5-year Cumulative Incidence Of Relapse Research Articles

Prognostic Value of Minimal Residual Disease Measured By Flow Cytometry in Two Cohorts of Infants with Acute Lymphoblastic Leukemia Treated with MLL-Baby and Interfant Protocols in Large Multicenter Networks

Acute lymphoblastic leukemia (ALL) in infants is a relatively rare disease with peculiar biological features, high frequency of KMT2A gene rearrangements and grim prognosis. Even with new therapeutic approaches, event-free survival (EFS) in infants with ALL does not exceed 50%. Currently large cooperative studies of infant ALL have been promoted by the Interfant and MLL-Baby networks. Minimal residual disease (MRD) monitoring is considered a strong tool for optimizing management of childhood ALL. In contrast to older children in this age group the prognostic impact of MRD detected by multicolor flow cytometry (MFC) is still unclear. Aim of the present study was to evaluate the prognostic value of MFC MRD measurement during induction in infants with ALL treated with Interfant-99 and Interfant-06 protocols in AIEOP centers in Italy as well as MLL-Baby protocol in Russia and Belarus. Patients and methods. Two independent groups of patients were investigated: study cohort of 139 consecutive infants with newly diagnosed ALL enrolled between September 2003 and April 2016 in Russian and Belorussian centers with MLL-Baby protocol and validation group of 146 ones enrolled in AIEOP centers in Interfant trials during the same period. By availability of MFC MRD data obtained at day 15 and/or end of induction (EOI), 81 and 86 patients of study and validation cohorts respectively were selected for outcome evaluation. In 61 MLL-Baby patients (75.3%) and 61 AIEOP cases (70.9%) different types of KMT2A gene rearrangements were identified. All patients were diagnosed as BCP-ALL, except one with cortical T-ALL. Overall, day 15 samples were studied in 64 MLL-Baby patients and 73 AIEOP cases while EOI samples in 75 and 63 cases respectively. MRD detection was performed in Reference Laboratories in Ekaterinburg, Minsk and Padua according the BFM AIEOP FLOW Network SOP. MRD negativity was defined as <0.01% of all bone marrow nucleated cells. Results. Patients were stratified according to the AIEOP-BFM-ALL day 15 stratification usually used for older children into three risk groups: standard risk (SR: MRD<0.1%), intermediate risk (IR: MRD 0.1% to 10%) and high risk (HR: MRD≥10%). Patients' distribution was similar in both study and validation cohorts: 34.4% and 32.9% in SR, 53.1% and 54.5% in ImR, 12.5% and 12.3% in HR respectively. At EOI significant differences in MRD-positive and MRD-negative patients' distribution was observed in different protocols: 44 (58.7%) and 31 (41.3%) cases respectively for MLL-Baby, but 17 (27.0%) and 46 (73.0%) cases respectively for AIEOP group. It was observed that KMT2A-rearranged cases in both trials have slower MRD response compared to the children with wild type KMT2A. In study cohort the 22 SR patients had a 5-year EFS and cumulative incidence of relapse (CIR) significantly better than other ones, thus we considered two major groups of patients with different outcome: SR with 5-year EFS 67.4%, standard error (SE) 10.2; CIR 23.3%, SE 9.4 and non-SR with 5-year EFS 30.8%, SE 7.2; CIR 52.6%, SE 7.9, (p=0.0039 and p=0.0229, respectively). Difference between these groups was observed also in KMT2A-rearranged cases (n=49) both for 5-year EFS (60.0%, SE 12.7 and 23.2%, SE 7.3, p=0.0160) and in 5-year CIR (33.3%, SE 12.7 and 59.2%, SE 8.8, p=0.0881). Analysis of outcome in validation cohort confirmed these data. In study cohort outcome of children being MRD-negative at EOI (n=31, 5-year EFS 60.8%, SE 8.8 and CIR 29.3%, SE 8.4) was significantly better than that of MRD-positive patients (n=44, 5-year EFS 31.1%, SE 7.1 and CIR 57.6%, SE 7.8 with p=0.0153 and p=0.0267, respectively). Outcome by EOI MFC MRD in the validation cohort is generally in keeping with that of the study cohort. Interestingly, in AIEOP cohort MFC data showed a prognostic impact also in KMT2A-rearranged subgroup. In multivariate analysis with KMT2A-status, each MRD time-point data showed independent impact on the risk of relapse. Conclusion. Our data was obtained by well-harmonized MFC MRD monitoring in a large group of infants with ALL treated in a multicenter setting with two different protocols. In spite of differences in therapy, we observed strong and independent prognostic impact of MFC MRD both at day 15 and at EOI regardless the protocol applied. We can conclude that MFC MRD can be used in combination with KMT2A-status to improve treatment allocation in future protocols. Disclosures Parasole: Servier: Honoraria; Baxalta: Honoraria; Eusapharma: Honoraria. Pieters:jazz farmaceuticals: Consultancy; medac: Consultancy.

Impact of Donor KIR and HLA Genotypes on Clinical Outcomes According to Pre-Transplant Remission Status after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

Impact of Donor KIR and HLA Genotypes on Clinical Outcomes According to Pre-Transplant Remission Status after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

Weight Adjusted Urinary Creatinine Excretion Predicts Transplant Outcomes in Adult Patients with Acute Myeloid Leukemia in Complete Remission

