Search

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57–69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6–11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10–4.72]), lack of response to CAR-T (2.33 [1.02–5.29]), age >65 years (HR 2.65 [1.49–4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61–5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

We observed high rates of bloodstream infections (BSIs) following fecal microbiota transplantation (FMT) for graft-versus-host-disease (33 events in 22 patients). To trace the BSIs' origin, we applied a metagenomic bioinformatic pipeline screening donor and recipient stool samples for bacteremia-causing strains in 13 cases. Offending strains were not detected in FMT donations. Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii could be detected in stool samples before emerging in the blood. In this largest report of BSIs post-FMT, we present an approach that may be applicable for evaluating BSI origin following microbiota-based interventions. Our findings support FMT safety in immunocompromised patients but do not rule out FMT as an inducer of bacterial translocation.

Second allogeneic hematopoietic stem-cell transplantation (HSCT2) is a therapeutic option for patients with AML/ MDS relapsing after a first transplant (HSCT1). However, patients allocated to HSCT2 may be a selected group with better prognosis and the added efficacy of HSCT2 is not well established. We retrospectively analyzed 407 consecutive patients with relapsed AML/MDS after HSCT1. Sixty-two patients had HSCT2 (15%) and 345 did not. The 2-year cumulative incidence rates of non-relapse mortality and relapse after HSCT2 were 26% (95% CI, 17-39%) and 50% (95% CI, 39-65%), respectively. The 5-year overall survival (OS) rates were 25% (95% CI, 14-36%) and 7% (95% CI, 4-10%) in the HSCT2 and no-HSCT2 groups, respectively. Multivariate-analysis identified female gender (HR 0.31, P=0.001), short remission duration after HSCT1 (HR 2.31, P=0.05), acute GVHD after HSCT1 (HR 2.27, P=0.035), HSCT2 from haplo-identical (HR 13.4, P=0.001) or matched-unrelated donor (HR 4.53, P=0.007) and relapse after HSCT1 in earlier years (HR 2.46, P=0.02) as factors predicting OS after HSCT2. Multivariate-analysis of all patients including HSCT2 entered as time-dependent variable identified relapse within 6 months after HSCT1 (HR 2.32, P

Tisagenlecleucel (tisa-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed/refractory large B-cell lymphoma. Outcomes of patients with out-of-commercial specification (OOS) CAR T products are not well characterized. We therefore assessed 37 adult patients who underwent leukapheresis for tisa-cel therapy in a single center. In nine (24%) patients, manufactured tisa-cel was considered OOS. Three of them (33%) received tisa-cel after institutional review board approval; 2/9 (22%) did not receive tisa-cel due to disease progression; and 4/9 (44%) received academic point-of-care (POC) CAR T-cell as salvage therapy, at a median of 35 days following OOS notification. Three of those four patients achieved a complete response. In univariate analysis, risk factors for OOS were ≥ 4 prior therapies or previous bendamustine exposure. In conclusion, we report high OOS incidence of 24% in real-life setting. Forty-four percent of those patients received POC CAR T-cell as salvage therapy.

Autologous stem cell transplantation (ASCT) is a standard of care in newly-diagnosed multiple myeloma (MM) patients. Several studies before the introduction of novel therapies in MM, demonstrated a pegylated G-CSF to be successful in mobilizing peripheral blood stem cells (PBSCs). Lipegfilgrastim is a novel long-acting G-CSF that is produced by the conjugation of a single 20-kDa polyethelene glycol to the natural O-glycosylation site of G-CSF. Twenty-four MM patients were included for PBSCs mobilization with a single SC injection of 6 mg lipegfilgrastim. PBSC collection was started when the CD34+ count was > 10 × 106 cells/L. The target progenitor cells were 6 × 106 cells/kg. The median day of apheresis was + 3 (range 2–5) following lipegfilgrastim. Median peripheral blood CD34+ count pre-mobilization was of 22.65 (range 3.36–105) × 106 cells/L. The median number of leukaphaeresis procedures was 2 (range 1–4). The median mobilized CD34+ cells/kg were 8.26 (range 0.77–12.42). One patient failed to mobilize and two patients mobilized

Risk stratification is important for balancing potential risks and benefits of allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. We retrospectively studied 1119 patients undergoing allogenic-HSCT in a single center for five hematological indications assessing the prognostic role of LDH at admission for survival (OS), progression-free survival (PFS), relapse incidence (RI), and nonrelapse mortality (NRM). In non-Hodgkin lymphoma (NHL) and acute myeloid leukemia (AML), higher than median LDH had an adverse effect on survival. The prognostic significance was strongest in AML, with higher LDH levels having lower 1-and 3-year survival 69.2% vs. 50.8%, P

Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has transformed the care of patients with relapsed/refractory large B cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients ultimately will experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. The objective of the present study was to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR-T therapy in LBCL patients. This was a multicenter observational study reporting the outcome of 39 adult LBCL patients who underwent allo-HCT following anti-CD19 CAR-T therapy. The median patient age was 47 years (range, 20 to 68 years). HLA-matched sibling, HLA-matched unrelated, and alternative donors were used in 36%, 36%, and 28% of transplantations, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was complete response in 41%, partial response in 38%, and progressive disease in 21%. Allo-HCT was performed at a median of 127 days (range, 82 to 206 days) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4%; 95% confidence interval; [CI], 6.2% to 28.5%), was observed. The 1-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) was 38.5% (95% CI, 23.2% to 53.6%) and 15.4% (95% CI, 6.1% to 28.5%), respectively. The 2-year cumulative incidence of moderate-severe chronic GVHD was 11.1% (95% CI, 3.3% to 24.3%). Overall, 2-year nonrelapse mortality and relapse/progression incidence were 26% (95% CI, 13% to 41%) and 43% (95% CI, 27% to 59%), respectively. With a median follow-up of 32 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 45% (95% CI, 31% to 66%) and 31% (95% CI, 19% to 50%), respectively. In multivariable analyses, pre-HCT elevated lactate dehydrogenase level and transformed lymphoma were predictive of OS and PFS, respectively. Our data suggest that allo-HCT after anti-CD19 CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rate.

Introduction: Achievement of an initial complete remission (CR) following induction chemotherapy is tightly correlated with survival in acute myeloid leukemia (AML) patients, yet patients in CR with incomplete hematologic recovery (CRi) still experience improved outcomes compared with nonresponding patients. Whether CRi predicts prognosis in patients referred to an allogeneic stem cell transplantation (allo-SCT) is incompletely defined. In this analysis, we evaluated whether clinical outcomes of transplanted AML patients in CR and CRi were significantly different. Methods: A retrospective single-center analysis of all de novo AML patients who underwent an allo-SCT between 2001 and 2015. The cohort included all adult patients with AML who underwent a first allo-SCT either in first or second CR or CRi at the time of transplantation. Results: The study cohort included 186 CR patients and 44 CRi patients. In univariate analysis, CRi was associated with inferior 3-year survival and 3-year nonrelapse mortality (NRM) compared to CR (41 vs. 62%; p = 0.022 and 27 vs. 10%; p = 0.006, respectively). In multivariate analysis, CRi was associated with decreased rates of survival (hazard ratio [HR] 2.01; 95% CI, 1.24–3.25; p = 0.005) and NRM (HR, 3.5; 95% CI, 1.6–7.8; p = 0.002). Conclusion: CRi in transplanted AML patients is potentially a potent predictor of increased NRM and survival.

