majority of cases. The time between anti-PD-1 therapy and allo-HSCT and PTCy is likely to be important in the successful outcome of the transplant. Disclosures Moiseev: Novartis: Consultancy, Honoraria, Other: Travel grants, Speakers Bureau; MSD: Other: Travel grants; Celgene: Consultancy, Other: Travel grants; Takeda: Other: Travel grants; Pfizer: Other: Travel grants; BMS: Other: Travel grants.

Successful outcome with reduced-intensity condition regimen followed by allogeneic hematopoietic stem cell transplantation for relapsed or refractory anaplastic large-cell lymphoma.

We report a retrospective analysis of 38 patients (age ≤ 30years) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) for relapsed or refractory anaplastic large-cell lymphoma (ALCL). Median follow-up for survivors after undergoing allo-SCT was 72months (range, 35-96months). Eight patients received reduced-intensity conditioning (RIC) regimens, including three patients with fludarabine plus melphalan-based regimens and five patients with fludarabine plus busulfan-based regimens. The remaining 30 patients received myeloablative conditioning (MAC) regimens. Median ages in the RIC and MAC groups were 24 and 15years, respectively. The 5-year overall survival rates in the RIC and MAC groups were 100% and 49%, respectively (P = 0.018). The 5-year event-free survival rates in the RIC and MAC groups were 88% and 43%, respectively (P = 0.039). In the RIC group, four of the eight patients showed residual disease at allo-SCT, but all eight patients survived with complete remission (CR), including one patient with relapse. This result suggests that allo-SCT using the RIC regimen may be effective for relapsed or refractory ALCL in children, adolescents, and young adults, even in non-CR cases.

Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for patients with secondary acute myeloid leukemia (sAML), though the impact of conditioning regimens on HCT outcomes for patients with antecedent lymphoid malignancy is largely unknown. This multicenter, retrospective registry study of the ALWP of the EBMT assessed HCT outcomes in this population. In all, 549 patients ≥18 years with sAML following an antecedent lymphoid malignancy treated with first allograft between 2000-2016 were included. Myeloablative (MAC) and reduced intensity conditioning (RIC) was given in 258 (47%) and 291 (53%), respectively. At 2 years, leukemia-free survival (LFS) was 31.7% (95% CI, 27.5-35.9), overall survival (OS) was 37.4% (95% CI, 33-41.8), nonrelapse mortality (NRM) was 28.9% (95% CI, 25-33), and GVHD-free, relapse-free survival (GRFS) was 22.8% (95% CI, 19-26.6). In multivariate analysis, patients receiving RIC regimens had lower risk of NRM (HR: 0.58, CI: 0.40-0.83, p = 0.003), and improved LFS (HR: 0.67, CI: 0.52-0.85, p = 0.001). Patients with prior autologous HCT had inferior LFS (HR: 1.30, CI: 1.01-1.67, p = 0.01). This study demonstrates that sAML patients following prior lymphoid malignancy treated with RIC regimens have a lower risk of NRM and improved LFS, OS, and GFRS. Other variables associated with inferior outcomes include older age, active disease, adverse cytogenetics, and prior auto-HCT.

SUN-266 Anti-Mullerian Hormone as a Marker of Ovarian Reserve in Female Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation

Background/Methods: Gonadal dysfunction leading to infertility is a common complication after hematopoietic stem cell transplant (HSCT). Previous work by our group has shown that there is a significantly higher risk of delayed puberty and premature ovarian insufficiency among girls who receive high intensity, myeloablative conditioning (MAC) regimens compared to reduced intensity conditioning (RIC) regimens. Anti-Müllerian Hormone (AMH) is not regulated by gonadotropins and has minimal inter-cycle variations; therefore, it can be used as a marker of follicular ovarian reserve and aid in fertility counseling. We sought to assess ovarian reserve utilizing AMH levels in a retrospective study of female pediatric patients undergoing HSCT from 2013-2017 who received either MAC or RIC regimens. Results: In total, 100 female patients with a median age of 7 years had AMH levels pre-HSCT, of whom 33 (33%) also had post-HSCT levels. A wide variety of diagnoses were included: 32% had malignancy; 19% had immunodeficiency; 17% had Fanconi anemia (FA), 17% had hemoglobinopathy; 12% had non-FA marrow failure, and 3% had a metabolic disorder. Among those with pre-HSCT AMH levels, 71 (71%) had normal AMH for age, and 29 (29%) had low AMH for age. Of the 33 patients who also had post-HSCT AMH, 24 (72%) had low levels following transplantation. Twenty-five patients had both a normal pre-HSCT AMH and subsequent post-HSCT levels performed, 13 of whom (52%) received a MAC regimen and 12 of whom (48%) received RIC regimen. All (13/13) of the patients who received a MAC regimen had low AMH post-HSCT, while only 25% (3/12) of the patients who received a RIC regimen had low AMH post-HSCT (p=0.0002). Eight patients had both a low pre-HSCT AMH and subsequent post-HSCT AMH levels performed, 5 of whom received a MAC regimen and 3 of whom received a RIC regimen. All subject with low pre-HSCT AMH levels additionally had low post-HSCT AMH regardless of conditioning regimen used. Conclusions: AMH levels can be a useful marker for detection of low ovarian reserve and fertility counseling, especially if trends are followed before and after exposure to alkylating agents used for HSCT preparation. Our data show a significantly higher risk of low, downtrending AMH after exposure to high intensity MAC regimens compared to RIC regimens during childhood HSCT, which likely indicates a greater potential for infertility in patients receiving MAC regimens. These data correlate with a previous analysis demonstrating a significantly higher incidence of premature ovarian insufficiency and delayed puberty among girls receiving MAC regimens vs RIC regimens. Long-term follow up of this cohort will provide more information to understand the effects of HSCT on ovarian function and the utility of AMH as a predictor of future fertility potential.

Risks and Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies in Patients with HIV Infection.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for hematologic malignancies in persons living with HIV (PLHIV), however, uncertainties exist in many domains related to their care, including optimal donor selection, conditioning regimen, immunosuppression for graft-versus-host disease (GVHD), and long-term outcomes. We undertook a comprehensive systematic review from multiple databases to evaluate the foregoing uncertainties. The final sample comprised 49 patients (median age at HCT, 34 years; 46 males [93.8%]). Acute GVHD (aGVHD) was reported in 19 patients (59.3%) in the overall cohort, with grade II in 12 (37.5%) and grade III in 2 (6.2%). In the entire cohort, overall survival (OS) was 81.6% at 6 months and 56.6% at 12 months. Among 32 patients, the OS at 6 months was 73.3% for patients who received myeloablative conditioning (MAC) and 88.2% for those who received reduced-intensity conditioning (RIC), and OS at 12 months was 53.3% for MAC and 58.8% for RIC. Twenty-four patients were alive in complete remission on long-term follow-up, with 25 deaths reported. Fifteen deaths (60%) occurred due to relapse, including 3 (12%) from infection, 2 (8%) from GVHD, and 5 (20%) from other causes, including renal failure, respiratory failure, and liver failure. To our knowledge, this is the largest series of allo-HCT in PLHIV reported to date, and our results indicate that clinical outcomes (including engraftment, infection rate, and survival) are not significantly different from those in patients without HIV (historical controls). RIC regimens are associated with a slightly greater likelihood of survival compared with MAC regimens. Prospective trials are critically needed to evaluate the optimal conditioning regimens, ideal donor source, and most appropriate GVHD prophylaxis.