Background: Sarcopenia, the loss of muscle mass, has been recognized as a prognostic factor for cancer patients. For example, low body mass index (BMI) was reported to be a risk of poor overall survival (OS) among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. However, low BMI was not associated with high non-relapse mortality (NRM) rate, and BMI may not directly reflect the physical condition. (Bone Marrow Transplant. 2014;49:1505-12). To evaluate the clinical impact of the muscle volume on the prognosis of allo-HSCT recipients, other biomarkers that directly reflect muscle mass may be warranted. Urinary creatinine excretion (UCE) has been reported to estimate muscle mass and have prognostic value for kidney transplant patients (Transplantation. 2008;86:391-8.). There is no report to evaluate clinical impact of UCE on the prognosis of allo-HSCT recipients. Therefore, we retrospectively analyzed the association between pre-transplant UCE and the transplant outcomes. Methods: We included 173 adult patients with acute myeloid leukemia (AML) in complete remission (CR) who underwent first allo-HSCT from 2006 to 2017 at our institute and measured UCE before allo-HSCT. Concerned the possibility of urine storage failure, two patients with low total daily urine volume (<0.5L/day) were excluded from this analysis. Therefore, we investigated the remaining 171 patients. In order to correct the physical disparities of individual patients, we evaluated the clinical impact of weight adjusted UCE (WA-UCE) ,i.e UCE / body weight [μmol/kg/day] (Intensive Care Med. 2018;44:1699-708.). We used receiver operating characteristics curve in order to determine the cutoff value of the WA-UCE and classified the patients into the high and low WA-UCE group. We evaluated transplant outcomes such as OS, progression-free survival (PFS), NRM, and cumulative incidence of relapse (CIR) between two groups. Results: The median age at allo-HSCT was 52 (range, 18-73) and there were more male patients (n=111) than female patients (n=60). Regarding cytogenetic risk, 15 (9.1%), 112 (65.8%), and 38 (23.0%) were categorized as favorable, intermediate, and poor risk, respectively (There were five patients without cytogenetic data). The median follow-up period of survivors was 704 (range, 9 to 3,857) days. We defined the cutoff value of the weight adjusted UCE as 148 μmol/kg/day in male and 128 μmol/kg/day in female. Among 171 patients, 90 patients (male = 59, female = 31) were in the high WA-UCE group and 81 patients (male = 52, female = 29) were in the low WA-UCE group. We found no significant differences between two groups in terms of the number of relapse before allo-HSCT, cytogenetic risks, conditioning regimens, hematopoietic cell transplantation comorbidity index, donor-recipient HLA matching, donor source, or estimated glomerular filtration rate. On the other hand, patient's age at allo-HSCT was significantly younger (low vs. high WA-UCE group: median, 53 [range, 18 - 73] vs. 48 [range, 19 - 68] years, P = 0.02) and BMI was lower (low vs. high WA-UCE group: median, 22.3 [range, 15.4 - 38.8] vs. 21.9 [range, 15.4 - 29.3] kg/m2, P = 0.003) in high WA-UCE group. In univariate analysis, we observed a significant difference in OS, PFS, and NRM between two groups (low vs. high WA-UCE group: 1-year OS, 60.1% vs. 80.9%, P < 0.01; 1-year PFS, 54.1% vs. 70.9%, P = 0.02; 1-year NRM, 24.8% vs. 12.3%, P = 0.02) (Figure1). On the other hand, there was no significant difference in 1-year CIR between two groups (low vs. high WA-UCE group: 21.1% vs. 16.8%, P = 0.63). In our cohort, the low BMI (< 18.5 kg/m2) was not significantly associated with OS, PFS, CIR, and NRM (low vs. high BMI group: 1-year OS, 77.6% vs. 69.9%, P = 0.51; 1-year PFS, 74.1% vs. 60.9%, P = 0.45; 1-year CIR, 14.8% vs. 19.5%, P = 0.02, 1-year NRM, 11.1% vs. 19.5%, P = 0.70) In multivariate analysis, the low WA-UCE was an independent risk factor for OS (Hazard ratio (HR) [95% confidence interval (CI)]; 2.29 [1.38 - 3.80], P < 0.01), PFS (HR [95% CI]; 1.76 [1.11 - 2.79], P = 0.02), and NRM (HR [95% CI]; 2.22 [1.13 - 4.36], P = 0.02) (table1). Conclusion: In allo-HSCT adult recipients with AML in CR, low WA-UCE before transplantation was associated with poor prognosis, which related to high NRM within 1 year. WA-UCE can be an independent, objective, simple, and reliable biomarker for evaluating muscle mass and predicting transplant outcome. Disclosures No relevant conflicts of interest to declare.

Achievement of Complete Remission (CR) with Measurable Residual Disease (MRD) Negativity Is Highly Prognostic in Patients (pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) Receiving First Salvage Chemotherapy

Achievement of Complete Remission (CR) with Measurable Residual Disease (MRD) Negativity Is Highly Prognostic in Patients (pts) with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML) Receiving First Salvage Chemotherapy

Measurable Residual Disease (MRD) Monitoring in Acute Myeloid Leukemia (AML) with t(8;21)(q22;q22.1) RUNX1-RUNX1T1 Identifies Patients at High Risk of Relapse: Results of the AML Study Group (AMLSG)

Measurable Residual Disease (MRD) Monitoring in Acute Myeloid Leukemia (AML) with t(8;21)(q22;q22.1) RUNX1-RUNX1T1 Identifies Patients at High Risk of Relapse: Results of the AML Study Group (AMLSG)

Outcomes after Treatment with Upfront Cyclophosphamide or Rituximab for Initial Acquired Thrombotic Thrombocytopenic Purpura

Background: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, life-threatening emergency caused by auto-antibodies against ADAMTS13. Current standard therapy utilizes plasma exchange (PLEX) and corticosteroids. Although this induces remission, disease relapse remains a common problem. Since more than 90% of aTTP is caused by an antibody to ADAMTS13, additional immunosuppressive therapy with rituximab (RTX) given upfront has been shown to lower relapse rates. An alternative therapy, Cyclophosphamide (CTX) has been used in relapsed disease, but data on its use in upfront management is limited to case reports only. Our study aims to compare outcomes at our institution between upfront CTX, RTX, and standard therapy alone. Our secondary objective is to identify initial presenting features that are predictive of higher relapse risk. Methods: In a retrospective cohort study, we identified all patients at our institution with a diagnosis code of TTP (ICD 9, 10: 446.6, M31.1) between 2009 and 2019. We only included patients with a confirmed diagnosis of aTTP, defined as having an ADAMTS13 level <10%, and either a positive ADAMTS13 inhibitor or antibody. We excluded patients with follow-up of less than 30 days, or thrombotic microangiopathy (TMA) due to other causes. Relapse was defined as recurrence of TMA in addition to an ADAMTS13 level <10%, or "laboratory relapse" evidenced as an acute drop of ADATMS13 level with a positive inhibitor with/without TMA. Time to first relapse was measured from the onset of remission, defined as the time of normalization of both platelets and lactate dehydrogenase (LDH) for at least 48 hours, until the time of relapse. The cumulative incidence of relapse (CIR) was estimated using Kaplan-Meier method, and its difference among treatment groups was examined by log-rank test. The effect of continuous and categorical covariates on relapse rate was estimated by univariate Cox model. The association of categorical variables was examined using chi-square test and the difference of continuous measurements among groups was tested using T-test or ANOVA. Results: A total of 42 patients with a diagnosis of aTTP were identified in our cohort. The average age at diagnosis was 43.7 years. All patients received standard therapy with PLEX and steroids upon initial diagnosis. The prophylaxis group (n=29) received additional upfront therapy with either RTX (n=22) or CTX (n=6), and the control group (n=12) was treated with PLEX and steroids alone. There were no significant differences in the baseline characteristics between both groups. The median time to first relapse was 34.9 months in the control group, and 108.3 months in the prophylaxis group. Treatment with standard therapy alone was associated with a multi-variate hazard risk of 6.38 (95% CI: 1.1-37.7, p<0.05) for time to initial relapse. CIR at 2, 4, and 8 years was higher in the control group (41.7%, 53.3%, and 68.8%) as compared to the prophylaxis group (31.3%, 43.8%, and 43.8%, respectively). No difference was noted in CIR with CTX versus RTX, which was 40% at 4 years with CTX compared to 47% with RTX, p = 0.97 (Figure 1). Similarly, no statistically significant difference was noted in the time to first remission between CTX and RTX treatment (18 days in with CTX versus 14.9 days with RTX, p=0.583). Inhibitor titer at diagnosis correlated inversely with duration of remission (HR: 1.29, 95% CI: 1.03-1.61, p<0.05). Initial presenting platelet count, peak LDH value or co-existing autoimmune disease were not predictive of the duration of remission. Conclusion: Our study is the first to examine outcomes in a subset of patients treated with upfront CTX therapy for initial aTTP, and suggests similar time to first remission and 4-year CIR as compared to RTX. Our institutional experience suggests that CTX may be considered as an alternative therapy in patients intolerant to RTX. However, given the small group of patients treated with CTX, larger, prospective studies are warranted to confirm this observation. Consistent with currently published literature, PLEX and steroid therapy alone was associated with a significantly shorter duration of remission compared to additional immunosuppressive therapy. Furthermore, higher inhibitor titers were predictive of a shorter duration of remission, suggesting a role for aggressive upfront immunosuppressive treatment in these patients. Disclosures No relevant conflicts of interest to declare.