We present three patients with aggressive non-Hodgkin's B-cell lymphoma (NHL) who received anti-CD19 chimeric antigen receptor T (CAR T) cells therapy after failure of several lines of chemotherapy that developed pseudo-progression. One-week clinical and radiological findings were consistent with tumor progression. Positron emission tomography-computed tomography (PET-CT) at 1 month post CAR T cells administration was consistent with treatment response. The rapid tumor growth and subsequent resolution are suggestive of tumor pseudo-progression mediated secondary to infiltration and immune activation of CAR T cells. Overall, 56 adult patients with NHL were enrolled in a phase 1b/2 in house clinical study with CD19 CAR T cells. Out of them 22/56 patients progressed as per PET-CT the 1 month post CAR T cells. In 14 patients, signs of progression started 7-10 days after CAR T cells infusion. In 11/14 patients, it was true progression, while in 3 it was pseudo-progression. Additional studies are warranted to describe the extent of this phenomenon and evaluate correlation with the CAR T activity and long-term disease control.

Acute graft-versus-host disease (aGVHD) is the major treatment-related complication after stem-cell transplantation (SCT) from unrelated donors. The proteasome-inhibitor bortezomib was added to GVHD prevention regimens with initial promise. However, two randomized studies failed to show efficacy. We explored the addition of carfilzomib, s second-generation proteasome inhibitor (20 mg/m2, intravenously on days +1 and +2) to cyclosporine/methotrexate backbone in 26 patients after SCT from unrelated donors. We compared outcomes to historical group of 100 patients given cyclosporine/methotrexate alone. Median follow-up was 34 months. There was no difference between the groups in engraftment or toxicities. The cumulative incidence of aGVHD grade II–IV, 6 months post transplant was 11% (95% CI, 4–32) and 39% (95% CI, 30–50), respectively (P = 0.01). The cumulative incidence of chronic GVHD, 2 years post transplant, was 49% (95% CI, 32–75) and 41% (95% CI, 33–52), respectively (P = 0.98). Three-year non-relapse mortality was 11% (95% CI, 4–33) and 18% (95% CI, 12–27, P = 0.45) while 3-year relapse rates were 8% (95% CI, 2–29) and 26% (95% CI, 18–36), respectively (P = 0.06). Three-year survival was 81% (95%CI, 66–96) and 56% (95% CI, 46–66), respectively (P = 0.05). In conclusion, carfilzomib with cyclosporine/methotrexate is safe, may reduce aGVHD, and possibly improve survival after unrelated donor SCT. These initial observations merit further study in larger comparative studies. ClinicalTrial.gov NCT01991301.

Oral mucositis (OM) is a common debilitating dose-limiting toxicity of cancer treatment, including hematopoietic stem cell transplantation (HSCT). We hypothesized that the oral microbiome is disturbed during allogeneic HSCT, partially accounting for the variability in OM severity. Using 16S ribosomal RNA gene sequence analysis, metabolomic profiling, and computational methods, we characterized the behavior of the salivary microbiome and metabolome of 184 patients pre- and post-HSCT. Transplantation was associated with a decrease in oral α diversity in all patients. In contrast to the gut microbiome, an association with overall survival was not detected. Among 135 patients given methotrexate for graft-versus-host disease prophylaxis pre-HSCT, Kingella and Atopobium abundance correlated with future development of severe OM. Posttransplant, Methylobacterium species were significantly enriched in patients with severe OM. Moreover, the oral microbiome and metabolome of severe OM patients underwent distinct changes post-HSCT, compared with patients with no or mild OM. Changes in specific metabolites were well explained by microbial composition, and the common metabolic pathway was the polyamines pathway, which is essential for epithelial homeostasis. Together, our findings suggest that salivary microbial composition and metabolites are associated with the development of OM, offering new insights on pathophysiology and potential avenues of intervention.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) may offer a cure for selected patients with multiple myeloma (MM). Effective prognostic markers to guide patient selection are warranted. We retrospectively studied a cohort of 100 relapsed refractory MM patients who underwent allo-SCT. With a median follow-up of 12.2 years, median overall survival (OS) and progression-free survival (LFS) were 9.2 months and 5.6 months, respectively. 5-years OS and PFS were was 18.0% and 16.8%. The cumulative incidence of 5-years relapse was 45.9% and non-relapse mortality (NRM) 36.0%. In a multivariable Cox model, decreasing albumin, increasing lactate dehydrogenase (LDH), advanced disease, and mismatched donors were predictive of both reduced OS and PFS. The probability of 5-years OS was higher in patients with LDH below vs. the upper limit of normal (22% vs. 5%, p = 0.004). In the multivariable analysis, the hazard of NRM was increased with low albumin, mismatched donor type, and declining estimated glomerular filtration rate (eGFR). Patients with a low eGFR had a 5-year NRM incidence of 31% vs. 56% in patients with higher levels (p = 0.02). Graft-versus-host disease was not associated with improved outcomes. In conclusion, LDH, renal function, and albumin are highly informative of outcomes in MM patients treated with allo-SCT.

Purpose of the study The prognosis of patients with relapsed/refractory precursor B-acute lymphoblastic leukemia (ALL) is dismal. Antibody-based therapies, such as blinatumomab or inotuzumab ozogamycin (IO) have led to improved outcomes. The impact of prior immunotherapy on chimeric antigen receptor (CAR) T-Cell therapeutic efficacy and toxicity is unknown. Methods We describe a case series of ALL patients with prior exposure to blinatumomab or IO, who were treated with anti-CD19 CAR T cells with CD28 co-stimulatory domain (NCT02772198). We then review the literature on CAR-T post antibody-based therapy with either antibodies. Results Five adult patients with B-ALL were included. Three had active disease, and two were in morphological complete remission (CR) with minimal residual disease (MRD+). Therapy before CAR-T included blinatumomab (3/5 [60 %]) and IO (3/5 [60 %]), with one patient receiving both. One patient experienced severe cytokine release syndrome and central nervous system toxicity and subsequently died. At 28 days following treatment, two patients achieved CR with MRD negativity, and two had an MRD + CR. Two patients received allogeneic hematopoietic stem cell transplantation. At a median of 10 months (range, 5–26, three out of the four patients are still in CR, and one relapsed. The literature review identified a deficiency on data on the influence of blinatumumab and IO on outcomes post CAR-T therapy. Conclusions CD19 CAR T-cell therapy after treatment with blinatumomab and/or IO in patients with relapsed/refractory B-ALL is feasible and results in promising response rates in this case series. Future trails should specifically address outcomes in this population.