Single Center Retrospective Analysis of Outcomes Following Hematopoietic Cell Transplantation (HCT) for Primary Immune Deficiency (PID)

Background Successful hematopoietic stem cell transplantation (HCT) is curative in primary immune deficiency (PID), but data on post HCT late effects are scarce. We describe outcomes and late effects in PID HCT survivors at 1 year post HCT. Methods Retrospective data analysis was conducted on consecutive PID HCT recipients from Sept 2007-2017 on IRB approved protocol 0707. Outcomes queried included engraftment, graft versus host disease (GVHD), and late effects in survivors. Data review at 2, 5, and 10 years post HCT including analysis of cognitive outcomes and immune reconstitution are ongoing; specifically impact of disease type, age at HCT, and graft source. Results Thirty-nine PID HCT patients received reduced intensity conditioning (RIC) HCT with 1-year overall survival (OS) of 82%. Median age at HCT was 0.5 years (range 0.08 – 17.4 years) and 72% (28/39) were males. Stem cell source was peripheral blood in 72% (19 unrelated, 9 related), umbilical cord blood in 25.5% (10 unrelated), and bone marrow in 2.5% (1 unrelated). Donors were 16 HLA matched and 23 mismatched. RIC regimen was Busulfan AUC 5000 mcmol/L*min x 2 days, Fludarabine 60 mg/m2 × 6 days, rabbit ATG 2mg/kg x 4 days ± Thiotepa 5mg/kg x 1 day. Incidence of > Grade 2 acute GVHD and limited chronic GVHD was 5% (2/39) and 5% (2/39), respectively. Seven patients died due to infection (4), veno-occlusive disease (1), Grade 4 acute GVHD (1), and intracranial hemorrhage (1). Graft failure (GF) rate was 5% (1 primary GF and 1 secondary GF with EBV infection). Donor chimerism (DC) including T cell, was >95% in 60% and those with mixed chimerism had full T cell DC at 1 year post HCT. In 32 survivors, no cardiac, liver, renal, pulmonary abnormalities, or secondary malignancies were noted. Growth was significantly impacted with median height z-scores of -3, with 69% being Conclusion Successful RIC HCT is curative with excellent 1 year OS of 82% with minimal organ toxicities in PID patients; however, significant growth impairment was observed in the majority with some endocrine abnormalities at 1 year post HCT. While further ongoing analysis is imperative, this emphasizes the need for standardized prospective medical surveillance in order to earlier identify post HCT problems systematically and intervene appropriately to improve outcomes in post HCT PID patients.

Recurrent Genetic HLA Loss in Acute Myeloid Leukemia Relapsed after Matched Unrelated Allogeneic Hematopoietic Cell Transplant

Introduction: Leukemic escape from the graft versus leukemia (GVL) effect of allogeneic hematopoietic cell transplantation (HCT) is poorly understood. During prolonged periods of post-transplant remission, immunologic selection pressure can favor relapse mediated by acquired resistance to GVL-mediated clearance, such as loss of mismatched HLA in haploidentical transplants. We hypothesized that genetic mechanisms of immune evasion can cause late relapses after matched unrelated donor transplants for myeloid malignancies.Methods: We evaluated 580 adult patients with myeloid malignancies who underwent allogeneic HCT at our institution between 2001 and 2014 and experienced subsequent disease relapse. In 19% of these patients (n=112) relapse occurred at least one year after transplantation. The 25 patients included in the study had specimens banked at each of three timepoints: 1) prior to transplantation, with AML or MDS involvement, 2) approximately 100 days after transplantation, during the period of remission 3) at the time of disease relapse. The indications for transplantation were AML (n = 20) and MDS (n = 5). Transplants were from matched unrelated (n=14), matched related (n=9), and mismatched unrelated (n=2) donors. 12 patients received myeloablative conditioning and 13 received reduced-intensity conditioning regimens. Targeted sequencing of 187 genes, selected based on pathogenic involvement in myeloid malignancies or suspected involvement in immune evasion, was performed on all three timepoints from each patient. Genome-wide microarray-based copy number assessment was performed onthe pre-transplant specimen and post-transplant relapse specimens.Results: We identified three recipients with relapse-specific HLA loss via 1-8 Mb deletions or chromosome 6p arm-level copy neutral uniparental disomy (UPD). One of the HLA alterations was a deletion spanning HLA-B and HLA-C in a donor/recipient pair mismatched at HLA-C. However, in two other cases, relapse-specific HLA losses were identified in donor/recipient pairs that were fully matched at A, B, C, and DRB1. These findings suggest that HLA loss may allow leukemic cells to escape allogeneic immune recognition of minor HLA discrepancies and/or the presentation of minor histocompatibility antigens in the context of matched MHC presentation. These three HLA losses were identified among 14 recipients of matched unrelated donor HCT. HLA losses were not identified among recipients of matched related (n = 9) or mismatched unrelated (n = 2) allogeneic HCT.To evaluate potential interactions between canonical myeloid driver mutations and immunologic alterations, we defined the genetic characteristics of paired pre-transplant MDS/AML samples and post-transplant relapsed samples. In 22 out of 25 cases, at least one driver mutation that was present in the pre-transplant sample was also detected in the relapse sample. Clonal genetic evolution was common at the time of relapse and predominantly involved the acquisition of new subclonal mutations affecting mitogenic signaling (n = 9) and myeloid transcription factors (n = 11). TP53 alterations, including point mutations and 17p deletions were identified in 6 out of 25 patients, including two that remained stable before and after transplantation, and four that were newly detected at the time of relapse.Conclusions: We identified recurrent HLA loss via 6p UPD and segmental deletions in 3 out of 14 patients with late relapse after matched unrelated HCT. Although HLA loss has been observed at relapse after haploidentical HCT, the role of HLA loss as a mechanism of relapse after non-haploidentical HCT has remained unclear. HLA loss in cases with late relapse indicates a prolonged period of immunologic equilibrium, where effective GVL serves as a selective pressure for clonal genetic mechanisms of alloimmune evasion. In the context of MURD HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention. DisclosuresHo:Jazz Pharmaceuticals: Consultancy. Nikiforow:Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Myeloablative Versus Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Secondary Acute Myeloid Leukemia in Patients with Prior Myelodysplastic Syndrome/ Myeloproliferative Disorders: An ALWP of EBMT Study