Extranodal NK/T Cell Lymphoma Nasal Type: A Cohort Study from Latin America

Introduction: Extranodal natural killer/T cell lymphoma (ENKTL) nasal type is a rare and highly aggressive subtype of lymphoid neoplasia, with a characteristic epidemiology, predominating in the Asian population and some sites in Latin and Central America. Diagnostic pitfalls and the lack of large randomized trials partly explain the unsatisfactory outcomes reported, even with the recent advances such as the incorporation of asparaginase in the frontline regimens and the description of new prognostic factors. Since few reports from Latin America and non-Asian population are available, we conducted this retrospective study to evaluate clinical characteristics and outcomes in a Brazilian referral center. Methods: This is a retrospective single-center study, conducted in an academic center in Brazil. All patients diagnosed with ENKTL from May 1993 to March 2019 were included. Staging was performed according to Ann-Arbor classification. Patients were treated based at discretion of the physician. Survival analysis was performed using the Kaplan-Meier method and log-rank test for comparison. Cumulative incidence of relapse (CIR) was calculated using death as a competitor. Results: A total of 37 patients with ENKTL was included. Median age was 46 years (range, 18 - 84), with male predominance (54%) and Caucasian ethnic majority (87%). Localized disease (Stages I and II) was predominant (81%) and five cases of primary extranasal disease were found. Skin was the most frequent extranasal site affected (60%). Five patients had central nervous system (CNS) disease (3 at diagnosis and 2 during progression/relapse). Tumor site infection at diagnosis was documented in 74%. Only six patients had EBV viral load available at diagnosis, with an median of 650 copies/ml (range, 482 - 997). Other features are summarized in Table 1. Five patients did not receive any regimen (3 subjects died from sepsis before treatment and 2 received only supportive care). Among the treated patients, anthracycline-based regimens (CHOP-like including or not methotrexate) were the most common regimen (16/32, 50%), followed by concomitant chemotherapy/radiotherapy (CCRT) strategy (8/32, 25%). Asparaginase was included in the treatment in 16% of cases (5/32) and 9% received isolated radiotherapy (RT) (3/32). RT was performed in 81%, mostly using sequential strategies (61%). Incidence of febrile neutropenia and grade 3/4 mucositis during treatment was 88% and 65%, respectively. Complete response (CR) rate after the first-line regimen was 62.5% (95% confidence interval [CI]: 43.7 - 78.3) and primary refractory disease was found in 18.7%. Regarding the patients who achieved CR, 5-year CIR was 19.1% (95% CI 6.6 - 36.4). Autologous stem cell transplantation (ASCT) was performed in two cases after achieving a second CR. Median follow-up was 8.7 years, with 5-year OS of 45.9% (95% CI: 31.4 - 67.1) for all patients and 53.9% (95% CI: 38 - 76.5) among the treated group (Figure 1). Albumin level (<3.5 g/dL) at diagnosis was associated with worse PFS (p = 0.011) and OS (p = 0.0057) in the univariate analysis (unadjusted hazard ratio [HR]=5.16 (95% CI 0.06 - 0.60, p = 0.004) (Figure 2 and 3). Sex, staging, age, blood counts, infection at diagnosis, extranasal type, international prognostic index or employed regimen were not associated with outcomes in our cohort. Conclusion: There are few reports of clinical characteristics and outcomes of ENKTL in the Latin American population. Although the current data show an increase in response and survival rates in localized stages, published reports from non-Asian population still display poor outcomes. Hypoalbuminemia, as previously described, was associated with worse outcomes in our cohort and, along with the higher toxicity and infection rates, denote the challenge of adapting regimens in the Brazilian population. Cooperative multicenter initiatives and prospective strategies are essential to improve outcomes of this rare and poorly described disease in the non-Asian population. Disclosures No relevant conflicts of interest to declare.

Post Transplantation Measurable Residual Disease (MRD) Monitoring Using Next-Generation Sequencing Is Highly Predictive for Relapseafter Allogeneic Stem Cell Transplantation

Post Transplantation Measurable Residual Disease (MRD) Monitoring Using Next-Generation Sequencing Is Highly Predictive for Relapseafter Allogeneic Stem Cell Transplantation

Long-Term Outcome of Children with Acute Leukemia (AL) Given Alphabeta T and B-Cell Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation (TBdepl-haploHSCT)