Summary The immunogenicity and safety of Pfizer‐BioNTech BNT162b2 mRNA vaccine in allogeneic haematopoietic stem cell transplantation (HSCT) recipients are unknown. We prospectively followed 152 HSCT recipients who were at least six months following transplantation and with no active acute graft‐versus‐host disease (GVHD). Blood samples were taken 2–4 weeks after the second vaccination and analyzed for receptor‐binding domain (RBD) antibodies and neutralizing antibodies (NA). 272 immunocompetent healthcare workers served as controls. At a median of 28 days after the second vaccination, 118 patients (77·6%) developed RBD immunoglobulin G (IgG) with a geometric mean titre (GMT) of 2·61 [95% CI (confidence interval), 2·16–3·16]. In the control group 269/272 (98·9%) developed RBD IgG, with a GMT of 5·98 (95% CI 5·70–6·28), P

Autologous stem cell transplantation (ASCT) is a standard of care in newly-diagnosed multiple myeloma (MM) patients. Several studies before the introduction of novel therapies in MM, demonstrated a pegylated G-CSF to be successful in mobilizing peripheral blood stem cells (PBSCs). Lipegfilgrastim is a novel long-acting G-CSF that is produced by the conjugation of a single 20-kDa polyethelene glycol to the natural O-glycosylation site of G-CSF. Twenty-four MM patients were included for PBSCs mobilization with a single SC injection of 6 mg lipegfilgrastim. PBSC collection was started when the CD34

Background Relapsed/refractory acute myeloid leukemia (R/R AML) remains a significant therapeutic challenge and while meaningful therapeutics gains have been achieved with the introduction of novel agents, clinical outcomes remain unsatisfactory. Anthracyclines constitute an essential component of induction chemotherapy for AML patients, however owing in part to the cardiotoxicity concerns, they are not broadly prescribed in R/R AML settings. Bisantrene, an anthracene with anthracycline-like activity, was shown in earlier studies to be an effective salvage therapy in R/R AML with no discernible cardiotoxicity. In this study, we assessed the clinical efficacy of bisantrene in a cohort of heavily pre-treated R/R AML patients. Aims To investigate the safety and efficacy of bisantrene in adult patients with R/R AML. Methods This phase 2, single center study (NCT03820908) enrolled adult R/R AML to receive bisantrene (250 mg/m2 daily for 7 days) which was administered via an intravenous infusion over 2 hours on days 1-7. Patient therapy was limited to one completed cycle of bisantrene including those who had achieved a partial response. Disease assessment included routine blood work and bone marrow studies which were performed at baseline and subsequently at blood count recovery or suspected disease progression. Next generation sequencing (NGS) was performed at baseline for all patients with adequate pre-study samples. Results In all, 10 patients were recruited to the study with a median of 3 lines of prior therapy including 7 patients who had relapsed following allogeneic stem cell transplantation. With regard to disease burden, three patients had an antecedent myeloid disorder while 4 patients had extramedullary disease at study recruitment. The most frequently reported grade ≥3 treatment attributed hematologic AE was thrombocytopenia whereas the most frequently reported grade ≥3 treatment attributed non-hematologic AE was mucositis. Of the ten patients, one (10%) achieved a complete remission and three patients achieved a partial remission resulting in an overall response rate of 40% with one patient being bridged to transplantation. NGS of patient samples identified a wide array of mutations associated with activated signaling, splicing, and epigenetic modification (table 1). Conclusion In conclusion, in the present study bisantrene induced clinical responses in 4 of 10 patients with R/R AML with acceptable toxicity. Given its marked activity in patients with leukemia cutis, chroromas and CNS disease, we speculate that bisantrene-based chemotherapy may have a significant applicability in patients with extramedullary disease. In view of the observed efficacy and low related toxicity, a follow-up study combining bisantrene with complementary anti-leukemic therapy is planned. Disclosures Canaani: Abbvie: Consultancy, Honoraria, Research Funding. Benjamini:Abbvie Inc: Consultancy, Research Funding. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.

Acute graft-versus-host disease (aGVHD) is the major treatment-related complication after stem-cell transplantation (SCT) from unrelated donors. The proteasome-inhibitor bortezomib was added to GVHD prevention regimens with initial promise. However, two randomized studies failed to show efficacy. We explored the addition of carfilzomib, s second-generation proteasome inhibitor (20 mg/m

Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (

Biomarkers measured in blood chemistry before allogeneic hematopoietic stem cell transplantation (HSCT) may reflect patients' physiological status. We hypothesized that selected markers are predictive for nonrelapse mortality (NRM) following transplantation and could contribute to risk assessment. We investigated the value of pre-HSCT albumin, estimated glomerular filtration rate (eGFR), and alkaline phosphatase (AlkP) in predicting NRM. We retrospectively analyzed clinical and laboratory data from 1217 patients receiving a first HSCT in 2 European centers between 2003 and 2015. Transplantation indications and conditioning regimens were diverse. Patients had a median age of 55 years and hematopoietic cell transplantation comorbidity index (HCT-CI) scores of 0 (24%), 1 to 2 (39%), and ≥3 (37%). Cutoffs of eGFR60 mL/min, albumin3.5 g/dL, and AlkP180 IU/L corresponded with 8.8%, 8.3%, and 6.5% of the patients, respectively. eGFR and albumin were associated with increased risk and higher cumulative incidence of day-100, 1-year, and 2-year NRM, both as continuous or categorized variables. A similar pattern was observed for AlkP, except for day-100 NRM. In multivariable analyses, eGFR and albumin were consistently among the top risk factors for early and late-term NRM, abrogating the role of age. Prediction models for day-100, 1-year, and 2-year NRM based only on HCT-CI resulted in c-statistics of .565, .575, and .577, respectively. Addition of both biomarkers increased c-statistics for day-100, 1-year, and 2-year NRM to .651, .633, and .624, respectively. Albumin and eGFR are prognostic biomarkers for NRM after HSCT and improve the discriminative power of the HCT-CI.

Comorbidity burden is a well-established risk factor for non-relapse mortality (NRM) following allogeneic stem cell transplantation (allo-SCT). We evaluated whether individual comorbidities could better characterize NRM risk. Furthermore, given differing toxicity profiles of conditioning agents, we hypothesized that the hazard of comorbidities is exerted in a regimen-specific manner. This retrospective study included 875 adults treated with an allo-SCT. Six conditioning regimens were considered. Across the entire cohort and within each regimen, the hazard ratio (HR) for NRM associated with individual comorbidities was assessed using multivariable Cox regressions. In the overall population, renal dysfunction, hypoalbuminemia, and severe hepatic disease were associated with the highest risk of NRM (HR 2.1, HR 1.9, HR 1.7, respectively). The risk associated with specific comorbidities was modified by the conditioning regimen and was not correlated with intensity. In patients conditioned with fludarabine/busulfan (Flu/Bu4), NRM risk was increased with cardiac disease (HR 5.54). Severe pulmonary disease and a pre-existing infection were associated with increased NRM risk in patients receiving fludarabine/melphalan (HR 4.9) and fludarabine/treosulfan (HR 3.6), respectively. Comorbidities may exert effects unique to particular conditioning regimens, suggesting that regimen selection should be driven in part by specific comorbidities.