▪Secondary acute myeloid leukemia (sAML) includes a heterogeneous group of diseases evolved from myelodysplasia, myeloproliferative disorders (MDS/ MPN), bone marrow failure syndrome or after exposure to leukemogenic agents such as chemotherapy and/or radiation therapy for malignant hematological (other malignant hematological diseases) or solid tumors.Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy but relapse is a frequent cause of failure after HCT occurring in more than 50% of patients. No systematic large analysis of HCT for sAML has evaluated risk factors and outcome based on a prior diagnosis of MDS or MPN. Therefore, the EBMT Acute Leukemia Working Party (ALWP) performed a multicenter retrospective registry study on patients undergoing HCT for sAML following MDS/MPN comparing myeloablative (MAC) to reduced intensity conditioning (RIC). ALWP-EBMT supplemental data forms were used to establish the occurrence of any prior hematological disorder or non-hematological malignancy as well as details of cytogenetic data and therapy.We studied 811 patients with a previous diagnosis of MDS/ MPD and available cytogenetic data who had received HCT for sAML from an HLA-identical sibling (MRD, n=344 [42.4%]) or unrelated donor transplant (URD- 9/10 or 10/10) during 2000-16. Median time from diagnosis (sAML) to transplant was 137 days (IQR 94-204). Median age at HCT was 59.57 years (IQR 52-65). sAML with adverse cytogenetics accounted for 269 (33.2%) patients. At the time of HCT, 401 (49.5%) patients were in CR1 and 367 (45.3%) had active disease. Median follow-up of surviving patients was 32 months (IQR, 11-62).Regimen intensity was assessed by EBMT criteria. MAC regimens were used in 326 (40.2%) patients while 485 (59.8%) received RIC. Older patients were more likely to receive RIC than MAC regimens (p<0.001). Most patients received peripheral blood stem cell grafts (n=731 [90.3%]; MAC 85.6% vs RIC 93.4%, p<0.001). A total of 534 (67.9%) patients were cytomegalovirus (CMV) seropositive pre-HCT. There were no significant differences in disease characteristics (e.g. disease status at transplant, cytogenetic risk category), donor source, year of transplant or CMV serology status between MAC and RIC cohorts. All patients received a calcineurin inhibitor-based combination as prophylaxis against graft versus host disease (GVHD) and 516 (63%) received in vivo T-cell depletion (rATG 474 (58%).A total of 667 (95.2%) patients engrafted (MAC 94.5% vs. RIC 95.6%; p=0.596). Acute GVHD (grade II-IV) within 100 days of HCT occurred in 24% (95% CI, 21-27; MAC vs. RIC, p=0.126) and 2-year cumulative incidence of chronic GVHD was 33% (95% CI 30-37; MAC vs. RIC, p=0.150). Three-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) were 41% (95% CI, 38-45; MAC 37% [31-42] vs. RIC 45% [40-49], p=0.029) and 25% (95% CI, 22-28%, MAC 25% [20-30] vs. RIC 25% [21-29], p=0.959), respectively. The Kaplan-Meier estimate of overall survival (OS) and leukemia free survival (LFS) at 3 years were 40% (95% CI, 37-44; MAC 44% [38-50] vs. RIC 38% [33-43], p=0.041) and 34% (95% CI, 31-38; MAC 38% [33-45] vs. RIC 31% [27-36], p=0.032), respectively (Figure 1).In multivariate analysis by Cox Regression, a higher RI was seen after RIC regimens (HR 1.72 [1.16-2.55]; p=0.0063). Patients receiving RIC regimens had a higher risk of chronic GVHD (HR 1.37 [1.02-1.84], p=0.0389). Non-relapse mortality (NRM) was equivalent in MAC and RIC groups.MAC regimens were associated with superior OS (HR 1.46, 95% CI 1.1-1.94; p=0.0085) and LFS (HR 1.37, 95% CI 1.02-1.85; p=0.0387). High risk cytogenetics and older age contributed significantly to inferior outcomes.In summary, this EBMT registry study of HCT for sAML after MDS/MPN is the largest cohort reported. Myeloablative conditioning regimens were associated with a lower relapse risk and superior survival. Given that NRM after HCT has declined in the current era, these data indicate that the outcome of HCT for sAML may be improved by careful patient selection for MAC regimens. Survival may be further enhanced by effective pre-HCT disease control (also associated with decreased NRM) and post-HCT pre-emptive therapy to decrease RI. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau. Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Schmid:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees; MoilMed: Membership on an entity's Board of Directors or advisory committees. Mohty:Sanofi: Honoraria, Speakers Bureau.