Background: TBdepl-haploHSCT is a suitable option for children with AL in need of an allograft, lacking an HLA-compatible donor. We previously published promising results in a cohort of 80 children with AL, given this type of allograft (Locatelli et al., Blood 2017), demonstrating a low incidence of acute and chronic graft-versus-host disease (GvHD) and low non-relapse mortality (NRM), translating into a final outcome comparable to that of patients transplanted from an HLA-compatible donor. We present the long-term follow-up analysis of this study (NCT01810120), now including 134 patients, with a minimum observation time of 100 days after the allograft. Patients and methods: Between October 2010 and April 2019, 134 children with AL in morphological complete remission (CR) received TBdepl-haploHSCT from an HLA-partially matched relative (a parent in 97% of cases) at Ospedale Pediatrico Bambino Gesù in Rome, Italy. All patients were prepared to the allograft using a fully-myeloablative conditioning regimen including a combination of cytotoxic drugs and/or total body irradiation (TBI). Anti-T-lymphocyte globulin (ATLG) was used before transplantation (12 mg/kg total dose, from days -5 to day -3) to modulate bi-directional donor/recipient alloreactivity. Rituximab (200 mg/sqm) was administered on day -1 to prevent post-transplantation EBV-induced lymphoproliferative disorders (PTLD). No patient received any post-transplant GvHD prophylaxis. Results: Characteristics of patients enrolled in the study are shown in Table 1. Median follow-up of surviving patients is 60 months (range: 3 months - 8.7 years). Only 3 patients did not achieve engraftment (all affected by acute myeloid leukemia and who did not receive TBI during conditioning regimen); median time to neutrophil and platelet recovery was 13 (range 9-22) and 11 (range 8-23) days, respectively. Cumulative incidence of grade II-III acute GvHD was 16.5% (95% CI 9.9-22.6). One patient developed gut GvHD, while for all other patients skin was the sole organ involved; no case of grade IV GvHD was recorded. Eight out of the 123 patients at risk developed chronic GvHD, in all cases of limited severity, the cumulative incidence of this complication being 7.6% (95% CI 2.3-12.6). Six patients died for transplant-related complications (2 because of idiopathic pneumonitis and 1 each of disseminated adenovirus infection, cardiac insufficiency, combined CMV/rhinovirus pneumonia and sepsis from Pseudomonas aeruginosa), the 5-year cumulative incidence of NRM being 4.5% (95% CI, 1.8-9.0). Since 25 patients relapsed at a median time of 173 days (range 59-1012) after HSCT, the 5-year cumulative incidence of relapse is 21.1% (95% CI, 14.2-29.1). The 5-year probability of overall and leukemia-free survival (LFS) were 74.6 (95% CI 65.1 -71.9) and 74.4% (95% CI 65.4-81.4) (Figure 1A), respectively. Use of TBI during the preparative regimen, age at transplant above the median value (Figure 1B) and disease status at transplantation (CR1 and CR2, Figure 1C) were associated with better patient's outcome, because of a reduced incidence of relapse (Figure 1D for TBI). All these 3 factors remained statistically significant in multivariable analysis for LFS: hazard ratio (HR) for TBI was 0.16 (95% CI, 0.06- 0.37, p<0.001, HR for age at HSCT was 0.27 (95% CI, 0.11-0.65, p=0.003), while that for disease status was 0.49 (95% CI, 0.26-0.91, p=0.02), respectively. The 5-year GvHD/relapse-free survival was 69.9% (95% CI 60.8-77.3). The median CD3+ cell count on day +30, +90, +180 and +360 were 187, 215, 660 and 1260/mcl, respectively. Conclusions: These data confirm in a larger population and with a longer follow-up that TBdepl-haploHSCT is a safe and effective transplant option, being associated with a low risk of both NRM and acute/chronic GvHD, resulting into a 5-year LFS comparable or even better with that reported in studies using either an HLA-identical sibling or an unrelated volunteer as donor. In particular, the low incidence of chronic GvHD preserves a good quality of life in patients with long life-expectancy. Leukemia recurrence represents the main cause of treatment failure and strategies based either on the use of a titrated number of donor T cells transduced with a safety switch or ex-vivo depleted of the alloreactive component could further improve patient's outcome. Figure 1 Disclosures Merli: Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Algeri:Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

High Dose Flamsa, CLAG or FLAG-Based Sequential Conditioning Regimen Followed By Allogeneic Hematopoietic Transplantation Results in Favorable Outcome for High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome, Myeloproliferative Neoplasia Patients: A Multicenter Study in Singapore

Introduction: Allogeneic haematopoietic cell transplant ( allo-HCT) is an effective consolidative treatment for patients with certain haematological malignancies and gives the best outcome when done in remission. However patients with refractory acute myeloid leukemia (AML) or some myeloproliferative neoplasia (MPN) and myelodysplastic syndrome (MDS) deemed unable to achieve remission with standard induction are often excluded from allo HCT with conventional conditioning regimen as pre-transplant remission could not be achieved. Recently, a sequential transplant approach, as developed by the Munich group, comprising of intensive cytoreductive chemotherapy FLAMSA (Fludarabine/Amsacrine/Cytarabine) to decrease leukemia cell burden shortly prior to conditioning regimen, has been successfully used for high-risk (HR) AML/MDS with promising results. Methods: We studied 48 patients (median age 53 years, range 26 - 68) with high risk AML (n=38), as defined by refractory, relapsed disease, secondary leukemia, complete remission with adverse-risk cytogenetics according to ELN criteria, or high/very risk refined Disease Risk Index (DRI), MPN(n=2) and HR MDS (n=8) according to IPSS-R, undergoing allo-HCT using the sequential transplant approach in 2 transplant centers in Singapore between January 2009 and October 2018. The sequential transplant approach combined a cytoreductive chemotherapy, which consisted of either FLAMSA (n=17), FLAG +/- Ida (fludarabine/Cytarabine/Granulocyte Colony Stimulating factor (GCSF) +/- Idarubicin] (n=23), or CLAG (Clofarabine / Cytarabine / GCSF) (n=8), followed by reduced intensity (RIC) (N=43) or myeloablative (MAC) (N=5) conditioning regimen. All patients received peripheral blood stem cell from matched related donors (N=27), matched unrelated donors (N=14), or mismatched unrelated donors (N=7). Post-grafting immunosuppression consisted of calcineurin inhibitor and mycophenolate mofetil in all patients. Thymoglobuline was added for GVHD prophylaxis for unrelated donor transplant. Results: The median time to neutrophil > 1000/μL was 10 days (range, 9-25). With a median follow-up of 48 months (range, 9 to 111 months), the Kaplan-Meier estimate of overall survival (OS) and leukemia-free (LFS) at 5 years were 48 % (95% CI, 33-62), 45% (95% CI, 30-58), respectively. At 2 years cumulative incidence of relapse and non-relapse mortality (NRM) were 51% (95% CI, 33-67) and 15% (95% CI, 7-27), respectively. Patients receiving FLAG or CLAG based sequential regimen showed, lower cumulative incidence of NRM (2-year CI NRM: 7% vs 40%; p=0.037), and similar relapse (2 year CI relapse: 49% vs 53%; p=0.63) as compared to patients given FLAMSA-based sequential regimen, resulting in a trend towards more favourable OS (5 year OS: 53% vs 40%; p=0.33) and LFS (5 year LFS: 54% vs 35%; p=0.23). In multivariable analysis, only refined DRI showed significant impact on OS (p=0.04), but has no significant impact on LFS, NRM and relapse. The 5-year OS for patients with intermediate/high risk and very high risk DRI were 60% and 24%, respectively (p=0.024), and the corresponding 5-year LFS were 57%, and 27% (p=0.065), respectively (Figure 1 & Figure 2). The intensity of conditioning regimen did not significantly impact on OS, LFS, relapse and NRM. Conclusions: Sequential transplant conditioning with FLAMSA, FLAG or CLAG followed by allo-HCT is an effective strategy in overcoming the dismal prognosis of high risk AML, MDS and MPN, and enabling favourable long-term disease free survival. More studies on effective strategies such as post-transplant maintenance therapy with prophylactic donor lymphocyte infusion, are needed to further eliminate the risk of relapse, without increasing risk of treatment related toxicity. Disclosures No relevant conflicts of interest to declare.

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.