Background Approximately 60% of patients with aggressive large B-cell lymphoma (ALBCL) treated with anti-CD19 chimeric antigen receptor T-cell (CAR T) will ultimately progress or relapse. Allogeneic hematopoietic cell transplantation (Allo-HCT) is a potentially curative treatment for lymphoma patients who relapse after CAR T-cell therapy. However, the efficacy and toxicity profile of allo-HCT following CAR T in aggressive lymphoma patients are not well defined. Herein, we report our experience. Methods and patients A total of 29 adult patients (median age 45 years [IQR 40-55]) who received allo-HCT for ALBCL between 2017 to 2021 were included. All patients were previously treated with anti-CD19 CAR T-cell (academic CD28-costimulatory domain product [n=23, 79%]; tisagenlecleucel [n=6, 21%]). Twenty-five (86%) and 4 (14%) had a diagnosis of DLBCL and PMBCL, respectively. Median number of previous therapies before CAR T was 3 (IQR 2-4). Eight (28%) patients underwent a previous autologous HCT. No patient underwent a previous allo-HCT. Median hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was 3 (IQR 2-3). Six (21%) patients had a Karnofsky performance status ≤ 80%. Allo-HCT was performed at a median of 4.1 months (IQR 2.2-5.4) post CAR T, with the majority of patients (48%) receiving transplant as first-line post CAR T. Reasons for allo-HCT were consolidation of complete response (CR) to CAR T in high-risk disease (n=4, 14 %), partial response (PR) to CAR T (n=7, 24%) and relapse /progression after CAR T (n=18, 62%). Disease response before allo-HCT was CR (n=11, 38%), PR (n=11, 38%) and progressive disease (n=7, 24%). Donors were matched siblings (n=13, 45%), matched unrelated (n=9, 31%) and mismatched unrelated /haploidentical donors (n=7, 24%). Myeloablative and reduced-intensity conditioning regimens were given in 13 (45%) and 16 (55%) patients, respectively. Methotrexate-based graft versus host disease (GVHD) prophylaxis was used in 20 (69%) patients. Antithymocyte globulin and post-transplantation cyclophosphamide were administered in 13 (45%) and 5 (14%), respectively. Results Median follow-up was 33 months (IQR 13-41). Neutrophil engraftment rate was 93% (two early deaths before engraftment due to infection and multi-organ failure). Two-year overall survival (OS) and progression-free survival were 44% (95% CI: 28-68) and 30% (95% CI: 17-55), respectively. Two-year cumulative relapse incidence and non-relapse mortality were 45% (95% CI: 25-63) and 25% (95% CI: 11-43), respectively (Figure). In a univariable Cox regression, factors significantly associated with a shorter OS were number of interim therapies between CAR T and allo-HCT (Hazard ratio [HR] 2.2 [95% CI: 1.3-3.9], p 0.006) and the length of time between CAR T and allo-HCT (HR 3.8 [95% CI: 1.2-12.1], p 0.02). Best response to CAR T and disease response before allo-HCT were not significant risk factors for a shorter OS. High rates of grade ≥ 3 hyperbilirubinemia (total bilirubin >3 ULN) and hepatic sinusoidal obstruction syndrome (SOS) were observed in 10 (35%) and 5 (17%) patients, respectively. These liver insults were not contributed to acute GVHD. All patients with SOS were treated with defibrotide and two patients died from related complications. Interestingly, 4/5 patients with SOS were conditioned with fludarabine and thiotepa. One-year cumulative incidence of grade II-IV acute GVHD was 34% (n=10; 95% CI: 18-52). Notably, 6 patients had grade IV acute GVHD, 4 of them were refractory to corticosteroids and 3 patients died due to acute GVHD. Two-year cumulative incidence of chronic GVHD was 23% (n=5; 95% CI: 7-46). Chronic GVHD was considered extensive in 4 of them. Bloodstream bacterial infection was documented in 11 (38%) patients. Invasive fungal infection occurred in 6 (21%) patients and included brain aspergillosis, cutaneous aspergillosis, 2 lung aspergillosis, hepatosplenic candidiasis and an ocular mucor mycosis. Conclusion Allogeneic hematopoietic cell transplantation is feasible after failure of CAR T-cell therapy in aggressive lymphoma, although with a relatively high rate of SOS and severe acute GVHD in these heavily pretreated patients. Overall survival is encouraging with approximately 30% of patients remaining alive and disease-free at two years. Larger scale studies are required to better define the role of allo-HCT in this setting. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avigdor: Takeda: Consultancy, Honoraria; Janssen: Research Funding; BMS: Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Up to 70% of large B-cell lymphoma (LBCL) patients will eventually experience relapse or progress following CD19-CAR-T therapy. Data guiding management of this challenging population are lacking. Therefore, we aimed to study the relationship between treatment strategies and outcomes following CD19-CAR-T failure. We included 273 adults, from two centers, treated with CD19-CAR-T (axicabtagene-ciloleucel [98, 36%], tisagenlecleucel [76, 28%], lisocabtagene-maraleucel [28, 10%], and an academic CD28-product [71, 26%]) for relapsed/refractory LBCL Cumulative incidence of relapse or progression was 40% (95% CI: 34%, 46%). Of 176 patients with residual or relapsed disease post-CAR-T (Fig. A), 133 received subsequent first-line anti-cancer therapy for active or residual disease (primary cohort) at a median of 79 days (interquartile range 49-124) after CAR-T infusion. Within the primary cohort, 65% of patients had stage III-IV disease at time of subsequent therapy. Most lymphomas remained CD19-positive after CAR-T therapy (45 biopsies, 91% positive by flow cytometry [58% normal, 33% dim expression]). At time of first treatment post-CAR-T, nearly all patients had either relapsed disease or stable/progressive disease (SD/PD), with eight patients in ongoing partial response (PR). With a median follow-up of 14.5 months (95% CI: 11.5-21.4), the median overall survival (OS) from time of first subsequent therapy was 8.6 months (IQR 6.9-12.0). We sought to identify determinants of survival among patients receiving initial post-CAR-T treatment. Variables measured pre- and post-CAR-T therapy and significantly associated (p < 0.1) with OS in univariable Cox regression were introduced into a multivariable model. Age ≥ 65y (HR 2.01 [95% CI: 1.23-3.29], p 0.005), bulky disease at apheresis (HR 2.05 [1.07-3.95], p 0.031), and disease refractory to CAR-T therapy (HR 1.89 [1.19-2.98], p 0.007) were associated with inferior OS in the multivariable analysis. Based on the cumulative burden of OS determinants, we propose a prognostic tool allowing risk stratification of patients receiving treatment post-CAR-T. Increasing number of these three risk factors was associated with greater mortality (HR 1.86 [1.32-2.62], p Therapy strategies post-CAR-T varied. Polatuzumab (n=25), anthracycline or platinum ("chemotherapy"; n=17), BTK inhibitors (n=13) and lenalidomide (n=12) based treatment were most frequently administered for non-localized disease (stage ≥2). Involved site radiation therapy (ISRT; n=20) was primarily given for stage I disease (Fig. C). Overall response rate (ORR) in the entire cohort was 47% (25% CR; 22% PR). Fig. D shows response rates by treatment. Remarkably, novel agents, including polatuzumab and lenalidomide-based therapies, had ORR of 52% (CR 35%) and 33% (CR 33%), respectively. In contrast, traditional chemotherapy-based approaches did not result in CR, and only 50% achieved PR. Survival was poorest with chemotherapy (6 month OS: 25% [95% CI: [11-59]), while rates with lenalidomide and polatuzumab-based therapies were 65% (42-100) and 67% (50-89). Patients and disease characteristics across treatment groups were unbalanced. However, the three prognostic factors comprising the OS prognostic tool: age ≥ 65y, bulky disease at apheresis and disease refractoriness to CAR-T, were similar across lenalidomide, polatuzumab, checkpoint inhibitors, and chemotherapy-based treatment groups. Patients who underwent alloHCT were significantly younger but achieved high rates of response. In conclusion, we present the most extensive and detailed experience of treatment outcomes post-CAR-T therapy. Our data suggest that novel agents may be preferable to traditional chemotherapies as the first post-CAR-T treatment. However, survival is still poor, and investigation of curative approaches is needed. We provide a tool to inform mortality risk in this difficult-to-treat population. Figure 1 Figure 1. Disclosures Scordo: i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; McKinsey & Company: Consultancy; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding. Batlevi: ADC Therapeutics: Consultancy; Juno/Celgene: Consultancy; Life Sciences: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Viatris: Current holder of individual stocks in a privately-held company; GLG Pharma: Consultancy; Xynomic: Research Funding; Seattle Genetics: Consultancy; Kite Pharma: Consultancy; TG Therapeutics: Consultancy; TouchIME: Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; Pfizer: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Dahi: Gilead sciences: Membership on an entity's Board of Directors or advisory committees; Kite pharma: Membership on an entity's Board of Directors or advisory committees. Giralt: PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Palomba: Pluto: Honoraria; Lygenesis: Honoraria; Magenta: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; WindMIL: Honoraria; Priothera: Honoraria; Nektar: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Kite: Consultancy; Ceramedix: Honoraria; Notch: Honoraria, Other: Stock; Novartis: Consultancy; PCYC: Consultancy. Salles: Ipsen: Consultancy; Regeneron: Consultancy, Honoraria; Genentech/Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Honoraria; Allogene: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Debiopharm: Consultancy; Velosbio: Consultancy; Rapt: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Avigdor: Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Equilium: Honoraria; Cidara: Honoraria; MorphoSys: Honoraria; Incyte: Honoraria, Other; Servier: Honoraria; Celgene: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Nektar Therapeutics: Honoraria, Other; Merck: Honoraria; Novartis: Honoraria, Other; NexImmune: Honoraria; Miltenyi Biotec: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria. Shouval: Medexus: Consultancy.

