Allo Stem Cell Transplantation Research Articles

Real-World Outcomes of Brexucabtagene Autoleucel (brexu-cel) for Relapsed or Refractory (R/R) Adult B-Cell Acute Lymphoblastic Leukemia (B-cell ALL): Evidence from the CIBMTR Registry

Background Brexu-cel is a CD19 CAR T therapy first approved by the FDA in 2021 for adult patients (pts) with R/R B-cell ALL. In the pivotal phase II ZUMA-3 single arm trial, brexu-cel achieved a high rate (71%) of complete remission or complete remission with incomplete hematological recovery (CR/CRi) with a manageable safety profile. Here, we report outcomes of brexu-cel in a broad real-world patient population. Methods A total of 197 pts with B-cell ALL were infused with brexu-cel and prospectively enrolled between July 2021 and May 2023 in the CIBMTR registry across 67 centers in the US. In this analysis, we included 138 pts with at least one scheduled follow-up at Day 100 and evaluable safety and effectiveness outcomes. Descriptive statistics, Kaplan-Meier estimator and cumulative incidence functions were used to summarize outcomes. Results Median age was 43 years (range, 19.4-79.4; 19% were age ≥60 years) and 52% were males. Pts had a diverse ethnic background: 50% non-Hispanic White, 28% Hispanic, 11% non-Hispanic Black and 7% non-Hispanic Asian. More than half (55%) of pts had poor cytogenic risk score at diagnosis. Prior to lymphodepletion (LD), the majority of pts had: ECOG performance status of 0 or 1 (80%); at least one clinically significant comorbidity (79%); and Ph-negative disease (64%). Furthermore, 44% had evidence of ≤5% bone marrow blasts; of these (n=49), 65% were MRD negative. Extramedullary disease and CNS involvement was observed in 22% and 10% of pts prior to LD, respectively. As such, based on adapted criteria available in the registry data, 91% of pts in this cohort would have been ineligible for ZUMA-3. Pts received a median of 4 prior lines of therapy (range 1-13); 46% had prior inotuzumab and 58% had prior blinatumomab. One third (35%) had prior allogeneic (allo) stem cell transplant (SCT). Moreover, 41% of pts received bridging therapy prior to LD. Median time from leukapheresis to brexu-cel infusion was 32 days (inter-quartile range [IQR] 27-42)) and median follow-up time was 5.9 months (95% CI: 5.1-6.1) (Table 1). Overall CR/CRi rate by Day 100 post infusion was 76%; 70% were still in remission at 6 months post initial response (95% CI: 55-80). For those who were not in response before LD, 63% of them converted into a CR/CRi. Relapse free survival at 6 months was 53% (95% CI: 42-62). The overall survival rate at 6 months was 78% (95% CI: 69-84); primary causes of death were primary disease (n=13/32, 41%) and infection (n=7/32, 22%). About one third (31%) of responders received a subsequent allo SCT. High response rates were observed in all pts regardless of age, prior exposure to blinatumomab, allo SCT, or presence of extramedullary disease prior to LD. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS, ASTCT consensus) occurred in 9% and 24% of pts, respectively (Table 2). Treatment for CRS and/or ICANS consisted mainly of tocilizumab (67%) and corticosteroids (51%). Most of these adverse events were resolved within 3 weeks of infusion (CRS, 94%; ICANS, 80%). Prolonged cytopenia and neutropenia 30 days post infusion was experienced by 42% and 33% of pts, respectively. Conclusion In this largest-to-date real-world evidence study of brexu-cel in adult pts with B-cell ALL, response and safety outcomes were consistent with findings from ZUMA-3, even with 91% of patients not meeting ZUMA-3 eligibility criteria. Updated data with longer follow-up will be reported at the time of presentation. *First and second authors are equal contributors

Real-World Efficacy and Safety of Rituximab, Lenalidomide and İbrutinib Combination in Patients with Relapsed and/or Refractory Non-Hodgkin Lymphoma

Background: Relapsed or refractory (R/R) Non-Hodgkin Lymphoma (NHL) is associated with poor outcomes and the therapic options are limited. Recently, the combination of rituximab, lenalidomide, and ibrutinib (RLI) suggest promising efficacy in some clinical studies. Consequently, we report outcome of patients with R/R HL treated with RLI in this retrospective study aiming at evaluating efficacy and safety of RLI in a real-life setting. Methods: This retrospective, single-center study analyzed the outcomes of RLI as an off label salvage theraphy in patients with R/R NHL between June 2020 and April 2022. All patients received Lenalidomide 10-25 mg po daily on days 1-21 every 28 days and Ibrutinib 560 mg po daily on days 1-28. Patients with diffuse large B-cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), marginal zone lymphoma (MZL) received Rituximab at a dose of 375 mg/m2 iv on day 1 of cycles 1-6 every 28 days, patients with mantle cell lymphoma (MCL) received the same dose of Rituximab once a week for 4 weeks during cycle 1, then on day 1 of cycles 2-12 every 8 weeks. Ibrutinib and/or lenalidomide was administered until progression or unacceptable toxicity. The response was assessed with according to the Lugano criteria. The primary end point was overall response rate (ORR). Secondary endpoints were complete response (CR), partial response (PR), time to response (TTR), duration of response (DoR), overall survival (OS), progression free survival (PFS) and safety. Results: We analyzed 21 patients including DLBCL (n = 16), PCNSL (n = 2), MCL (n = 2), MZL (n = 1). The median age was 60 years (range, 24-84). The majority of patients had advanced disease stage (53%) and were refractory to their last therapy (57%). The non-GCB type was more common (67%) in patients with DLBCL and PCNSL. Nine patients (56%) with DLBCL had MYC and BCL2 and/or BCL6 rearrangements. Median number of prior therapies was 3 (range, 2-6). Eleven patients had prior auto and/or allo stem cell transplantation. Median follow-up time was 6.6 months (range, 0.4-22.3). Eleven patients (52%), 6 patients (29%) and 2 patients (10%) received RLI for ≥ 3, 6 and 12 months respectively. Patients had received a median of 3 (range, 1-19) cycles of RLI. Progressive disease (PD) was the most common reason for treatment discontinuation (53%). All of the patients were evaluable for response. The median TTR was 2 months (range, 1.7-3.8). The ORR was 38% (95% CI 15%-61%) with 29% CR and 9% PR. At the time of the analysis, the median DoR was 12.8 monts (range, 4.4-19.5+). Deaths were reported for 13 (62%) patients [n = 10 PD, n = 3 adverse events (AEs)]. The median OS was 7.9 months (95% CI 2.2-13.5) and median PFS was 3.5 months (95% CI 0.0- 8.3). The most common non-hematologic AEs were fatigue (48%), infection (38%), diarrhea (29%). AEs were frequently reported at the 25 mg lenalidomise dose, but the majority (77%) of patients experienced a grade 1-2 AE. The hematologic AEs were neutropenia (48%) [grade 3-4 (100%)], thrombocytopenia (19%) and anaemia (19%). AEs led to discontinuation in 5% (n = 1) of patients (sepsis). Conclusions: Our results suggest that RLI is a viable therapeutic option with promising activity and favorable toxicity profile in patients with R/R NHL patients.

Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T

CD19-targeted chimeric antigen receptor T lymphocytes (CAR-T) has demonstrated a high proportion of complete remission in the treatment of relapsed refractory acute B cell lymphoblastic leukemia (r/r B-ALL). It is of great clinical significance to explore which factors will impact long-term disease-free survival of patients with r/r B-ALL after CAR-T therapy without bridging bone marrow transplantation. Our study found that, in patients with r/r B-ALL without bridging transplantation, the patients' age; infusion dosage; whether they had undergone allo-stem cell transplantation before CAR-T therapy, using CD-19-targeted or CD19/CD22-dual-targeted CAR-T; whether there is fusion gene; tumor burden before therapy; and comorbidity had no significant relationship with their long-term disease-free survival. We found only that CAR-T persistence was highly correlated with patients' long-term disease-free survival. So, we further profiled CAR-T cells using single-cell sequencing and found that there is a specific Tcell subset that may be associated with the long-term persistence of CAR-T. Finally, according to the single-cell sequencing results, we established cell production process named PrimeCAR, which shared common signaling pathways with the Tcell subset identified. In the preliminary clinical study, prime CAR-Ts yield good persistence in peripheral blood of patients with B-ALL and lymphoma, without observing grade 2 or higher cytokine release syndrome.