Value of Flow Cytometry for MRD-Based Relapse Prediction in B-Cell Precursor Acute Lymphoblastic Leukemia in a Multi-Center Setting

Background: PCR of rearranged antigen receptor genes is the method of choice for MRD quantification in ALL. Although FCM-MRD is faster and biologically more informative than PCR, the analysis requires a high level of training. The only larger published studies using FCM-MRD based stratification (Borowitz, Blood, 2008 and 2015) showed a clear association with clinical outcome in BCP-ALL. However, MRD analyses were centralized and these studies included only one MRD-based stratification (MRD levels at the end of induction). Patients and methods: We examined FCM-MRD as stratification tool in BCP-ALL at various timepoints in a large-scale multicenter (18 MRD centers) study. A total of 1487 patients with BCP-ALL (1298 children (younger than 18 years) and 189 adults (18-45 years) are included in the study and were treated according to the NOPHO ALL2008 protocol between July 2008 and February 2016. The median follow-up time for patients in first remission was 51 months (IQR 32-75). MRD was measured by FCM and/or real time quantitative PCR on days 15, 29 (end of induction) and 79 (for standard (SR) and intermediate risk (IR) patients) and prior to and after high risk blocks. A 6-colour FCM analysis including 3 standardized antibody combinations was used and performed in 18 laboratories. Patients were stratified by FCM-MRD, or by PCR-MRD if no FCM-MRD marker was available. End-of-induction MRD (cut-off 10-3) was used to stratify patients to standard risk (SR) vs intermediate risk (IR) or IR vs high risk consolidation therapy (in case of WBC > 100 x 109/L at diagnosis). Patients with MRD >=2.5x10-1 on day 15 were stratified to high risk block therapy. Patients with MRD >=5x10-2 on day 29 or day 79/post high risk-2 block MRD >=10-3 were stratified to HSCT. Primary outcomes were 5year event-free survival (5y EFS) and 5year cumulative incidence of relapse (5y CIR). Results: Only two patients (0.14% of total) had neither an informative FCM nor a PCR marker, and an informative FCM marker combination for MRD monitoring was identified in 96.2% of patients. There was a significant correlation between FCM- and PCR-MRD levels on day 15 (r=0.77, p<0.0001, n=153) and 29 (r=0.81, p<0.0001, n=140). Based on FCM-MRD only, the median MRD level on day 15, 29 and 79/post high risk-2 block was 5x10-3, 1.1x10-4, and below detection limit, respectively. Adults had significantly higher MRD levels at all time-points (p<0.0001 for day 15 and 29, p=0.0019 for day 79, Mann-Whitney). The 5y EFS was 86.1% (95% CI 84.1-88.1) with a 5y CIR of 9.5% (95% CI 7.8-11.3, n=1487). The day 29 FCM-MRD level was closely associated with clinical outcome and a higher hazard of relapse was seen independently for a FCM-MRD >=10-3 (hazard ratio (HR) 2.4, CI 1.6-3.7, p<0.0001), age>18 year (HR 3.0, CI 1.7-5.3, p<0.0001), WBC>=100 (HR 2.7, CI 1.6-4.6, p=0.0001), and B-other (HR 2.1, CI 1.2-3.5, p=0.0052) or high risk B-ALL cytogenetic aberration (rearranged KMT2A/iAMPchr21/hypodiploid) (HR 3.2, CI 1.6-6.1, p=0.0006) (multivariate cause-specific Cox regression, n=1328). Patients with a day 79 FCM-MRD >=10-4 and <10-3 had a significantly higher CIR (22.1%, CI 10.8-33.5%, n=68) compared to FCM-MRD <10-4 (7.5%, CI 2.1-12.8%, n=110) or undetectable (6.3%, CI 4.5-8.2%, n=999, p=0.0087 for FCM-MRD >=10-4 and <10-3vs <10-4 or undetectable). After adjusting for WBC, age, and the day 29 FCM-MRD level, a day 79 FCM-MRD >=10-4 and <10-3 was still significantly associated with a worse 5y CIR for non-transplanted patients (HR 2.3, CI 1.19-4.36, p=0.012 compared to undetectable FCM-MRD, n=1171). Patients with day 15 FCM-MRD <10-3 had a significantly better 5y EFS (92.0%, CI 89.2-95.0%) and CIR (3.9%, CI 1.7-6.1%, n=432) than patients with FCM-MRD >=10-3 and <2.5x10-1, who had a 5y EFS of 85.5% (CI 82.7-88.3%, p=0.0016, n=837) and a 3-fold higher 5y CIR (11.0%, CI 8.4-13.5%, p<0.0001, n=432). Among patients with day 15 FCM-MRD<10-3, the relapse incidence was comparable for patients with FCM-MRD 10-4 - <10-3 and below 10-4 (CIR 3.6, CI 0.5-6.7 vs. CIR 4.1, CI 1.0-7.2, p=0.83, n=432). Conclusion: FCM-MRD performed in a multi-center setting is a clinically useful method for disease monitoring and MRD-based treatment stratification in BCP-ALL. Moreover, FCM-MRD is a reliable indicator of outcome in BCP-ALL independently of other key risk factors. Residual disease >=10-4 and <10-3 at day 79 in SR/IR patients not allocated to HSCT further identifies patients with a high risk of relapse. Disclosures No relevant conflicts of interest to declare.

Outcomes Following Second Allogenic Haematopoietic Cell Transplantation in Patients with Myelofibrosis: A Retrospective Study on Behalf of the Chronic Malignancies Working Party of EBMT

Outcomes Following Second Allogenic Haematopoietic Cell Transplantation in Patients with Myelofibrosis: A Retrospective Study on Behalf of the Chronic Malignancies Working Party of EBMT

A Phase 2 Study of Glasdegib for the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients with High Risk of Post-Allogeneic Stem Cell Transplantation Relapse

A Phase 2 Study of Glasdegib for the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients with High Risk of Post-Allogeneic Stem Cell Transplantation Relapse

Maintenance Sorafenib Is Superior to Prophylactic DLI in Improving the Prognosis of FLT3-ITD-Positive AML after Allogeneic HSCT

Background: Compared with traditional chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve the prognosis of patients with FLT3-ITD positivity. Relapse after transplantation is still an important factor affecting survival. Prophylactic donor lymphocyte infusion (DLI) and maintenance sorafenib are two methods for preventing relapse after allo-HSCT in FLT3-ITD-positive acute myeloid leukemia (AML) patients, and their roles in these patients after allo-HSCT need to be further studied. Methods: From January 2014 to December 2018, 69 FLT3-ITD-positive patients who received allo-HSCT at our center were included in this retrospective study. All patients were divided into four groups according to the different treatments received: group A (23 patients who received maintenance sorafenib), group B (12 patients who received prophylactic DLI), group C (33 patients who received neither prophylactic DLI nor maintenance sorafenib), and group D (1 patient who received a combination of prophylactic DLI with maintenance sorafenib), because there was only one patient in group D, it was not included in the analysis. Results: For all patients, the 2-year estimated overall survival (OS) and leukemia-free survival (LFS) were 79.9% and 78.3%, respectively, and the 2-year cumulative incidence of relapse (CIR) was 17.2%. The 2-year estimated OS, LFS and CIR in group A, group B and group C were 95.7%vs75%vs66.8%, 95.7%vs74.1%vs70.2% and 4.3%vs6.7%vs26.1%, respectively. Group A was the best one in OS, LFS and CIR. Between the group A and group C, there were significant difference in OS(P=0.03) and LFS(P=0.04), but not in CIR(P=0.06).The OS in group A was significantly higher than group B(P=0.047), but the difference was not statistically in LFS and CIR (P=0.14 and P=0.21). Conclusion: Maintenance sorafenib after allo-HSCT was associated with improved outcomes for FLT3-ITD positive AML patients and was superior to prophylactic DLI in promoting FLT3-ITD-positive patients obtain a better survival after allo-HSCT. Figure Disclosures No relevant conflicts of interest to declare.