Background Risk stratification is a critical step when considering allogeneic hematopoietic stem cell transplantation (HSCT). While Lactate dehydrogenase (LDH) is a readily available biomarker with a prognostic role in the front-line therapy setting of hematological malignancies, its' role in the pretransplantation setting is undefined. Methods This was a retrospective study on a cohort of patients who underwent allogeneic-HSCT at a single center between 2000 and 2016. Pre transplant LDH levels and other clinical features were extracted from medical record. The primary outcome was overall survival (OS), and secondary outcomes included non-relapse mortality (NRM) and relapse (considered as competing events). The median follow-up time was 59 months (IOR 27 - 112). We analyzed the association between median LDH levels, per disease category. Associations meeting a p-value below 0.05 for the primary outcome were further explored in a multivariable Cox regression (cause-specific Cox for competing events). The model was adjusted for age, disease risk index (DRI), year of HSCT, donor type, and conditioning regimens. Results A total of 1,250 adult (median age 52.8 years) patients with the following disease were included; Acute myeloid leukemia (AML, n=594; 48%), non-Hodgkin lymphoma (NHL, 211, 16.9%), acute lymphoblastic leukemia (ALL, n=175, 14%), myelodysplastic syndrome (n=165, 13%), and plasma cell dyscrasia (PCD, n=105, 8%). In the univariate analysis, AML patients with higher than median LDH levels (>193 IU/L) had lower 3-year OS (51.9% vs. 39.2%, p 228 IU/L) was associated decreased OS (51.9% vs. 39.2%, p Conclusion Using a systematic approach, we showed that pre-transplantation LDH is a potent biomarker that could be used for risk stratification for AML and NHL patients who are candidates for allogeneic-HSCT. While further validation is warranted it may be rewarding to incorporate LDH in future prognostic models assessing the risk of transplantation.

Background In recipients of allogeneic hematopoietic stem cell transplantation (HSCT), organ toxicity is a barrier to administering high-intensity conditioning. We hypothesized that determinants of acute organ toxicity are specific to individual regimens. We sought to characterize these toxicities, evaluate their prognostic implication, and derive predictors of severe toxicity at the regimen level. Methods This retrospective study included adults undergoing first allogeneic HSCT at a single center between 2001 and 2014. Patients received grafts from matched sibling or unrelated donors and received any of the following regimens: Cy/TBI, Bu/Cy, Flu/Bu 12.8 mg, Flu/Bu 6.4 mg, Flu/Treosulfan 36-42 gr/m2, and Flu/Mel 100-140 mg/m2. Studied toxicities included acute kidney injury (AKI) per KDIGO definition and increases in total bilirubin, AST, ALT, and alkaline phosphatase (Alk Phos) per CTCAE grading. The incidence of toxicities from conditioning through 30-days post-HSCT was tabulated. Risk factors for severe organ toxicity were assessed within each regimen using multivariable logistic regressions. Results In a cohort of 707 patients, the main indications were acute leukemia (57%), myelodysplastic syndrome (13%), and aggressive lymphoma (9%). GvHD prophylaxis included methotrexate in 80% of patients, and 56% received ATG. The incidence of AKI and increased serum bilirubin in each regimen is shown in Figure 1A/B, respectively. Sinusoidal-obstructive syndrome (6% overall) accounted for only 17% of gr. ≥ 3 bilirubinemia in the entire cohort. Elevations in AST, ALT, and Alk Phos of gr ≥ 3 were not common ( Conclusion Allogeneic transplantation recipients are at high risk for acute organ damage. We describe patterns of renal and liver toxicity across several regimens. Determinants of acute severe organ toxicity, defined as those associated with short-term mortality, are regimen dependent. Our findings suggest these factors should be considered in selecting the preparative regimen. While requiring validation, the newly-defined composite endpoint of acute severe organ toxicity (ASOT) may be valuable in studying transplantation strategies.