Patterns and Prognostic Impact of CNS Infiltration in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia

Acute lymphoid leukemia (ALL) is a subtype of acute leukemia which portends a high risk of central nervous system (CNS) infiltration. At the diagnosis, 5-10% of ALL patients have CNS involvement, which has been demonstrated to decrease overall survival (OS). Based on pediatric trials, conventional cytology (CC) has been the standard for CNS disease assessment, although, more recently, flow cytometry (FC) has gained space across several centers. In this study, we intend to: i) access the impact of CNS involvement (defined by CC or FC) on OS, event-free survival (EFS) and relapse of ALL patients treated in a public health center; ii) find variables associated with CNS infiltration in this cohort. Methods: This retrospective study encompassed 105 cases of ALL newly diagnosed at Instituto do Cancer de Sao Paulo (ICESP). Clinical data were collected from Leukemia clinic database, already approved by Local Ethics Committee. Variables related to cerebrospinal fluid (CSF) were collected from the first lumbar puncture (LP). Traumatic LP was defined as more than 10 red blood cells/µL. CNS status was assessed through the COG's classification and divided into positive/negative for analysis purposes. Patients were treated with different regimens, but intensive intrathecal chemotherapy was given in CNS2 or 3 cases, while cranial irradiation was scheduled for CNS3 patients, only. Results: A total of 105 cases were diagnosed from 2014 to 2020. Only one was excluded (death before the first LP). Median age at diagnosis was 37 years (range, 15-79) with a male majority (58%). Most cases had a B-cell phenotype (76%), followed by T (19%) and ambiguous (5%). Philadelphia chromosome was found in 39%. Eighty-nine percent received corticosteroid at the time of LP with a median time of 7 days. Traumatic LP was reported in 50%. CSF resulted positive for disease in 15% (16/104) and 26% (19/72), by CC and FC, respectively. Among those with a positive CC, 56% (9/16) had a traumatic LP. By COG's classification, CNS1, CNS2 and CNS3 were found in 84%, 14% and 2% of cases, respectively. At the time of PL, 44% of patients presented blasts in peripheral blood. By comparing CC and FC, we noticed only one case with CCpos/FCneg whereas 9/19 with FCpos did not have CCpos. Sensitivity and specificity of CC for CNS disease were 53% and 98%. Traumatic LP and positive CC were not statistically correlated (p=0.8) and prior chemotherapy was associated to higher traumatic LP rates (56 vs 31%, p=0.019). Higher white-blood cell (WBC) counts were found in subjects with positive CC or FC (Mann-Whitney test, p=0.007 for CC). Furthermore, the blast percentage was also relevant for CNS positivity (p=0.027). Genetic subgroup, age, CD34 expression and phenotype were not correlated with CNS invasion, among others. Most patients received adapted versions of BFM (n=43), GRAAPH (n=24) and GRAALL-Elderly (n=18) regimens. Five patients received cranial irradiation. Median OS for the whole cohort was 16.4 months, with a 3y OS of 42.5% (95% CI 33.5-54). For BFM subset (Philadelhpia-negative, below 50 years-old), OS and EFS were 53.5% and 37.3%. We did not find correlation between CNS disease with OS or EFS in univariate analysis. Three-year relapse rate was 38.5% (95% CI 29-49) whereas non-relapse mortality (NRM) was 33%. In multivariate analysis, a positive CC increased relapse rate (HR= 2.3 [95% CI 1.1-4.9, p 0.029]). Initial WBC was also correlated with relapse in our cohort. Among relapses, only one was isolated in CNS, while 13 had concomitant bone marrow and CNS involvement. Eighteen patients proceeded to allo-stem cell transplantation so far. Conclusion: Several studies have demonstrated correlation between CNS infiltration and shorter OS in ALL, even though it relies on how these patients are managed and how CNS is assessed upfront. Our data showed that those who had a positive CSF cytology had a higher risk of relapse, whereas FC was not able to discriminate this risk. Survival rates seem to be increasing over the last years by the adoption of a stratified risk strategy. CSF contamination do not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1194: A PHASE IB TRIAL OF ITACITINIB COMBINED WITH ALEMTUZUMAB IN PATIENTS WITH T-CELL PROLYMPHOCYTIC LEUKEMIA (T-PLL)

Background: T-cell prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm with an aggressive clinical course including rapid lymphocyte proliferation, progressive organomegaly, lymphadenopathy, pleural and pericardial effusions, skin manifestations, and severe B-symptoms. Overall prognosis has been poor, with inadequate response to conventional chemotherapy and limited efficacy of allo stem cell transplant (SCT). The CD52 monoclonal antibody alemtuzumab (CAMPATH) has been the most effective therapy for T-PLL, but responses are not durable. Three quarters of cases of T-PLL harbor activating mutations in the JAK-STAT pathway (JAK1, JAK3, STAT5b, IL2RG). Aims: We designed astudy to evaluate the combination of the JAK1 inhibitor itacitinib with CAMPATH to target activated JAK-STAT signaling. Methods: 15 pts were enrolled (Table 1). 8 pts (53%) were newly diagnosed and 7 pts (47%) were previously treated, with a median of 1 (1-3) prior therapies, including 2 (33%) with prior SCT. 10 pts (67%) had chromosome 14 abnormality by conventional cytogenetics, and 6/6 (100%) pts tested by FISH had TCL1 positivity. 5/7 (71%) tested pts having activating mutations in the JAK-STAT pathway. Pts received a median of 4 cycles (1-12) of therapy, including a median of 2 (1-4) combination cycles and a median of 3 (0-10) maintenance cycles. Of 8 evaluable frontline pts, there were 4 (50%) complete remissions (CR), all MRD (-) by flow cytometry, and 3 (38%) partial remissions (PR) for an overall response rate of 88%. Of 7 evaluable previously-treated pts, there were 3 (43%) CR, all MRD (-) by flow cytometry, 1 (14%) PR, 2 non responders (29%), and 1 (17%) early death in a pt that declined transfusions, for an ORR 57%. The median number of cycles to best response were 2 (1-4) and 1 (1-2) in the frontline and salvage cohorts, respectively. While no objective responses were observed in WBC or lymph nodes during the 2 week window of single-agent itacitinib, pts experienced improvement in B-symptoms, splenomegaly, and rash during this period prior to CAMPATH. The regimen was well tolerated. The most common grade 3/4 AEs on study were lung infection (4), allergic reaction (3), other infection (2), neutropenic fever (1), and kidney injury (1). No AEs were attributed to single-agent itacitinib. 3 of the 6 (50%) responding frontline pts went on to allogeneic SCT, 1 patient (81 years old) died after 11 cycles on protocol of unknown cause, and 2 pts are ongoing on protocol. The median OS was 18.6 m and 8.5 m in the frontline and salvage cohorts, respectively. Results: Single-agent itacitinib was associated with patient reported improvements in B-symptoms, rash, appetite, and reduced splenomegaly. Response rates with the combination were encouraging in frontline and salvage, with favorable OS. Further study of the combination without a 2-week window (of itacitinib alone) and with objective measurement of patient reported symptoms is planned. Image:Summary/Conclusion: The combination of itacitinib 200 mg daily and CAMPATH in pts with T-PLL was safe and well tolerated with no dose-limiting toxicities. Single-agent itacitinib was associated with patient reported improvements in B-symptoms, rash, appetite, and exam findings of reduced splenomegaly. Response rates with the combination were encouraging in frontline and salvage, with favorable OS. Further study of the combination without a 2-week window (of itacitinib alone) and with objective measurement of patient reported symptoms is planned.

Impact of a shared-care model between community and academic centers for facilitating access to allogeneic and autologous stem cell transplantation.