Pre-Transplant MRD Negativity Predicts Favorable Outcomes of CAR-T Therapy Followed By Haploidentical HSCT for Relapsed/Refractory Acute Lymphoblastic Leukemia: A Multi-Center Retrospective Study

Patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) usually have a very poor prognosis and an expected survival of less than 6 months.The complete remission (CR) rates in the setting of the first salvage chemotherapy are about 30% to 46% and these rates drop sharply to 18% to 25% after the second salvage chemotherapy. Chimeric antigen receptor T cells (CAR-T) can induce high CR rates of 70-95% (MRD negative CR rates of 60-90%) among patients with R/R ALL. Howeve, relapse after CAR-T treatment is supposed a main obstacle for long-term outcome. Some reports have described relapse rates of 20-70% when the follow-up was long enough. It remains controversial whether these patients should receive allo-HSCT after CAR-T treatment or not. We designed a multi-center retrospective study to assess the efficacy and safety profiles of CAR-T therapy followed by haplo-HSCT. A total of 31 patients treated with CAR-T therapy followed by haplo-HSCT were included. Eleven patients who progressed to MRD positive or relapse subsequently underwent haplo-HSCT (MRD positive or relapse group) and the rest 20 patients with MRD negativity received haplo-HSCT (MRD negative group). The median time from CAR-T infusion to haplo-HSCT was 83 (range 62-114) days. After a median follow-up period of 288 (range 189-554) days post-transplantation, the 100-day cumulative incidence (CI) of grade III~IV aGVHD was 0% and 10.5% in the MRD positive or relapse group and MRD negative group, respectively (P>0.05)(Figure 1a). One and 2-year CIs of cGVHD requiring systemic steroid therapy were 52.3% and 31.1% (P>0.05), 52.3% and 39.7% (P>0.05) in the MRD positive or relapse group and MRD negative group, respectively(Figure 1b).The 1-year cumulative incidence of CMV viremia was 90.9%, 68.4% and 77.8% in the MRD positive or relapse group, MRD negative group and the whole population respectively (P>0.05). The 2-year cumulative incidence of CMV viremia was 90.9%, 78.9% and 85.2% in the MRD positive or relapse group, MRD negative group and the whole population respectively (P>0.05). The 1-year cumulative incidence of EBV viremia was 90.9%, 79.6% and 84.2% in the MRD positive or relapse group, MRD negative group and the whole population, respectively (P>0.05). And the 2-year cumulative incidence of EBV viremia was 90.9%, 89.8% and 89.5% in the MRD negative or relapse group, MRD negative group and the whole population, respectively (P>0.05). Onset of CMV and EBV viremia occurred in 33.5 (26.3-50.0) days and 44.0 (28.5-57.0) days after transplantation in 24 and 25 patients, respectively. Median peak CMV DNA and EBV DNA load were 1.5X104 (2.6X103-3.4X104) copies/ml and 2.2X104 (1.1X104, 4.1X104) copies/ml, respectively. One and 2-year CIs of relapse were 84.8% and 6.7% (p<0.001), 100% and 15.2% (p<0.01%) in the MRD positive or relapse group and MRD negative group, respectively (Figure 1d). One-year GVHD and relapse free survival (GRFS), leukemia free survival (LFS) and overall survival (OS) in the MRD positive or relapse group and MRD negative group were 18.2% and 58.9% (P=0.024), 15.2% and 93.3% (P<0.001), 43.6% and 100% (P=0.002), respectively (Figure 1f). Two-year GRFS, LFS and OS in the MRD positive or relapse group and MRD negative group were 0% and 50.5% (P=0.007), 0% and 84.8% (P<0.001), 14.5% and 83.3% (P<0.001), respectively (Figure 1c,e,f). No patient died of therapy-associated complications. Relapse or MRD positivity at the time of haplo-HSCT is the only independent factor associated with poor LFS [hazard ratio (HR): 23.6, 95% confidence interval (CI): 2.78-201.63, P=0.004] and OS [HR: 10.4, 95% CI: 1.12-94.45, P= 0.037]. In conclusion, our trial provided data to illustrate the safety and efficacy profiles of a novel combining therapeutic strategy against R/R ALL by using the combination of CAR-T cells for re-induction followed by haplo-HSCT for consolidation. We confirmed that achieving pre-transplant MRD negativity after CAR-T treatment is a suitable basis for haplo-HSCT. Our study results imply that CAR-T therapy followed by haplo-HSCT could further improve LFS and OS without increasing risks of treatment-related toxicity in such a previously heavily treated population. Further evaluation is needed from larger scale studies with a more homogeneous patient population and longer follow-ups. Figure 1 Disclosures Blaise: Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria; Pierre Fabre medicaments: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Outcome of Autologous Hematopoietic Cell Transplantation in First Complete Remission(CR1) in Patients with Peripheral T-Cell Lymphomas(PTCLs)