Introduction Allogeneic stem-cell transplantation (SCT) is curative therapy in patients with AML or MDS. However, disease recurrence is the major cause of treatment failure. We explored the use of low-dose azacytidine maintenance therapy for the prevention of relapse after SCT in patients with high-risk AML/MDS. Methods Patients considered to be at high risk for relapse after SCT were given azacytidine at 32-50 mg/m2 for 5 days every 28 days for a planned duration of 2 years. Sct outcomes were compared with a historical group matched for age, disease, status at SCT, cytogenetics, conditioning and donor type and time from SCT to the start of maintenance. Patients relapsing after SCT and achieving second CR with chemotherapy were also eligible for secondary azacytidine prophylaxis. Results Forty patients with AML (n=32) or MDS (n=8), median age 62 years (25-74), were given azacytidine after SCT from sibling (n=8) or matched-unrelated (n=32) donors. The conditioning regimen was myeloablative (n=20) or reduced-intensity (n=20). The status at SCT was untreated MDS (n=10), CR1 (n=19), CR2 (n=4), refractory AML (n=7). 15 had normal karyotype, 9 complex karyotype and 16 other cytogenetic abnormalities (12 of them high-risk). Fifteen patients were in CR after SCT but at high-risk for relapse due to active disease (n=7) or positive measurable residual disease (MRD, n=3) at SCT, or poor-risk cytogenetics (n=5). 17 patients were given azacytidine pre-emptively for mixed-chimerism (n=9) or positive MRD (n=8) after SCT. 8 patients were given azacytidine as secondary prevention after achieving CR with chemotherapy for post-transplant relapse. The estimated leukemia-free survival (LFS) in this group of patients is less than 20%. Patients started azacytidine in a median of 2.2 months (1.2-6.9) after SCT and received a median of 14 courses (1-50). 3 patients were also given donor-lymphocyte infusions concomitantly. 12 of 23 patients given prophylactic azacytidine remained in CR, 11 relapsed and 7 of them died. 15 of 17 patients given azacytidine preemptively achieved a response (10 CR) and 7 remained in CR, 9 died of disease progression and one of non-relapse cause. With a median follow-up of 22.5 months (10.2-45.2), the estimated 3-year overall survival (OS) and LFS rates are 53.9% (95%CI, 29.5-78.4) and 40.0% (95%CI, 21.2-58.6), respectively. In the matched control group, 8 patients are alive, 26 died of relapse and 6 of non-relapse causes. The estimated 3-year OS and LFS rates are 27.1% (95%CI, 13.2-41.0, P=0.002, Figure 1) and 19.7% (95%CI, 7.9-32.1, P=0.005, Figure 2), respectively. Conclusions Maintenance azacytidine is safe and effective therapy when used prophylactically or preemptively after SCT in high-risk AML/MDS patients and may improve survival. Azacytidine maintenance should be further explored, possibly in combination with other methods to prevent relapse.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) may offer a cure for selected patients with multiple myeloma (MM). Effective prognostic markers to guide patient selection are warranted. We retrospectively studied a cohort of 100 relapsed refractory MM patients who underwent allo-SCT. With a median follow-up of 12.2 years, median overall survival (OS) and progression-free survival (LFS) were 9.2 months and 5.6 months, respectively. 5-years OS and PFS were was 18.0% and 16.8%. The cumulative incidence of 5-years relapse was 45.9% and non-relapse mortality (NRM) 36.0%. In a multivariable Cox model, decreasing albumin, increasing lactate dehydrogenase (LDH), advanced disease, and mismatched donors were predictive of both reduced OS and PFS. The probability of 5-years OS was higher in patients with LDH below vs. the upper limit of normal (22% vs. 5%, p = 0.004). In the multivariable analysis, the hazard of NRM was increased with low albumin, mismatched donor type, and declining estimated glomerular filtration rate (eGFR). Patients with a low eGFR had a 5-year NRM incidence of 31% vs. 56% in patients with higher levels (p = 0.02). Graft-versus-host disease was not associated with improved outcomes. In conclusion, LDH, renal function, and albumin are highly informative of outcomes in MM patients treated with allo-SCT.

Allogeneic stem cell transplantation is a curative therapy for myelofibrosis. The optimal conditioning regimen has not been well defined. We retrospectively compared transplantation outcomes in patients with myelofibrosis (n = 67) conditioned with myeloablative (MAC, 36%) and reduced-intensity (RIC, 46%) regimens, and more recently with the combination of thiotepa, busulfan, and fludarabine (TBF, 18%). Patients were transplanted from HLA-matched sibling (n = 26) or unrelated donors (n = 41) between the years 2003 and 2018. The median follow-up was 2.9 years for all patients but shorter in the TBF group (1.1 years). The probability of 3-year progression-free survival (PFS) was 43%. At 1 year, the rate of PFS was 80%, 54%, and 45% with TBF, MAC, and RIC, respectively (p = 0.031). In a multivariable model, there was a greater risk for death with MAC (hazard ratio [HR] 12.26, p = 0.026) and lower PFS with both MAC (hazard ratio [HR] 7.78, p = 0.017) and RIC (HR 5.43, p = 0.027) compared with TBF. Relapse was higher with RIC (HR 8.20, p = 0.043) while nonrelapse mortality was increased with MAC (HR 9.63 p = 0.049). Our results indicate that TBF is a promising preparative regimen in myelofibrosis patients transplanted from matched sibling or unrelated donors, and should be further explored.