1510 Background: Despite curative or disease-controlling roles in AML/MDS and MM, access to allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (SCT) remains far from universal. Socioeconomic status (SES) and geographic distance from SCT centers have been shown to be barriers to SCT access. In 2016, Hartford HealthCare (HHC) and the Memorial Sloan Kettering Cancer Center (MSK) pioneered a Shared-Care Model (SCM) to streamline access to allo and auto SCT at MSK, featuring a dedicated nurse SCT coordinator, shared hematology tumor boards, MSK-led didactics for HHC providers, and an electronic health record sharing pipeline. We sought to determine if this has improved access to SCT for HHC patients. Methods: A retrospective chart review was conducted of HHC patients aged 18-70 with new diagnoses of AML, MDS, and MM between 2016 and 2020. Socioeconomic status (SES) was estimated by 9-digit zip-code using the Area Deprivation Index (ADI), shown to be a surrogate for healthcare access. Referral or not to a SCT center, referral to MSK through the SCM, and reasons for non-referral were abstracted from the medical record. For patients referred for SCT at MSK, we also captured the number of peri-SCT days in New York City (NYC) and number of subsequent MSK and HHC clinic visits/hospitalizations within 1-year post-SCT. Results: A total of 126 patients was included, with 81 (64%) treated for AML/MDS and 45 (36%) for MM. The median age was 60 years (interquartile range [IQR]: 53-66). The majority were white (n = 101, 80%) followed by 10% (n = 13) Black/African American; 10% (n = 12) were of Hispanic ethnicity. The median ADI percentile was 38 (IQR: 20-51; higher percentiles reflect decreased SES). The median ADI for MSK SCT referrals from New York, New Jersey, and Connecticut 2016-2020 for the same indications was 19 (IQR: 10-30, p < 0.001). A total of 90 patients (71%) were referred to SCT centers. Leading reasons for no referral were favorable-risk disease (n = 10), goals of care (n = 9), and death prior to referral (n = 5); 3 patients were not referred due to comorbidities/performance status. No differences were found between patients referred to MSK vs. other centers. Thirty-four HHC patients were referred to MSK (21 AML/MDS, 13 MM), vs. 3 between 2010 and 2015. Twelve patients underwent allo SCT, with median 97 days in NYC (range: 68-247); 8 underwent auto SCT, with median 21 days in NYC (range: 15-48). Conclusions: Our findings show the feasibility of a shared-care model between a non-SCT-providing large regional hospital system and a major academic transplantation center. Close collaboration between institutions may minimize time patients spend away from home. The SES of HHC referrals was lower than the general MSK population, suggesting that a shared-care model may facilitate access to SCT for patients with previous barriers for this potentially curative therapy.

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Introduction:Acute myeloid leukemia (AML) is heterogenous disease with a range of cytogenetic and molecular changes. Several molecular mutations identified in AML patients at diagnosis have prognostic implications and play important roles in guiding induction and consolidative treatment decisions. The prognostic impact of mutations peri allogeneic stem cell transplant are less well characterized. In this study, we examine the significance of pre and by D100 Post-transplant mutation status in AML patients underwent Fludarabine/Melphalan conditioned reduced intensity allogeneic stem cell transplant (SCT).Methods:AML patients who are in morphologic complete remission (CR1 or greater) with available molecular mutation at diagnosis, within 6 weeks prior to allogeneic SCT, and by 100 days post-transplant were included. Variables analyzed included baseline demographics, clinical variables (CIBMTR disease risk index (DRI), type of transplant, ELN risk, performance status) and 23 recurring molecular mutations. Analysis was also performed by grouping mutations into six pre-defined gene groups based on gene function (Table 2). Multivariable cox regression analysis was adjusted for age, gender, DRI and molecular mutation. Backward selection method was used to select the best combination of genes that is associated with overall survival (OS) and relapse-free survival (RFS).Results: A total of 142 AML patients with molecular genetic data available from 2014 to June, 2020 at Weill Cornell Medicine/New York Presbyterian Hospital were analyzed. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (range 20 -78). Total of 261 mutations were detectable at diagnosis (Table 3). Prior to allo SCT and by D100, the detectable mutations were 87 and 40 respectively, which represent 56 and 26 patients. High-dose chemotherapy was less effective on clearing DNMT3A, ASXL1, TET2 (DAT) or IDH mutations, resulting in over-representation of DAT and IDH mutations prior to transplant.With a median follow-up time of 25 months, the median overall survival for the group was 40.8 months. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced OS and RFS, and Age >60 at diagnosis was associated with worse OS (HR 1.7 CI 1.04-3, p 0.03).Presence of any molecular mutation prior to transplant did not impact OS or RFS. For patients with any persistent mutations by D100 post-transplant, both OS (HR 2.04, p 0.027, CI 1.08-3.8) and RFS (HR 1.99, p 0.025, CI 1.09-3.6,) were reduced in the univariate analysis, but not on multivariate analysis (HR 1.88, p 0.5, CI 0.99-3.49). Analysis based on six mutational groups (table 2) did not show any difference in their OS or RFS. However, worse RFS was independently associated with persistent IDH1 (HR 3.8, p 0.004, CI 1.07-56,), TET2 (HR 3.9, P 0.04, CI 1.04-14.1), and FLT3-ITD (HR 4.5, p 0.01, CI 1.7-52). Worse OS was independently associated with persistent TET2 (HR 3.9, p 0.013, CI 1.04-14.1), with a trend towards worse OS for IDH1, FLT3-ITD, with a trend towards worsening OS and RFS for ASXL1 (OS HR 7.4, p 0.06, CI 0.86 -63; RFS HR 4.9, p 0.06, CI 0.9-26) and DNMT3A (OS HR 2.3, p 0.12, CI 0.86-6.9; RFS 2.9, p 0.08, CI 0.98-8). Association with worse clinical outcomes remained significant after multivariate analysis for TET2 (both OS HR 3.98 p 0.041, CI1.07- 32 and RFS HR 5.8, p 0.032, CI 1.1- 29), IDH1 (RFS HR 8.02, p 0.049, CI 1.02 - 65) and FLT3-ITD (RFS HR 11.4, p0.010, CI 2.2- 80).Conclusions:Presence of TP53 mutations was associated with worse OS. Presence of pre-transplant mutation did not impact RFS or OS. Persistent presence of mutations in TET2, IDH1 and FLT3-ITD after Fludarabine/melphalan conditioning regimen allogeneic SCT were associated with shorter RFS and OS (in the case of TET2) independent of CIBMTR DRI. This analysis supports association of adverse outcomes in AML patients with selected persistent mutations by D100 post-transplant in reduced intensity transplant setting. Post-transplant strategies that can further eliminate persistent mutations should be investigated in prospective studies. [Display omitted] DisclosuresLee: Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Desai: Kura Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Takeda: Consultancy; Janssen R&D: Research Funding; Astex: Research Funding. Ritchie: Protaganist: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; NS Pharma: Research Funding; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Roboz: MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Mesoblast: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Consultancy; Agios: Consultancy; Amgen: Consultancy; Astex: Consultancy; Astellas: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

A Phase Ib Pilot Study of Itacitinib Combined with Alemtuzumab in Patients with T-Cell Prolymphocytic Leukemia (T-PLL)