Abstract Background Patients with peripheral T cell lymphomas (PTCLs) generally have a poor prognosis with conventional chemotherapy. Most studies demonstrates that, compared to the patients who did not achieve complete remission (CR) after initial therapy, the patients of PTCL who received autologous stem cell lymphoma (ASCT) as consolidation treatment show clearly advantage in survival. However, given the absence of randomized controlled studies, it is unproven that clinical value of consolidative ASCT for PTCL patients achieving CR1. There is a possibility that the survival is similar with or without up-front ASCT group. Thus, we collected the data of PTCL patients who attain CR1 following conventional chemotherapy in our center during the past 10 years. And the objective of this study is to evaluate overall survival(OS), progression-free survival(PFS), and cumulative incidence of relapse (CIR) between observation and first-line ASCT group. Patients and Methods Weconducted a retrospective study of patients with PTCL who were treated in our center from January 2009 to April 2019. The histopathologic diagnosis of all PTCL patients according to the World Health Organization classification. Exclusion criteria were the following: (1) anaplastic lymphoma kinase (ALK)-positive anaplastic large T-cell lymphoma; (2) cutaneous T cell lymphoma (CTCL); (3) concurrent B cell lymphomas; (4) natural killer/T-cell lymphoma (NK/TCL); (5) patients who underwent allogeneic stem cell transplantation. Furthermore, patients with PTCL age ≤65 years were included. Overall survival(OS )and progression-free survival(PFS) rates were estimated using the Kaplan-Meier method and Survival was compared using the log-rank test. Cumulative incidence of relapse (CIR) was compared by Gray's test competing risk test statistic. The level of statistical significance was set at p < 0.05. Results A total of 97 patients who met inclusion criteria were enrolled in our center from January 2009 to April 2019. And 59 (59/97, 60.8%)achieved CR1 after receiving induction chemotherapy. Table 1 summarizes the baseline characteristics for the patients in CR1. Of the 59 patients, 43 patients underwent observation and waiting in CR1, 16 patients underwent consolidative ASCT. PTCL NOS accounted for more than 50% at diagnosis in both groups. However, there was significant difference in median age between Non-ASCT group and ASCT group. Patients receiving ASCT were younger and in better physical condition. There were no difference in initial chemotherapy between two groups. Median follow-up time in the entire patient cohort for CR1 (59) was 31months. The median OS and PFS for patients who underwent observation in CR1 was 105 months and 20 months, the median OS and PFS for patients who underwent ASCT as consolidation treatment was 133 months and 91 months. There were no statistical significance in OS (105m vs. 133m, P=0.541) (Figure 1) and PFS (20m vs. 91m, P=0.237) (Figure 2). The estimated 2-year OS was 68.7% and 74.5% in the non-ASCT group and ASCT group, respectively. The estimated 2-year PFS was 41.9% and 62.5%, respectively. When considering incidence of disease relapse, the 2-year cumulative incidence of relapse in the non-ASCT and ASCT group was 41% and 25%, respectively. Again, however, this did not meet statistically significant(P=0.504) (Figure 3). Notably, among patients with advanced-stage disease, elevated LDH, extranodal involvement>1 sites or intermediate-to-high IPI scores, patients who received ASCT as consolidative treatment did not have long time survival compared to the non-ASCT group. Conclusion In conclusion, for PTCL patients achieving CR1 following induction therapy, consolidative ASCT does not extend overall survival and progression-free survival compared to observation. Similarly, consolidative ASCT also failed to reduce cumulative incidence of relapse. We favor proceeding to observe and wait because of high toxic of hematopoietic stem cell transplantation. However, The finding still needs to be confirmed in a larger, prospective study. Table 1 Disclosures No relevant conflicts of interest to declare.

Comparative Analysis of Alpha-Beta T-Cell and B-Cell Depleted (abTCD) HLA-Haploidentical Hematopoietic Stem Cell Transplantation (haplo-HSCT) Versus Abtcd Haplo-HSCT with T-Cell Add-Back of Rivogenlecleucel Cell [Donor T Cells Transduced with the Inducible Caspase 9 (iC9) Gene Safety Switch] in Children with High-Risk Acute Leukemia (AL) in Remission

Background: For children with AL candidate to receive an allograft and lacking a suitable HLA-matched donor, HLA-haplo-HSCT after abTCD may represent a valid alternative. Due to delayed recovery of adaptive T-cell immunity with abTCD-haplo-HSCT alone, we conducted a phase I/II trial testing the safety and efficacy of post-transplant infusion of a titrated number of donor-derived T cells transduced with the iC9 gene (rivogenlecleucel; ClinicalTrials.gov id: NCT02065869) in children with malignant and non-malignant diseases. Here, we report on the cohort of 70 patients with AL treated in Italy with abTCD-haplo-HSCT+rivogenlecleucel, comparing the results with those of 88 patients given abTCD-haplo-HSCT alone and previously published by our group (Blood 2018; 132:2594-2607). Patients and methods: Patients (age < 18 years) were transplanted between 2010 and 2018. Patient and disease characteristics are shown in Table 1. Median age at HSCT was 6 years (range 0.3-18), and median follow-up was 71 and 31 months for abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. Compared to the control group, abTCD-haplo-HSCT+rivogenlecleucel recipients were transplanted more recently and from a younger donor, and received a higher number of CD34+ cells (Table 1). Diagnosis did not differ between the 2 groups, acute lymphoblastic leukemia (ALL) being the most frequent diagnosis. All patients were transplanted in morphological complete remission (CR1 and CR2) and received myeloablative preparation. Graft composition is reported in Table 1; notably all patients received >10x106 CD34+cells/Kg and <1x105 alpha-beta+ T-cells/Kg. Patients did not receive any pharmacological post-transplant graft-versus-host disease (GvHD) prophylaxis. Results: Graft failure occurred in 2% of patients in each group. Median time to neutrophil and platelet engraftment was 14 (6-23) and 11 (5-56) days, with no differences between groups (p=0.28). Rivogenlecleucel were infused at a median time of 21 days (range 11-59). Treatment was well tolerated; no infusion-related side effects were recorded. Cumulative incidence (CI) of 100-day grade II-IV acute GvHD was 18.9% vs 15.9% (p=0.77) and CI of 1-year chronic GvHD was 6.9% vs 5.7% (p=0.56) in abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. The 4-year non-relapse-mortality (NRM) was significantly lower in abTCD-haplo-HSCT+rivogenlecleucel (1.4% vs 8%, p=0.05) (Figure 1). There was no statistically significant difference in the 4-year CI of relapse (RI) (17% vs. 25%, p=0.30), respectively. Disease recurrence was the most common causes of death in both groups, viral and fungal infections being the most frequent non-relapse fatalities. The 4-year overall survival (OS) and leukemia-free survival (LFS) was 70% vs 87%, p=0.01 (Figure 2) and 67% vs 82%, p=0.05, for abTCD-haplo-HSCT and abTCD-haplo-HSCT+rivogenlecleucel, respectively. There was no difference in 4-year CI of CMV reactivation between the 2 groups (p=0.68), median time to CMV reactivation being 29 and 30 days (p=0.29), respectively. Once infused, rivogenlecleucel expanded (mainly in the CD8+ subset), reaching a peak at 9 months after infusion. At 6-months, median CD3+, CD3/CD4, CD3/CD8, CD3-/CD56 and CD20/CD19 count/microL were 820, 265, 225, 141, 171, for abTCD-haplo-HSCT and 898, 294, 288, 214, and 161 for abTCD-haplo-HSCT+rivogenlecleucel, (p=ns, p=ns, p=0.02, p=0.03, p=ns), respectively. The advantage in the recovery of CD3/CD8 and CD3-/CD56 after abTCD-haplo-HSCT+rivogenlecleucel persisted at 1 year (p=0.01, p=0.03, respectively). In multivariable analysis, abTCD-haplo-HSCT+rivogenlecleucel was associated with better OS (HR 0.27, p=0.003) and LFS (HR 0.40, p=0.001); there was also a trend for lower relapse risk (HR 0.50, p=0.098). Age below the median value at HSCT (HR 2.62, p=0.01), CR1 at HSCT (HR 0.35, p=0.03) and use of irradiation in the conditioning regimen (HR 0.32, p=0.02) were other factors correlating with OS and LFS. Conclusions: These data confirm that the infusion of donor-derived rivogenlecleucel is safe and well tolerated. Rivogenlecleucel cells infusion contributed to enhance recovery of cytotoxic T and NK cells, improving patients NRM and OS/LFS. Rivogenlecleucel (with the possibility of inducing apoptosis of donor T cells) may facilitate the cellular therapy approaches aimed at optimizing immune recovery after HSCT. Disclosures Merli: Amgen: Honoraria; Bellicum: Consultancy; Novartis: Honoraria; Sobi: Consultancy. Algeri:Bluebird bio: Consultancy, Honoraria; Miltenyi: Honoraria; Atara Biotherapeutics: Consultancy, Honoraria. Woodard:Bellicum Pharmaceuticals, Inc: Employment, Other: Stock, Stock options. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy.