Clinical decisions in allogeneic hematopoietic stem cell transplantation (allo-HSCT) are supported by the use of prognostic scores for outcome prediction. Scores vary in their features and in the composition of development cohorts. We sought to externally validate and compare the performance of 8 commonly applied scoring systems on a cohort of allo-HSCT recipients. Among 528 patients studied, acute myeloid leukemia was the leading transplant indication (44%) and 46% of patients had a matched sibling donor. Most models successfully grouped patients into higher and lower risk strata, supporting their use for risk classification. However, discrimination varied (2-year overall survival area under the receiver operating characteristic curve [AUC]: revised Pretransplantation Assessment of Mortality [rPAM], 0.64; PAM, 0.63; revised Disease Risk Index [rDRI], 0.62; Endothelial Activation and Stress Index [EASIx], 0.60; combined European Society for Blood and Marrow Transplantation [EBMT]/Hematopoietic Cell Transplantation-specific Comorbidity Index [HCT-CI], 0.58; EBMT, 0.58; Comorbidity-Age, 0.58; HCT-CI, 0.55); AUC ranges from 0.5 (random) to 1.0 (perfect prediction). rPAM and PAM, which had the greatest predictive capacity across all outcomes, are comprehensive models including patient, disease, and transplantation information. Interestingly, EASIx, a biomarker-driven model, had comparable performance for nonrelapse mortality (NRM; 2-year AUC, 0.65) but no predictive value for relapse (2-year AUC, 0.53). Overall, allo-HSCT prognostic systems may be useful for risk stratification, but individual prediction remains a challenge, as reflected by the scores’ limited discriminative capacity.

// Nira Varda-Bloom 1, 2, * , Ivetta Danylesko 1, 2, * , Roni Shouval 1, 2, 3, 4 , Shiran Eldror 1, 2 , Atar Lev 1, 2, 5, 6 , Jacqueline Davidson 1, 2 , Esther Rosenthal 1, 2 , Yulia Volchek 1, 2 , Noga Shem-Tov 1, 2 , Ronit Yerushalmi 1, 2 , Avichai Shimoni 1, 2 , Raz Somech 1, 2, 5, 6 , Arnon Nagler 1, 2 1 Sheba Medical Center, Ramat-Gan, Israel 2 Sackler Faculty of Medicine, Tel-Aviv University, Israel 3 Dr. Pinchas Bornstein Talpiot Medical Leadership Program, Sheba Medical Center, Israel 4 Bar-Ilan University, Ramat Gan, Israel 5 Pediatric Immunology Service, Jeffrey Modell Foundation, USA 6 Edmond and Lily Safra Children’s Hospital, Israel * These authors contributed equally to this work Correspondence to: Ivetta Danylesko, email: alexivetta@gmail.com Keywords: nilotinib, stem cell transplantation, immune reconstitution, mitogens, thymic activity Received: September 30, 2016 Accepted: November 08, 2016 Published: November 18, 2016 ABSTRACT Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180−270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation.

Human recombinant granulocyte colony-stimulating factor (G-CSF), filgrastim (Neupogen; Amgen, Thousand Oaks, CA, USA), has been widely used for the mobilization of CD34(+) hematopoietic stem cells (HSC) from healthy donors. The experience with biosimilar G-CSF agents in this area is limited. We performed a prospective study assessing Tevagrastim (biosimilar filgrastim, XMO2; Teva, Israel) for mobilization of CD34(+) peripheral blood HSC in HLA-matched healthy sibling donors for transplantation in 24 patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndromes (MDS) (NCT01542944). Results were compared to a historical control group of sibling donors who received filgrastim for stem cell mobilization for allogeneic stem cell transplantations in patients with AML and MDS. The healthy donors received Tevagrastim or filgrastim in a dose of 10 μg/kg body weight (BW) subcutaneously for 4 days. The target yields of CD34(+) cells was 5 × 10(6) CD34(+) cells/kg BW of the recipient. A median 10.2 × 10(6) (range, 2.52 to 35.4) and 9.35 × 10(6) (range, 3.7 to 30.6) CD34(+) cells per kg BW were collected in the Tevagrastim and filgrastim groups, respectively. All patients promptly engrafted with a median day of absolute neutrophil count (ANC) of.5 × 10(9)/L and1 × 10(9)/L of 13 days (range, 10 to 21) and 13.5 days (range, 10 to 22), respectively in the Tevagrastim group and 12 days (range, 10 to 18) and 13 days (range, 10 to 18) in the filgrastim group, respectively. Platelets reached counts of20 × 10(9)/L and50 × 10(9)/L within a median of 14 days (range, 11 to 33) and 17 days (range, 12 to 33) in the Tevagrastim group and 13 (range, 10 to 29) and 15 (range, 10 to 32) days in the filgrastim group, respectively. The donors developed only mild and transient side effects, which were not different between the Tevagrastim study group and the filgrastim historical control group. Similarly, the transplantation-related toxicities and outcomes did not differ between the patients who underwent transplantation with Tevagrastim-mobilized grafts and the filgrastim historical controls. In summary, we observed a similar yield of CD34(+) stem cell mobilization in the Tevagrastim study group and the filgrastim historical control group with similar engraftment kinetic, hematopoietic reconstitution, and transplantation outcome. Tevagrastim administration was safe with minimal side effects and toxicity not different than historical controls. The lack of significant differences for all parameters of stem cell collection, engraftment, and safety with the biosimilar XMO2 Tevagrastim demonstrate the "similarity" of the biosimilar and recombinant human G-CSF in this indication.