Background: T-cell prolymphocytic leukemia (T-PLL) is a rare, mature T-cell neoplasm often characterized by an aggressive clinical course including rapid lymphocyte proliferation, progressive lymphadenopathy and organomegaly, pleural and pericardial effusions, skin manifestations, and severe B-symptoms. Overall prognosis has been poor, with inadequate response to conventional chemotherapy and limited efficacy of allo stem cell transplant (SCT). The CD52 monoclonal antibody alemtuzumab (CAMPATH) has been the most effective therapy for T-PLL, but responses are not durable. Molecular characterization of T-PLL has recently found up to 76% of cases harboring activating mutations in the JAK-STAT pathway (JAK1, JAK3, STAT5b, IL2RG). We hypothesized that the combination of the JAK1 inhibitor itacitinib with CAMPATH could target activated JAK-STAT signaling and provide clinical benefit.Methods: This is a phase Ib study for pts ≥ 18 years with T-PLL with adequate organ function, ECOG performance status ≤ 2, and platelets ≥ 30,000. Patients (Pts) with newly diagnosed or previously treated T-PLL were eligible. The study had a 3+3 dose de-escalation design, starting at an itacitinib dose of 200 mg daily and de-escalating if the dose was above the MTD. De-escalation was not required. During cycle 1, pts received itacitinib alone on Days 1-14 to assess single-agent activity; starting on cycle 1 Day 15 and beyond, pts received the addition of CAMPATH 30 mg IV every other day, after a 3-day ramp up. Pts continued on the combination of CAMPATH + itacitinib for up to 4 cycles or until best response. At the time of best response, pts could proceed with maintenance therapy with single-agent itacitinib for up to 8 cycles. Primary objective was safety and efficacy of the combination. Secondary endpoints included response, EFS, and OS.Results: 13 pts were enrolled on study. Baseline characteristics are shown in Table 1. The median age was 64 yrs (range, 39-83). 7 pts (54%) were newly diagnosed and 6 pts (46%) were previously treated, with a median of 2 (1-3) prior therapies, including 2 (33%) with prior SCT. Nine (69%) pts had complex karyotype, 8 (62%) had chromosome 14 abnormality by conventional cytogenetics, and 6 (46%) pts had TCL1 positivity by FISH. Mutations detected by NGS are summarized in Table 1, with 5/7 (71%) tested pts having activating mutations in the JAK-STAT pathway. Pts received a median of 4 cycles (1-11) of therapy on protocol, including a median of 2 (1-4) combinations cycles and a median of 1 (0-7) maintenance cycles. Of 6 evaluable frontline pts, there were 3 (50%) complete remissions (CR), all MRD (-) by flow cytometry, and 3 (50%) partial remissions (PR) for an overall response rate of 100%. Of 6 evaluable previously-treated pts, there were 2 (33%) CR, all MRD (-) by flow cytometry, 1 (17%) PR, and 1 (17%) early death in a pt that declined transfusions, for an ORR 50%. The median number of cycles to best response were 2 (1-4) and 1 (1-2) in the frontline and salvage cohorts, respectively. While no objective responses were observed in WBC or lymph nodes during the 2 week window of single-agent itacitinib, pts experienced improvement in B-symptoms, splenomegaly, appetite, and rash during this period prior to CAMPATH. The regimen was well tolerated. The most common grade 3/4 AEs on study were lung infection (4), allergic reaction (2), other infection (2), neutropenic fever (1), and kidney injury (1). No AEs were attributed to single-agent itacitinib. 3 of the 6 (50%) responding frontline pts went on to allogeneic SCT, 1 patient (81 years old) died after 11 cycles on protocol of unknown cause, and 2 pts are ongoing on protocol. The median OS was not reached and 8.5 m in the frontline and salvage cohorts, respectively. The median EFS was 11.7 m and 7.8 m in the frontline and salvage cohorts, respectively.Conclusion: The combination of itacitinib and CAMPATH in pts with T-PLL was safe and well tolerated with no dose-limiting toxicities at the starting itacitinib dose of 200 mg daily. Single-agent itacitinib was associated with patient reported improvements in B-symptoms, rash, appetite, and exam findings of reduced splenomegaly. Response rates with the combination were similar to historical expectations in frontline and salvage, but OS and EFS appear favorable, with short follow up. Further study of the combination without a 2-week window (of itacitinib alone) and with objective measurement of patient reported symptoms is planned. [Display omitted] DisclosuresKadia: AstraZeneca: Other; Astellas: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Ascentage: Other; Cure: Speakers Bureau; Novartis: Consultancy; Genfleet: Other; BMS: Other: Grant/research support. Ravandi: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Astex: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Research Funding; Xencor: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jain: Fate Therapeutics: Research Funding; TG Therapeutics: Honoraria; Beigene: Honoraria; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Precision Biosciences: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pharmacyclics: Research Funding. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding; AstraZeneca: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Wierda: Janssen: Research Funding; KITE Pharma: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta Pharma Inc.: Research Funding; Loxo Oncology, Inc.: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Karyopharm: Research Funding; Juno Therapeutics: Research Funding; AstraZeneca: Research Funding; Miragen: Research Funding; Xencor: Research Funding; Cyclacel: Research Funding; Gilead Sciences: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Kantarjian: NOVA Research: Honoraria; Astra Zeneca: Honoraria; Novartis: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; BMS: Research Funding; Ipsen Pharmaceuticals: Honoraria; Ascentage: Research Funding; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

Topotecan Plus Cytarabine Is an Effective and Safe Regimen for Newly Diagnosed and Adverse ELN-Risk Acute Myeloid Leukemia Subset in Patients with Cardiac Comorbidities

IntroductionThe standard first line treatment for acute myeloid leukemia (AML) for patients eligible for intensive chemotherapy is a combination of cytarabine and anthracyclines called “3+7” regimen. However, some patients are ineligible because of cardiac comorbidities or prior exposure to anthracyclines in the case of therapy-related AMLs. To date, there is no consensual regimen for these patients. In this study, we retrospectively analyzed the results of 3 cytarabine-based, anthracycline-free, regimens in which topotecan, clofarabine or fludarabine were used.MethodsFrom 2008 to 2016, 52 AML patients aged ≥18 years with comorbidities were treated intensively in 3 French centers (CHU of Nice, Antoine Lacassagne Center and Paoli-Calmettes Institute). All patients had new diagnosed or relapsed/refractory (R/R) AML (APL were excluded) and at least one contra-indication to receive “3+7” regimen. 3 types of regimen were used for induction. FLAG regimen combined fludarabine (days 1-4, 30 mg/m²/d), cytarabine (days 1-4, 2000mg/ m²/d) and G-CSF (day 0 up to ANC > 1 x 109/l, 400 µg/m²/d). CLARA regimen combined clofarabine (days 1-3(or 5), 30mg/m²/d) and cytarabine (days 1-7 (or 10), 20mg/m²/d). TA regimen combined topotecan (days 1-4, 1.25 mg/m²/d) and cytarabine (days 1-4, 1000 mg/m²/12 h days 1-4). Responses were scored according to ELN 2010. Overall (OS), Event free survival (EFS) were censored to allo stem cell transplantation (ASCT). All statistical analyses were performed using SPSS v.22 software (IBM SPSS Statistics).ResultsAmong 52 AML patients, sex ratio M/F 27/25, median age was 66 years (20-79, range). 50/52 patients had performans status £ 2. 30 (58%) and 22 (42%) patients had de novo or relapsed/refractory AML, respectively. ELN risk categories were favorable, intermediate and adverse in 4 (8%), 27 (52%) and 20 (39%) patients, respectively. 7/28 patients were FLT3-ITD and 4/28 were NPM1 mutated. 24 and 28 patients were treated by TA or FLAG/CLARA regimens, respectively. Main comorbidities leading to use of TA/FLAG/CLARA regimens were cardiac in 50% and prior anthracyclin exposure above MTD in 50% of patients. 56% achieved complete remission after induction (74% in TA and 40% in FLAG/CLARA, p=0.11 in newly diagnosed AML; and 25% in TA and 53% in FLAG/CLARA, p=0.59 in R/R AML). Although duration of neutropenia was similar in both groups, (25 vs 26 days in TA and FLAG/CLARA subgroups, respectively, p=0.62), we observed a significant difference for duration of thrombopenia less than 50 Giga/l (24 vs 34 days in TA and FLAG/CLARA subgroups, respectively, p=0.03). Median OS was no significant different between the 2 groups (10.2 months [1.1-19.2] vs 9.8 months [1.1-22.1] in TA and FLAG/CLARA subgroups, respectively, p=0.59). There was a trend for a better median EFS in TA subgroup (8.8 months [5.6-11.9] vs 1.6 months [3.6-9.2] in TA and FLAG/CLARA subgroups, respectively, p=0.09) which reached statistical significance after censoring for ASCT (16.1 months [8.4-23.7] vs 4.7 months [4.3-5.1] in TA and FLAG/CLARA subgroups, respectively, p=0.001). This effect was marked only in new diagnosed AML group (16.1 months [11.2-20.9] vs 5.9 months [4.3-7.6], in TA and FLAG/CLARA subgroups, respectively, p=0.03). This effect was confirmed in the unfavorable ELN-risk group (17.8 months [1.1-32.5] vs 4.1 months [2.1-6.1] in TA and FLAG/CLARA subgroups, respectively, p=0.006). Finally, we observed no significant difference for cardiac toxicity between TA and FLAG/CLARA subgroups (29% vs 23%, respectively, p=0.78).ConclusionTA, FLAG and CLARA regimens are efficient strategies in AML patients with comorbidities ineligible for classical “3+7” regimen. Safety was acceptable for all regimens. TA showed a better EFS in newly diagnosed AML and adverse ELN-risk and need to be confirmed in a larger study, especially in this subgroup of patients with cardiac comorbidities. DisclosuresCharbonnier:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Outcomes, Toxicities, and Patterns of Use of Programmed Death-1 (PD-1) Inhibitors in Hodgkin Lymphoma Patients in the United States: A Multicenter Retrospective Study