Peripheral blood stem cell versus bone marrow transplantation: A perspective from the Acute Leukemia Working Party of the European Society forBloodand Marrow Transplantation.

Over the past decade, transplantation of peripheral blood hematopoietic cells has increased and is now the predominant graft source for related or unrelated adult allogeneic hematopoietic stem cell transplantation. At the same time, increasing numbers of patients are receiving reduced-intensity conditioning (RIC) prior to hematopoietic stem cell infusion. In prior work using smaller patient numbers and limited data, RIC peripheral blood stem cell (PBSC) transplantation was shown to be noninferior to RIC bone marrow (BM) transplantation for acute leukemia. A recent, large registry analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation showed that peripheral blood grafts result in superior outcomes compared with BM after RIC regimens for acute leukemia. The T-cell-replete PBSC allografts are associated with significant graft-versus-leukemia (GVL) benefits that are important drivers of improved leukemia-free survival and overall survival. However, an increased risk of chronic graft-versus-host disease (cGVHD) after peripheral blood grafts is concerning and long-term follow-up comparing peripheral versus BM grafts after RIC regimens is needed. Further assessment of the long-standing risks should be undertaken in an effort to better understand whether the risk of cGVHD among peripheral blood graft recipients translates into continued GVL effects and long-term remissions and cures or if it results in late morbidity and mortality.

Both high and low levels of cellular Epstein-Barr virus DNA in blood identify failure after hematologic stem cell transplantation in conjunction with acute GVHD and type of conditioning.

The level of Epstein-Barr virus DNA in blood has proven to be a biomarker with some predictive value in allogeneic hematopoietic stem cell transplantation patients (HSCT). We evaluated the impact of EBV load on survival of 51 patients (32M/19F, median age: 32 years, from < 1 to 68 years old), who had received HSCT for different types of malignancies (49 cases) or non-malignancies (2 cases). The overall survival [1]was compared between patients with extreme and moderate cell bound EBV DNA levels. Different sources of stem-cells (peripheral blood stem, n = 39; bone marrow, n = 9; or umbilical cord blood, n = 3) were used. Twenty patients received reduced-intensity conditioning regimen while the other 31 received myeloablative conditioning. Patients with high or very low level of cell bound EBV-DNA levels had a shorter OS than those with moderate EBV load: OS at 5 years was 67% vs 90% (p < 0.03). There was a conspicuous relationship between EBV load and the reconstitution dynamics of total and EBV-specific T cells, CD4+ and CD4- CD8- (double negative) T cells in the few patients where it was analyzed. This was not statistically significant. Two other factors were associated to early mortality in addition to high or low EBV load: acute GVHD II-IV (p < 0.02) and pre-transplant conditioning with total body irradiation (TBI) ≥6 Gy, (p < 0.03). All the patients meeting all three criteria died within two years after transplantation. This points to a subgroup of HSCT patients which deserve special attention with improvement of future, personalized treatment.

Durable Long-Term Remission with Allogeneic Hematopoietic Cell Transplantation (HCT) for Relapsed/Refractory Follicular Lymphoma (FL)

Allogeneic HCT is the only curative treatment modality for relapsed/refractory follicular lymphoma (FL), but is less frequently utilized due to the concern for treatment related morbidity and mortality. Recent improvements in supportive care and use of reduced intensity conditioning (RIC) regimens have resulted in lower toxicity with comparable efficacy, mitigating some of these concerns. We undertook a retrospective analysis of 34 FL patients who underwent an allogeneic HCT at our institution between September 1995 and July 2014. Patient and disease characteristics along with treatment outcomes were analyzed and prognostic factors for survival evaluated. Final analysis included 33 patients after 1 patient was excluded for incomplete data. Our population was mostly male (67%), Caucasian (97%) with a median age at transplant of 43 yrs. Number of prior therapies £3 in 48% and 24% had received a prior auto transplant. Prior therapies included rituximab (70%), anthracycline (88%) and platinum (45%) containing regimens, while 30% had received R-CHOP chemotherapy. Disease status prior to transplant was complete remission in 12%, partial remission in 67% and relapsed/refractory in 21% of the cohort. 67% received HLA-identical sibling donor (MSD) transplant; 55% had myeloablative condition (MAC) regimen using Bu/Cy±VP16 and 45% received RIC regimen using Flu/TBI (400 cGy). Grade 3-4 acute GVHD was observed in 36%, while 67% experienced chronic GVHD. Crude relapse rate (RR) was 24% with majority of these events occurring within 18 months post-transplant. RR plateaued after 2 years indicating that a durable remission was observed in a proportion of the patients. 5 year non-relapse mortality (NRM), relapse free survival (RFS) and overall survival (OS) were 33%, 52% and 55% respectively. Among the 17 deaths observed, disease relapse and chronic GVHD (24% each) were the leading causes of death. In univariable analyses, we found no patient, disease or transplant characteristics as predictive of RFS or OS, and hence, multivariable analyses were not pursued. Conditioning intensity had no impact on outcomes; HR for RFS was 1.24 for MAC vs. RIC regimens (95% CI, 0.47-3.26, P=0.66) and HR for OS was 1.54 (95% CI, 0.57-4.22, P=0.40). Unlike previous studies, in our analysis, disease status prior to transplant was not prognostic for survival and this disparity could be attributed to the sample size. In conclusion, allogeneic SCT resulted in long-term disease remission in a proportion of our patients with relapsed/refractory FL. Flu/TBI RIC regimen was associated with comparable RFS and OS compared to MAC regimens. Allogeneic HCT should be considered as a potential treatment option in a select subgroup of relapsed/refractory FL patients.Figure 2RelapseView Large Image Figure ViewerDownload Hi-res image Download (PPT)