Background: Richter's transformation (RT) is a rare complication of Chronic Lymphocytic Leukemia (CLL), usually into clonally related diffuse large B cell lymphoma (DLBCL). Currently there is no effective therapy to RT and CLL relapse after targeted therapy. Chimeric antigen receptor-modified T (CART) cells directed to CD19+ B-cell malignancies have promising results in relapsed DLBCL. However, its effectiveness in CLL relapse after targeted therapy and RT is less clear and no systematic reports are available. Methods: From July 2019 to May 2020 we enrolled eight CLL patients with disease transformation after chemoimmunotherapy and therapy with BTK and/or BCL2 inhibitors as part of single center phase 2 CAR T-cell therapy in B-cell malignancies (NCT02772198). Following lymphodepletion consisting of cyclophosphamide and fludarabine patients received an infusion of locally produced 1x106 CD19-CART- cells/kg, which were generated by modifying autologous T cells with retroviral vector encoding a CAR comprising FMC63 anti-CD19 ScFv linked to a CD28 costimulatory domain, and CD3-zeta intracellular signaling domain. Results: All 8 patients (pts) were relatively young with median age at CLL diagnosis of 56y (47-62). Disease transformation developed after a median of 8 years (range 1-16) from CLL diagnosis. Patients treated with CD19-CAR T-cells at median age of 64 y (54-73) having median comorbidity G-CIRS score 2 (0-5), performance status ECOG 1 (0-2) and CCT 66ml/min (26-89). Pts had history of CLL with del17p/TP53 in 83%, 5/6 available, del11q 2/6 prior to transformation. Disease transformation included RT in 6 pts with DLBCL, 1 accelerated CLL and 1 prolymphocytic transformations. Among RT pts 67% (4/6) had advanced stage DLBCL, 50% (3/6) extarnodal and 33% (2/6) bulky disease. Patients received median of 3 (0-5) CLL therapies and 2 (1-3) large cell lymphoma directed therapy. CLL therapies included chemoimunotherpay: 5 Fludarabine, cyclophosphamide, rituximab/obinutuzumab (FCR/FCO), 1 bendamustin rituximab (BR); 5 dual targeted therapy (ibrutinib and Venetoclax), 2 ibrutinib only, 1 venetoclax only. Last CLL treatment was Venetoclax in 71% (5/7) and ibrutinib in 29% (2/7) with 32 (range 15-39) months duration on ibrutinib and 10 (2-17) months on venetoclax. The reason for ibrutinib discontinuation was CLL progression (PD) in 5, disease transformation in 2, and venetocalx discontinuation due to progressive disease (PD) - 4 and transformation - 2. Post transformation all RT pts were treated with R-CHOP, second line tx 2, one patient with prolymphocytic transformation was treated with alemtuzumab, allo-SCT, ibrutinib and venetoclax. All pts had PD before treatment with CAR T-cells, 63% (5/8) had elevated LDH and 5/8 evaluable PET CT before treatment had deauville score (DS) 5 with median SUVmax 8.7 (3.7-21). After infusion of CAR T-cells 7 patients had cytokine release syndrome (CRS), 4 grade 1 and 3 grade 3-4 that required tocilizumab. Three patients had CNS toxicity, two grade 3. Seventy five percent (6/8) developed neutropenia, (3/8) grade 3-4, all neutropenia resolved except in one patient that succumbed to PD, 2 pts had infections (campylobacter and H1N1 influenza, each). There were no fatalities due to CAR T-cell toxicity. There were two fatalities due to disease progression. All 71% (5/8) responders achieved complete response with DS1 in PET CT scan on day 28. After median follow up duration of 6 (4-10) months, 2 patients proceeded to allo-SCT. Conclusion: CD19-CART-cell therapy in CLL patients with disease transformation is safe and has high complete remission rate with promising clinical response. Long term remission rate after CD19-CART-cell therapy for RT needs to be further evaluated in more patients. Disclosures Benjamini: Abbvie Inc: Consultancy, Research Funding. Tadmor:AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Medison: Consultancy, Speakers Bureau; Neopharm: Consultancy, Speakers Bureau; 6. Novartis Israel Ltd., a company wholly owned by Novartis Pharma AG: Consultancy, Speakers Bureau. Fineman:Abbvie Inc: Consultancy, Research Funding. Jacobi:Novartis: Consultancy. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding.

Background Oral mucositis (OM) is a debilitating multifactorial complication of hematopoietic stem cell transplantation (HSCT). We hypothesized that the oral microbiome is disturbed during transplantation and may partially account for the variability in OM severity across patients. Methods In this single-center study, we prospectively collected saliva samples weekly in a cohort of 184 adults undergoing allogeneic HSCT. A total of 625 samples were collected starting from 7 days before HSCT to 34 days post-transplant. Samples underwent 16S rRNA gene sequencing. Sixty pre- and post-HSCT samples underwent mass spectrometry-based metabolomic profiling (Metabolon, Durham, NC). OM was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Results Myeloablative conditioning regimens were used in 70% of patients. The median time to OM development was 7 days; 58% and 43% of patients developed grade 2-4 and grade 3-4 OM, respectively. Pre-transplantation oral α-diversity, as measured by the Shannon Index, was similar to that of healthy controls (n=20) (p=0.460), but later decreased, reaching a nadir on day 12 (Fig. A). Among patients with grade 2-4 OM, the reduction in α-diversity over time was more pronounced compared to transplant-recipients having no or only mild OM (grade 0-1) (Fig. B). In the group treated with MTX (n=135), patients harboring Rothia, Kingella, and Atopobium in the saliva before stem cells infusion were more likely to develop grade 3-4 OM than their counterparts. Furthermore, in samples collected between days 7 to 13, there was a higher abundance of Methylobacterium among patients with grade 3-4 OM, while Treponema and the genus TG5 (Fig. 3) were more common in patients with grade 0-1 OM (Fig. C). Finally, metabolic profiling of saliva collected pre and post HSCT showed marked changes before and after transplantation among patients who developed mucositis. Microbiome-associated metabolites enriched in patients with mucositis included histidine, phenylalanine, tyrosine, and tryptophan. Conclusions In this largest analysis of the oral microbiome in HSCT recipients, we demonstrate that the oral microbiota is disrupted during allogeneic HSCT. Microbiota injury is more profound in patients who developed oral mucositis. Our findings indicate that there may be a distinct microbiological and metabolic signature in patients with mucositis, with some changes preceding the clinical phenotype. These may serve as potential intervention points to treat and prevent mucositis.

Steroid-resistant (SR) acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic stem cell transplantation. Vedolizumab is a monoclonal antibody that impairs homing of T cells to the gastrointestinal (GI) endothelium by blocking the α4β7 integrin. We retrospectively analyzed outcomes following vedolizumab administration for treatment of SR GI GvHD. Overall, 29 patients from three transplantation centers were included. Histopathology was available in 24 (83%) patients. The overall response rate (ORR) was 23/29 (79%); 8 (28%) patients had a complete response and 15 (52%) a partial response. Vedolizumab was administered as a 2nd-line or ≥3rd-line treatment in 13 (45%) and 16 (55%) patients, respectively. ORR in the former groups was 13/13 (100%) versus 10/16 (63%) in the latter (p = 0.012); corresponding CR rates were 7/13 (54%) versus 1/16 (6%) (p = 0.005). Early administration of vedolizumab was also associated with a greater likelihood of patients being off immunosuppression ((9/13 (69%) versus 3/16 (19%), p = 0.007) and free from fatal infectious complications (5/13 versus 14/16, p = 0.006). Overall, our data suggest that vedolizumab, especially if administered early in the disease course, may ameliorate severe SR GI aGvHD. The timing, role, and safety of vedolizumab should be further explored in prospective clinical trials.

Second malignancies are a rare but well-defined late complication after autologous and allogeneic hematopoietic stem-cell transplantation (SCT). Solid malignancies occur in up to 15% of patients 15 years after SCT with myeloablative conditioning, with no plateau in the incidence rates. They are responsible for 5–10% of late deaths after SCT. The incidence is increased with advanced age at SCT. The major risk factors are the use of total body irradiation, which is associated with adenocarcinomas and with chronic graft-versus-host disease which is associated with squamous cell cancers. There is less data on the incidence of second malignancies after reduced-intensity conditioning, but it may not be lower. The types of solid tumors reported in excess include melanoma and other skin cancers; cancers of the oral cavity and head and neck, brain, liver, uterine cervix, thyroid, breast, lung; and possibly gastrointestinal cancers. Therapy-related myeloid neoplasms (t-MN) are more common after autologous SCT and may be related mostly to pre-transplant therapies. Post-transplant lymphoproliferative disease is donor-cell-derived lymphoma that is more common after allogeneic SCT with T-cell depletion or intensive immune-suppression state. Second malignancies are most often treated similarly to the standard therapy for similar malignancies. Lifelong cancer screening and prevention interventions are required for all transplantation survivors.