IntroductionGreater than 8,000 patients (pts) are diagnosed with classical Hodgkin lymphoma (cHL) in the United States each year. While cHL is a highly curable malignancy, 20% will not be cured with conventional treatments. PD-1 inhibition has resulted in impressive activity in the relapsed/refractory (R/R) setting, thus leading to FDA approval of nivolumab in 2016 and pembrolizumab in 2017. There is limited information on “real world” experience with these agents in cHL treated outside of clinical trials.MethodsWe performed a multicenter, retrospective analysis of R/R cHL pts treated with programmed death-1 (PD-1) inhibitors (PD-1i) in the non-trial setting. The primary objective of the study was to describe progression free survival (PFS) and overall survival (OS) in this population. PFS and OS were calculated from the date of PD-1i initiation to the date of disease progression or death, respectively, or the date of last follow-up. Secondary objectives included overall response rates (ORR) and complete response rates (CR), toxicities, discontinuation patterns, and post-PD-1i therapies. OS and PFS were calculated using the Kaplan-Meier method.ResultsForty two pts from 7 centers in the United States were identified. Pt characteristics include: median age 34 years (range 20-67), 62% male, 60% stage III/IV at diagnosis, 71% NS type, 52% with prior auto stem cell transplant (SCT) and 7% with prior allo SCT. Pts received a median of 4 lines of therapy prior to PD-1i (range 1-10); 85% had ABVD/AVD as frontline therapy and 95% had brentuximab (BV) prior to PD-1i.Nivolumab was the initial PD-1i used in all 42 pts; 78% received the 3 mg/kg every 2 weeks dosing schedule. Concurrent therapies with PD-1i were used at some point in 19% of pts (RT in 4, BV in 4). The ORR to nivolumab as assessed by the treating physician interpretation was 62% with CR 45%. The median time to best response was 3 months (mo) (range 1-10). At median follow-up of 13 mo, the median PFS and OS have not been reached (Figure 1). The 12-mo OS and PFS were 96% and 65%, respectively. The median duration of therapy was 9 mo (range 1-26). Median duration of response in pts with CR and partial response (PR), respectively was 13 mo (range 3-28) and 9 mo (range 7-25). Dose delays occurred in 33% of pts (N=14), most commonly due to toxicity in 43% (N=6), non-adherence in 29% (N=4), and pt preference in 14% (N=2). Dose delays did not impact PFS (p = 0.85). Original PD-1i was discontinued in 52% of pts (N=21). The cause for discontinuation was progression in 52% (N=11), patient preference/non-compliance in 14% (N=3) and toxicity in 14% (N=3). Four of 42 pts (10%) died, all due to disease progression.In 40 pts with available toxicity data, 43% (N=17) experienced toxicity attributed to PD-1i. The most common toxicities were hypothyroidism in 10% (N=4), rash in 10% (N=4), pneumonitis/dyspnea in 7% (N=3), and colitis in 7% (N=3). Toxicities resulting in drug discontinuation included encephalitis (N=1), colitis (N=1) and skin GVHD (N=1). Toxicity management included systemic steroids in 10% (N=4), thyroid replacement in 10% (N=4), drug discontinuation in 7% (N=3), dose delay in 5% (N=2), or local steroid therapy in 5% (N=2). There were no treatment-related deaths. In 21 pts who discontinued PD-1i, 67% (N=14) pts had subsequent systemic therapies and 12 were evaluable for response (Table 1). Clinical benefit of systemic therapy immediately after PD-1i was seen in 75% (1 CR, 5 PR, 3 SD) with 5 pts responding to cytotoxic chemotherapies. Four pts underwent SCT after PD-1i (3 auto, 1 allo). Four pts were treated with pembrolizumab containing regimens after nivolumab of which 1 pt had a clinical response.ConclusionsTo our knowledge, this multi-center retrospective analysis is the first to describe the “real world” experience with PD-1i in cHL pts in the United States. ORR, median PFS and OS, and toxicities are similar to those observed in published clinical trials. The treating physician assessment of CR rate was higher than previously reported although independent confirmation of response was not performed. Patterns of discontinuation and dose delays are different from published studies, but do not affect outcomes. Systemic therapies after PD-1i discontinuation appear to be active. Our results support the important role of PD-1i therapy in R/R cHL and provide insight into practice patterns. [Display omitted] DisclosuresFeldman:AbbVie: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Kite Pharma: Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Consultancy. Shah:Oncosec: Equity Ownership; Jazz Pharmaceuticals: Consultancy; Exelixis: Equity Ownership; Geron: Equity Ownership. Reddy:Abbvie: Consultancy; BMS: Consultancy; Celgene: Consultancy; Gilead: Speakers Bureau. Andreadis:Amgen: Research Funding; Incyte Pharmaceuticals: Research Funding; Astellas: Honoraria; Genentech Inc.: Employment, Equity Ownership, Honoraria; Gilead Sciences: Honoraria; Pharmacyclics: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Cellerant Therapeutics: Research Funding; Seattle Genetics: Honoraria. Ujjani:Gilead: Consultancy; Genentech: Consultancy; Abbvie: Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Dwivedy Nasta:Immunogen: Research Funding; Takeda: Research Funding; Incyte: Research Funding. Landsburg:Curis: Consultancy, Research Funding; Takeda: Research Funding. Mato:Kite: Consultancy; Pharmacyclics: Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; DTRM: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; AbbVie: Consultancy, Research Funding. Schuster:Gilead: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy; Nordic Nanovector: Consultancy; Merck: Research Funding. Svoboda:BMS: Consultancy, Research Funding; Kite: Consultancy; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding.

Epidemiology and Clinicopathology of Hepatosplenic T-Cell Lymphoma (HSTCL): Analysis of a Pooled Database

Introduction: HSTCL is a rare and rapidly progressive extranodal T-cell lymphoma. It accounts to for 1-2% of all T/NK cell lymphomas. Afflicting adolescents and younger adults, HSTCL commonly presents with constitutional symptoms, cytopenias, and hepatosplenomegaly. Up to a third of all the reported cases arise within a clinical context of immunosuppression. This analysis was conducted to update and expand our existing knowledge of this rare disease. Methods: In order to study the demographic characteristics, cytogenetic and molecular signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 360 cases. Kaplan-Meier survival curves were constructed. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathology factors on overall survival (OS). Results: A total of 360 patients with confirmed HSTCL were identified. The median age was 30 (0.8-86) years with a peak incidence between ages 13 and 26. There is male predominance with M:F ratio of 2.6 in the whole group, 6 in the immunosuppressed, 2.2 in γδ, and 1.2 αβ. HSTCL with TCRαβ tended to be more CD5+, CD8+, and CD57+. More than 90% presented with constitutional symptoms and had bone marrow involvement. Median overall survival of the whole group was 12 months. The median duration of symptoms to diagnosis is 2 months. The median time from immunosuppression to diagnosis is 5.3 years. Sex, age, jaundice, autoimmune hemolytic anemia, hemophagocytosis, and bone marrow involvement did not affect OS. Furthermore, i7 and/or +8 and TCR type did not impact OS. Compared to no treatment, combination chemotherapy and auto and allo stem cell transplant (SCT) were statistically superior with a median OS of 1, 9, 34, and 30 months respectively. While OS of combination chemotherapy was inferior to that of SCT, there was no significant difference between auto and allo SCT. Immunosuppression adversely impacted OS in the whole group (HR:0.40, p<0.0001) and among the SCT subgroup (HR:0.38, p=0.06). There was no difference between immunosuppression with and without TNFα inhibitors. The quality of response prior to transplant also seemed to impact outcome though it did not reach statistical significance (p=0.07) with OS of 15, 30, and 44 months for none/transient, response less than CR, and CR respectively. Splenectomy improved survival in the whole group (HR:0.66; 95%CI 0.47-0.93). Further analysis revealed that splenectomy impacted survival in the context of combination chemotherapy but not SCT. Conclusions: This study presents an updated epidemiologic and clinicopathologic data from a pooled cohort of patients with HSTCL. It identifies the impact of immunosuppression, quality of response, treatment modalities as well as splenectomy on OS. Disclosures No relevant conflicts of interest to declare.

Bortezomib, lenalidomide, and dexamethasone (VRD) is superior to lenalidomide, adriamycin, and dexamethasone (RAD) prior to risk-adapted transplant in newly diagnosed myeloma.

8521 Background: High-dose chemotherapy (HDT) followed by autologous stem cell transplant (SCT) remains a standard of care in patients (pts) with newly diagnosed (ND) multiple myeloma (MM). While lenalidomide (R) maintenance is acknowledged to improve outcomes, intensified consolidation (such as tandem-SCT) has yielded conflicting results. Allogeneic (allo) SCT holds the promise of curative potential at the cost of higher treatment-related mortality (TRM). In a previous phase 2 study, we showed a very low TRM rate (6.1%) and feasibility of 12 months (mos) of R maintenance (maint), with auto/allo SCT after R/adriamycin/dexamethasone (RAD). This prompted us to compare, on a randomized rather than a “biological assignment” basis, a second auto- versus (vs) an allo-SCT in pts with an unfavorable prognosis. Methods: The current protocol (DSMM XIV, NCT01685814) was set up according to a double 2x2-factorial design. Post-induction (PInd) CR rate was the efficacy endpoint for the comparison of RAD vs bortezomib (V)/RD (VRD; 3 cycles each). If pts had achieved >VGPR to HDT, a second randomization (2ndR) compared immediate R maint (arm A2) with a second auto-SCT (B2). In case of < VGPR, pts were randomized between a second auto- (C2) and allo-SCT (D2). Planned R maint. duration was 36 mos, except after allo (12 mos). Results: Between 05/2012-06/2016, 476 pts were randomized and 469 received at least one dose of study drug. Pts’ median age was 55 (range, 32–65) years. 11.3% of pts had FISH del17p; 11.6% had t(4;14); and 4.4% had t(14;16). PInd CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD and 13.0% (90% CI, 8.9-18.0) with VRD (P = .697). 382 pts underwent R2 with 279 pts. (73%) in >VGPR and 103 (27%) in < VGPR, respectively. Median duration of R maint (N = 298) was 21.2 mos for A2, 23.1 mos for B2, 27.4 mos for C2, and 11.0 mos. for D2. At a median follow-up of 40.2 (0.5-87.0) months, median PFS from first randomization with RAD was 41.7 (95% CI, 35.4-48.5) mos vs. 53.7 (95% CI, 46.2-63.1) mos with VRD (P = .0439). Median PFS from 2ndR was 38.7 (95% CI, 30.3-47.3) mos for the 181 RAD vs. 50.7 (95% CI, 44.4-64.9) mos for the 201 VRD pts (P = .0126). Median overall survival (OS) cannot be estimated. With 47 deceased RAD vs 36 VRD pts, HR was .671 (95% CI, .435-1.037; P = .0703). Conclusions: In this study, median PFS benefit was 12 mos in favor of VRD vs. RAD despite comparable PInd CR. We show for the first time a len-PI to be superior to a len-chemo triplet, confirmed with positive OS trends. 3-year PFS for all consolidation arms will be presented. Clinical trial information: NCT01685814 .

Busulfan Pharmacokinetics Using 25% Adjusted Body Weight in Obese Stem Cell Transplant Patients

Introduction The use of adjusted body weight for dosing of conditioning chemotherapy is recommended in obese stem cell transplant (SCT) patients. Busulfan (Bu), specifically, has several acceptable dosing regimens per evidence based guidelines. We evaluated whether a 25% correction in dosing weight may underestimate the targeted area under the curve (AUC) for this narrow therapeutic agent. Objectives The primary objective was the number of patients requiring a clinically relevant PK-guided dose adjustment (change in dose of 10% or more). Secondary objectives include any increase or decrease in dosing, as well as the magnitude of dose adjustments. Methods Single center retrospective chart review of adult obese SCT patients receiving Bu as a part of their conditioning regimen. Bu was administered intravenously once daily at a dose of 130 mg/m2 for 4 planned doses in the allogeneic (allo) and 3 planned in the autologous (auto) population with an AUC goal of 5000 µmol*min/dose. The dose was calculated using the 25% adjusted body weight equation (AdjBW25) and pharmacokinetic (PK) samples were sent from the first day of Bu. Results Fifty-five obese SCT patients (51 allo and 4 auto) were identified between 2017 to 2019 who underwent PK levels with Bu. Majority of allo patients were transplanted for acute myeloid leukemia (61%); received matched unrelated (43%) or matched related donor transplants (33%), and received fludarabine/Bu (95%) based conditioning. All the auto patients received thiotepa, Bu, and cyclophosphamide (TBC) regimen. Forty-four (80%) patients required a clinically relevant dose adjustment. In the allo SCT group, 45/51 (88%) patients required a dose change with 36 (71%) requiring a median increase in dose by 37% (range 3 -126%) and 9 (18%) requiring a median decrease in dose by 12% (range 7-29%). Following the first dose, the median AUC was 4318 µmol*min (range 2994 - 5854 µmol*min) and after PK-guided adjustment the median AUC of all doses was 4934 µmol*min (range 4215 - 5061 µmol*min). In the auto SCT group, 4/4 (100%) patients required a dose change with 1 (25%) requiring an increase in dose by 28%, and 3 (75%) requiring a median decrease in dose by 100% (range 13 – 100%). Following the first dose, the median AUC was 6285 µmol*min (range 4213 - 8995 µmol*min) and after PK-guided adjustment the median AUC of all doses was 4948 µmol*min (range 4609 - 5997 µmol*min). Conclusion Overall, the majority of our allo SCT patients required a clinically significant increase in Bu dose. However, in our auto SCT patients, the majority required a significant decrease in dose that translated into omitting the last dose in two patients. Using PK-guided dose adjustments were critical in achieving our desired AUC goal and, based on our findings, using AdjBW25 may not be adequate. Further studies are warranted to identify the most appropriate dosing weight for obese patients, as well as allo versus auto recipients.

Outcomes after Plerixafor Plus FLAG-IDA (PLERIFLAG) Versus FLAG-IDA +/- Gentuzumab for Adult Patients with First Relapsed/Refractory AML: A Propensity Score Analysis from the Pethema Registry

BACKGROUND AND OBJECTIVES: Chemosensitization using plerixafor combined with FLAG-IDA (PLERIFLAG regimen) showed promising results (48% CR/CRi) in a phase 2 trial for primary refractory and early relapsed (duration of first CR <12 months) Adult AML patients. We aim to compare retrospectively results of the PLERIFLAG cohort versus historical cohorts of patients salvaged with FLAG-IDA (Fludarabine, Idarubicine, Cytarabine, G-CSF as priming agent), or FLAGO-IDA (Gemtuzumab plus FLAG-IDA) registered in the PETHEMA epidemiologic AML registry (NCT02006004). To match different cohorts, we used two risk-score classifications: EPI/HOVON (De Breems, JCO 2005) and SALFLAGE (Bergua, BJH 2016). The purpose is to analyse the complete remission (CR+CRi) rate, the rate of patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT). The disease-free survival (DFS) and overall survival (OS) were adjusted using established risk factors (time to relapse (TTR), karyotype, FLT3-ITD, previous stem cell transplant (SCT)) using propensity score analysis. Patients: Of the 540 patients in the data base we analysed 300 patients relapsed or resistant to induction therapy, which had all data available. 241 patients were treated with FLAG-IDA, 41 with FLAGO-Ida, and 42 with PLERIFLAG. Differences between treatment cohorts were tested using Fisher exact test. Treatment cohorts (PLERIFLAG vs FLAG-IDA vs FLAGO-IDA) were similar in Age (p=0.5), Sex (p=0.5), FLT3-ITD mutated (p=0.5), EPI/HOVON cytogenetics score (p=0.5) and previous myelodisplasia (p=0.2). The three cohorts differed in time to relapse (p=0.001), previous stem cell transplantation (0.001), HOVON score (p=0.03) and SALFLAGE score (0.001). RESULTS There were no differences in terms of CR+CRi between the three types of treatment adjusted by Hovon risk score (Pleriflag: 48%, FLAG-IDA: 50% or FLAGO-IDA: 58%; Chrochan Maentel-Haenszel test, p=0.466) or SALFLAGE score (Chrochan-Maentel-Haenszel test, p=0.23). More patients were allografted in the PLERIFLAG (61%) group even not achieving CR/Cri, as compared to FLAG-IDA (38%) or FLAGO-Ida (61% vs 38% vs. 18%, p=0.0001). To compare PLERIFLAG against the other two types of salvage treatment we performed a Propensity Score in a proportion 1:3. We adjust variables like age, previous allogeneic transplant, time to relapse (refractory, <12 months and >12 months), karyotype using MRC, and FLT3-ITD status. Karyotype risk was considered by HOVON criteria (inv16, t(8;21) vs others), and SALFLAGE (inv 16, intermediate risk, and unfavourable risk by MRC risk plus t(8;21)). The propensity score analyses showed that Compared to FLAG-IDA, PLERIFLAG was associated to increased survival (median OS 10.56 months vs. 5.6, p=0.03), but not improved EFS (2.83 months vs 1.41 months, p=0.8). The benefit in OS but not in EFS could be explained in part by frequent use of Allo SCT in patients who had not achieve CR/CRi in the PLERIFLAG cohort. In conclusion, our historical control study show that PLERIFLAG regimen is an acceptable therapeutic option for first relapsed/refractory adult AML patients. Disclosures Esteve: Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau. Salamero:Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Daichii Sankyo: Honoraria. Perez Encinas:CELGENE: Consultancy; JANSSEN: Consultancy; GILEAD SCIENCES: Research Funding. Montesinos:Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau.

Profound MRD negativity rates after frontline tandem autologous-allogeneic stem cell transplantation followed by bortezomib maintenance in high-risk or young myeloma patients

Prior studies suggest that allogeneic (allo) stem cell transplant (SCT) can overcome high-risk (HR) cytogenetics associated with poor outcome in multiple myeloma (MM). Despite being the only potentially curative therapy for MM, the use of allo SCT remains controversial due to unacceptably high nonrelapse mortality (NRM; 10-15%), morbid extensive chronic graft-versus-host disease (cGVHD; 50-80%) and high relapse rates (50-60%). We hypothesized that bortezomib (BTZ) after allo SCT might decrease both relapse and cGVHD in HR disease and young MM patients (pts) who have the greatest loss in years of life from MM.

Quality of life (QOL) in patients undergoing CAR-T therapy versus stem cell transplant (SCT).

6594 Background: Given the significant short-term adverse effects of CAR-T cell therapy, it is important to evaluate its impact on QOL of patients in addition to efficacy, compared with established forms of cellular therapy like SCT. Methods: QOL was evaluated prospectively in patients undergoing CAR-T therapy, autoSCT & alloSCT for hematologic malignancies. QOL was assessed with FACT-G at baseline, 2 weeks and monthly for 6 months thereafter. Functional well-being (FWB), physical WB (PWB) emotional WB (EWB) & social WB (SWB) and change over time were compared across groups. Results: 45 patients were recruited (CAR-T: 10; Auto SCT: 22; Allo SCT: 13) with follow up for 2 weeks & 1 month available for 23 &15 patients, respectively (Table). There was no statistically significant difference in baseline total QOL scores (p=0.13), though scores were lower in the alloSCT group (85,84,68). EWB &FWB were numerically higher in the CAR-T group, followed by autoSCT group. At 2 weeks, overall QOL decreased by only 2 points in CAR-T group vs. 22 & 18 points in auto & alloSCT groups (p=0.09). Change in PWB vs. baseline was less pronounced in the CAR-T group (-1, -9, -13, p=0.03). At 1 month, overall QOL was 6 points lower than baseline in CAR-T group vs. 3 and 14 points lower in auto & alloSCT groups, respectively (p=0.34). Importantly, PWB had at least returned to baseline in the CAR-T group. Conclusions: Preliminary data show that patients undergoing CAR-T cell therapy do not experience a more significant decline in QOL compared with auto & allo SCT, and may experience fewer physical side effects in the short-term. Accrual & follow-up are ongoing. [Table: see text]

Multi-organ failure induced by Nivolumab in the context of allo-stem cell transplantation

BackgroundImmune checkpoint inhibitors have radically changed the landscape of anti-tumor therapies in several malignancies. However the adverse events associated with immune checkpoint blockade in combination with other treatments remains to be thoroughly documented. Here we report the case of a 33-year-old male with classical Hodgkin lymphoma who was successfully treated for lymphoma but experienced serious and eventually fatal multisystem organ failure following nivolumab administration and allogeneic stem cell transplantation.Case presentationThe patient was diagnosed with stage IIIa nodular sclerosing Hodgkin lymphoma. Originally treated by chemotherapy and autologous stem cell transplantation, he subsequently received two allogeneic stem cell transplants from matched and haplo-identical siblings upon successive disease recurrences. Nivolumab treatment was administered prior to the second allograft, after which complete remission of lymphoma was achieved (year 10), as evidenced by clinical and radiographic examination. However within the next 3 months, the patient went on to develop a constellation of symptoms affecting multiple organs, including acute pneumonia with no evidence of bacterial infection, widespread cutaneous eruptions on trunk and lower limbs, mucosal ulcerations, myositis, diarrhea and colitis. Further complications included hepatic cytolysis, acute renal failure, pancreatitis, as well as complete heart block. Some of these injuries being suggestive of graft-versus-host disease, the patient was administered immunosuppressive therapy (mycophenolate, steroids and polyvalent immunoglobulins), but died shortly afterwards. Tissue biopsies revealed extensive lymphocytic infiltration (mostly CD3 + T cells) in skin, liver, and most peculiarly in muscles, including the myocardium. Massive lymphoid-histiocytic infiltration of muscle fibers was accompanied by acute necrotizing myositis and endomysial inflammation.ConclusionsMulti-organ failure represents a rare but potentially fatal outcome of immune checkpoint blockade in patients receiving allogeneic stem cell grafts. Nivolumab may induce atypical immune-mediated tissue inflammation and damage, such as the extensive muscular polymyositis described here in a patient with Hodgkin lymphoma. Nivolumab might also worsen GVHD symptoms in the context of allogeneic stem cell transplantation. Irrespective of the actual pathological mechanisms, clinicians should be alerted to these fatal drug-related toxicities.

Allogeneic Stem Cell Transplantation Provides Durable Remission in Patients with Primary Mediastinal Large B-Cell Lymphoma

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a subset of aggressive B-cell non-Hodgkin lymphoma (B-NHL) with distinct biological and clinical features. Although most patients are cured with frontline chemoimmunotherapy with or without radiation therapy (RT), relapsed or refractory (rel/ref) PMBCL is much harder to control. Standard treatment of rel/ref PMBCL is similar to other aggressive B-NHLs, including salvage therapy and autologous (auto) stem cell transplantation (SCT) in chemosensitive patients. Recently, immunotherapy with PD-1 blockade and chimeric antigen receptor modified T-cells has proven to be effective in rel/ref PMBCL. Despite this, allogeneic (allo) SCT retains an important potential role as it has curative potential for patients with advanced aggressive B-NHLs. However, there are scant modern data on alloSCT outcomes in patients with PMBCL, limited to case reports or small series. We therefore performed a multicenter retrospective study to evaluate alloSCT outcomes in patients with rel/ref PMBCL.Methods: We retrospectively studied consecutive patients with rel/ref PMBCL who underwent alloSCT at Fred Hutchinson Cancer Center, Dana-Farber Cancer Institute, Massachusetts General Hospital, or City of Hope between 1/2000 and 5/2014. Baseline and transplant characteristics are reported descriptively. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Incidence of relapse and non-relapse mortality were calculated using competing risks methods.Results: 28 patients with rel/ref PMBCL underwent alloSCT at participating institutions during the study period. Among these patients, median age at SCT was 36 years, 54% were female, median number of prior therapies was 4 (range, 2-7), 57% were refractory to frontline therapy, 86% received prior RT, and 71% had prior autoSCT. At alloSCT, 1 (4%) patient was in complete response (CR), 21 (75%) were in partial response (PR), and 6 (21%) were refractory to pre-alloSCT therapy (18 patients were assessed with PET). Most patients (86%) received reduced intensity conditioning, most commonly fludarabine/melphalan +/- ATG or Zevalin (25%), fludarabine/TBI200 (21%), or fludarabine/busulfan (14%). GVHD prophylaxis most frequently consisted of a calcineurin inhibitor (CNI) with mycophenolate mofetil (12, 43%), CNI with sirolimus +/- methotrexate (8, 29%), or CNI with MTX (4, 14%). 15 (54%) patients had a matched (8/8) related donor, 8 (29%) had a matched unrelated donor, 2 had a mismatched unrelated donor (7/8), and 3 had umbilical cord donors. All patients received peripheral blood stem cell grafts except for the 3 cord recipients.The median follow-up time in survivors was 5.0 (range 0.5-14.0) years. The 2 year PFS and OS in the cohort were 39% and 45%, respectively, while non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) were 32% and 29%, respectively. The 5-year PFS, OS, NRM, and CIR were 34%, 45%, 32%, and 33%, respectively. The cumulative incidence of grade II-IV and III-IV acute GVHD were 39% and 4% at day 100, while the incidence of chronic GVHD at 1 year was 21% (18% extensive). Among patients in CR/PR at the time of alloSCT, the 2-year PFS and OS were 50% and 58%, respectively, as compared to a 2-year PFS and OS of 0% in patients who were refractory at the time of alloSCT (p=0.046 for PFS, p=0.014 for OS).One patient received post-alloSCT lenalidomide as maintenance therapy and remained in ongoing CR. Of the 9 patients who relapsed after alloSCT, 3 out of 4 patients exhibited a response to immunosuppression taper, while 4 out of 5 patients responded to subsequent systemic therapy. 2 patients underwent a donor lymphocyte infusion (DLI) and both developed subsequent GVHD - 1 patient had a CR documented 64 days after DLI while the other had continued disease progression. In the 9 patients who relapsed after alloSCT, the 2-year OS was 33%.Conclusions: AlloSCT can produce durable remissions in a subset of patients with heavily treated, rel/ref PMBCL. Patients with refractory disease at alloSCT had dismal outcomes. Despite the expanding treatment options available for these patients, alloSCT should be considered in the management of patients with rel/ref PMBCL who are sensitive to salvage therapy.Figure 1A PFS and OS After AlloSCT in Patients with Rel/Ref PMBCLFigure 1B PFS in Patients with Sensitive versus Refractory PMBCL at AlloSCT [Display omitted] DisclosuresHerrera:Merck, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; AstraZeneca: Research Funding; Gilead Sciences: Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Research Funding. Maloney:Roche/Genentech: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding; Seattle Genetics: Honoraria; Janssen Scientific Affairs: Honoraria. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Chen:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; REGiMMUNE: Consultancy; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Armand:Otsuka: Research Funding; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Infinity: Consultancy; Merck: Consultancy, Research Funding; Adaptive: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Shadman:Acerta Pharma: Research Funding; AbbVie: Consultancy; Genentech: Research Funding; Beigene: Research Funding; Verastem: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Mustang Biopharma: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Genentech: Consultancy.

2501. Impact of Influenza A and B Infection on Stem Cell Transplant Patients During the 2017–2018 Season at a Single Center

BackgroundSeasonal influenza causes significant morbidity and mortality on HSCT recipient. The 2017–2018 influenza has been characterized in the United States by prolonged high rates of both influenza A (IAV) and B (IBV) and low vaccine effectiveness. The aim of this study was to assess the impact of both IAV and IBV during 2017–2018 influenza season on a cohort of stem cell transplant (SCT) recipients at Weill Cornell- NYP.MethodsWe reviewed charts of HSCT recipients that were diagnosed with influenza by PCR on nasopharyngeal swabs. Demographics, clinical and microbiological data, and outcomes were collected. The study was approved by Weill Cornell Institutional review board.ResultsFrom September 2017 to March 2018, 30 stem cell transplant recipient at NYP were diagnosed with influenza. IAV cases peaked in January (11 cases) while IBV infected-patients were equally distributed from December to March. Infected subject were more likely to be male (n = 20, 66.6%) with mean age of 57 ± 12 (IAV) vs. 59 + 11 (IBV). Nine patients had received auto SCT and 21 patient allo SCT. Most commons symptoms were cough (present in all patients), fever (28/30), nausea, dyspnea. Patient received oseltamivir (for 5 or 10 days) in 28/30 cases, with one patient developing resistance under treatment. Interestingly both IAV and IBV caused lower respiratory tract infection (LRTI, 7 cases) with severe pneumonia (IAV 1 cases, IBV 2 cases) and intubation. In two severe cases IV was detected in the BAL. 13 subjects (56%) with a URTI and 4 (43%) subjects with LRTI had not received the influenza vaccine for the season. Prolonged shedding of influenza on oseltamivir treatment was documented in 7 patients.ConclusionBoth IAV and IBV are serious threat in SCT population. Vaccination and oseltamivir are useful tools. Resistance testing should be considered in subjects with prolonged disease.Disclosures S. G. Jenkins, Merck: Grant Investigator, Grant recipient. M. J. Satlin, Hardy Diagnostics: Grant Investigator, Research support. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Achaogen: Consultant, Consulting fee. L. F. Westblade, Accelerate Diagnostics: Grant Investigator, Grant recipient. Biomerieux: Grant Investigator, Grant recipient. Allergan: Grant Investigator, Grant recipient. Merck: Grant Investigator, Grant recipient.

Sex-mismatched after stem cell transplant: A case report

Introduction Ovarian failure associated with stem cell transplantation is generally awarded to total body irradiation and chemotherapeutic agents. The particularity of this observation is that describes a change in cell line in our patient following bone marrow transplant from her HLA matched brother. Case report A 15-year old girl was referred to our department of endocrinology with secondary amenorrhea. She was diagnosed with lymphoblastic Leukemia at the age of 13. She received chemotherapy and total body radiation after which she had bone marrow transplantation. Patient had menarche at 12 years and 9 months, she had regular menstruations for 5 months. Breast development was automatically since the age of 10 years and physical examination showed normal female genitalia, Tanner stage 3. The hormonal profile showed elevated FSH and LH, low estrogen, and normal prolactin, confirming the POI. Pelvic ultrasound showed a pubertal uterus and two small ovaries without follicles. Bone age was 14 years. Chromosomal analysis was 46, XY. The cytogenetic analysis carried out on a skin fibroblasts which showed a normal female karyotype identic with her chromosomal analysis before transplantation. Conclusion Ovarian failure is common after allo-stem cell transplant (SCT). It is usually secondary to POI due to chemotherapy. Sex-mismatched after SCT is defined when there is a male donor and female recipient and vice versa, it does not affect fertility. Only the karyotype of hemocyte is 46 XY, but other somatic cells and germ cells are 46 XX as somatic and germ cells originated during the embryonic stage.