Full Donor Chimerism after Allografts for Myelofibrosis: The Role of Conditioning Regimen

Background : The conditioning regimen for patients with myelolfibrosis undergoing an allogeneic HSCT is usually composed of a combination of fludarabine (FLU) with one alkylating agent, busulkfan (BU), thiotepa (THIO) or melphalan. In a recent prospective randomized study comparing BU-FLU versus THIO-FLU, the proportion of patients with full donor chimerism at 6 months, was respectively 63% and 65% (Patriarca et al, BBMT 2019). Aim of the study. Assess the rate of full donor chimerism in patients with myelofibrosis, after conditioning with one or two alkylating agents. Methods. We analyzed 113 patients with myelofibrosis, for whom chimerism data were available on day +30 . There were two groups: 35 patients were conditioned with either thiotepa-cyclophosphamide , thiotepa-fludarabine or busulfan-fludarabine (ONE-ALK), whereas 78 patients were prepared with thiotepa, busulfan, fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years, p=0.008), were less frequently splenectomized pre-HSCT (30% vs 54%, p=0.03), had more frequently intermediate-2/high DIPSS scores (89% vs 74%, p=0.04) , and had comparable transfusion burden pre-HSCT (p=0.7). Chimerism was assessed via STR (PowerFlex-Promega) Results. The proportion of patients with full donor chimerism on day +30 in the TBF vs the ONE-ALK group was 87% vs 51% (p=0.00002); on day +60 these figures were 93% vs 13% (p<0.0001) and on day +90 , the figures were 90% vs 21% (p<0.00001). Full donor chimerism on day+30 was achieved in 81% of patients with DIPSS int1 (n=16), 74% of patients with int2 DIPSS, and 70% of patients with high risk DIPSS (p=0.6). Acute GvHD grade II-IV occurred in 27% vs 37% of patients in the two groups (p=0.7), and moderate severe chronic GvHD in 20% and 21% (p=0.8). The 5 year cumulative incidence of relapse was 8% in the TBF group, versus 50% for the ONE-ALK group (p<0.0001), whereas the CI of TRM was 25% vs 11% (p=0.1). The 5 year actuarial disease free survival (DFS) was respectively 65% for TBF and 38% for the ONE-ALK group (p=0.004). Complete chimerism day+30. When looking at whether patients had (n=84) or not (n=29) full donor chimerism on day +30, the CI of relapse was respectively 44% vs 15% (p=0.002), the CI of TRM 18% vs 15% (p=0.5), and the 5 year DFS 65% vs 32% (p=0.001). Conclusions. Early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis undergoing an allogeneic HSCT. The combination of 2 alkylating agents in the conditioning regimen, provides a significantly higher chance of achieving full donor chimerism on day+30, and thus long term disease control. Figure Disclosures Angelucci: Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; Roche: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; BlueBirdBio: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC.

Does Addition of Rituximab (R) to BEAM Conditioning Improve Outcomes of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)?

Introduction: Rituximab-based high-dose therapy (HDT) is frequently prescribed to DLBCL patients (pts) undergoing auto-HCT. However data supporting the benefit of adding R to auto-HCT conditioning are not available. Herein, we report the impact of R-based conditioning on auto-HCT outcomes of DLBCL pts. Methods: Using the Center for International Blood and Marrow Transplant Research registry, 862 adult (≥18 years) DLBCL pts undergoing auto-HCT, between 2003-2017 were included. Analysis was limited to pts receiving BEAM (BCNU, etoposide, cytarabine, melphalan)-based HDT, as R was infrequently used with non-BEAM conditioning regimens. All pts received R-containing chemoimmunotherapy in the frontline setting and had chemosensitive disease prior to HCT. Early chemoimmunotherapy failure (ECitF) was defined as not achieving a complete remission (CR) after frontline chemoimmunotherapy or relapsing within 1 year of initial diagnosis. Primary outcome was overall survival (OS). Secondary outcomes included non-relapse mortality (NRM), relapse, progression-free survival (PFS) and infectious complications within 100 days post-HCT. Results: The study cohort was divided into 2 groups; BEAM (n=667) and R-BEAM (n=195). The baseline characteristics of the 2 cohorts were comparable including age at auto-HCT, disease stage, Karnofsky performance score, extranodal involvement, time from diagnosis to auto-HCT, number of prior therapies, remission status, and ECitF. However, significantly more R-BEAM cohort patients received R as part of last therapy line before auto-HCT (75% vs. 86%; P=0.001). Median follow-up of survivors was 48 (range 1-171) and 64 (range 3-142) months in the BEAM and R-BEAM cohorts, respectively. On univariate analysis, the 4 year cumulative incidence of relapse (41% vs 44%), NRM (11% vs 9%), PFS (48% vs 47%; Figure 1) and OS (58% vs 61%; Figure 2) were similar in the R-BEAM and BEAM groups, respectively (Table 1). On multivariate analysis, no significant difference was seen in OS (HR 0.81; 95% CI 0.81-1.31; P=0.83) or PFS (HR 0.94; 95% CI 0.76-1.18; P=0.61) (Table 1) between the two cohorts. Addition of R had no impact on risk of relapse (HR 0.83; 95% CI 0.65-1.07; P=0.15) or NRM (HR 1.43; 95% CI 0.909-2.26; P=0.12). Variables independently associated with lower OS included older age (HR 3.05; 95% CI 1.81-5.13; P<0.001), not being in CR at auto-HCT (HR 1.67, 95% CI 1.39-2.07; P<0.001) and presence of ECitF (HR 1.52, 95% CI 0.54-3.26; P<0.001). Older age (HR 2.26, 95% CI 1.48-3.45; P<0.0002) and not being in CR at auto-HCT (HR 1.78, CI 1.47-2.14; P<0.0001) were also associated with inferior PFS. There was no significant difference in the 100-day cumulative incidence of bacterial, viral or fungal infections between the two cohorts. Disease relapse was the main cause of death in both BEAM and R-BEAM cohorts (66% vs 55%). Conclusion: In this large registry analysis of DLBCL pts undergoing auto-HCT, adding R to BEAM conditioning had no impact on transplantation outcomes. Older age, absence of CR and ECitF were associated with inferior survival. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Consultancy; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Atara Bio: Consultancy. Sureda:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Hamadani:ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau.