Primary Refractory Acute Myeloid Leukemia Research Articles

Treosulphan versus busulphan: pros and cons.

Treosulphan versus busulphan: pros and cons.

Loss-of-function mutations in BCOR contribute to chemotherapy resistance in acute myeloid leukemia

Primary refractory acute myeloid leukemia (AML) is unresponsive to conventional chemotherapy and has a poor prognosis. Despite the recent identification of novel driver mutations and advances in the understanding of the molecular pathogenesis, little is known about the relationship between genetic abnormalities and chemoresistance in AML. In this study, we subjected 39 samples from patients with primary refractory AML to whole-exome and targeted sequencing analyses to identify somatic mutations contributing to chemoresistance in AML. First, we identified 49 genes that might contribute to chemotherapy resistance through the whole-exome sequencing of samples from 6 patients with primary refractory AML. We then identified a significantly higher frequency of mutations in the gene encoding BCL-6 co-repressor (BCOR) in patients with primary refractory AML through the targeted sequencing of all coding sequence of 49 genes. Notably, the presence of BCOR mutations appeared to have a negative impact on prognosis in our cohort and previous larger studies. Subsequently, to investigate the biological effect of BCOR mutations on sensitivity to anticancer drugs, we established BCOR knockout human leukemic cell lines using the CRISPR/Cas9 system. Here, BCOR knockout cell lines exhibited statistically significant reductions in sensitivity to anticancer drugs, compared with the wild-type controls both in vitro and in vivo in xenograft mouse models. In conclusion, loss-of-function BCOR mutations appear to contribute to chemotherapy resistance and may be a promising therapeutic target in primary refractory AML.

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting.

PurposeWe report the efficacy and safety of venetoclax plus decitabine-based treatment in heavily pre-treated relapsed or refractory acute myeloid leukaemia (RR-AML) in a real-world setting.Patients and MethodsThere were 22 patients in this study and the median age was 47.5 (12–84) years old, including 11 males and 11 females. Among them, 8 patients were relapsed AML including 2 patients relapsed after HSCT and 14 patients with primary refractory AML including 4 secondary AML. The median number of cycles of previous chemotherapy was 4 (range, 2–10).ResultsAfter a course of venetoclax plus decitabine-based treatment, 9 patients achieved complete remission (CR) and 1 patient achieved complete remission with incomplete haematological recovery (CRi). The overall response rate (ORR) was 45.5% and the CR rate was 40.9%, and the median time to reach CR/CRi was 21 (13–46) days. Four of the 10 CR/CRi patients relapsed again, and the median time of relapse was 5 (1.0–24) months. The one-year overall survival rate was 31.8%, and the median survival time was 6 months (95% CI, 1–9 months). The one-year overall survival rate of 10 CR/CRi patients was 59.1%, and the 12 NR patients was 10.4% (p=0.001). Nausea and vomiting occurred in 11 patients (50.0%). All patients had grade IV neutropenia and IV thrombocytopenia (100%). Pneumonia occurred in 14 patients (63.6%) and septicaemia occurred in 2 patients (9.0%). The cause of death in all patients was primary disease progression, and no patients died due to the side effects.ConclusionThe efficacy of venetoclax plus decitabine-based treatment in the real-world treatment of heavily pre-treated RR-AML is similar to that in clinical trials, and the side effects are controllable.

Sequential Therapy for Patients with Primary Refractory AML — a Retrospective Analysis of the German and Israeli Experience

Introduction -primary refractory AML is associated with a dismal prognosis with only 30% of the patients responding to salvage chemotherapy and continuing to allogeneic hematopoietic cell transplantation (HCT). HCT with a standard myeloablative conditioning regimen ,given to patients with a primary refractory leukemia,is associated with 10-20% long- term overall survival. The fludarabine, amsacrine, and cytarabine (FLAMSA)-reduced-intensity conditioning (TBI-based or treosulfan-based) protocol, established by the German group, has been described to be effective approach in patients with relapse/refractory AML undergoing HCT. Modified protocol (without amsacrine and with TBI-based RIC, FITCy) has been also used in the last several years.Methods - We retrospectively analyzed the HCT characteristics and outcomes of all consecutive patients ,diagnosed with primary refractory AML who underwent HCT with either the FLAMSA or FITCy regimens in the University of Cologne and the Tel Aviv Medical Center. Patients who underwent sequential therapy for relapsed disease (either chemosensitive or refractory) were excluded from this analysis.Results - Between the years 2003 and 2017, we identified 43 patients that were eligible for this analysis. Median age was 54 (range, 23-73) years (Table). Median follow-up for surviving patients was 32 (range, 1-148) months. Twelve patients (28%) received only one line of chemotherapy (mostly 7+3) before proceeding at a refractory state to HCT. Preparative regimens were FLAMSA-TBI based, FLAMSA-Treo based and FITCy in 12 (28%), 12 (28%), and 19 (46%) patients, respectively. Prior to HCT, 5 (12%) patients had ongoing documented infections (either microbiology or clinically) - aspergilus pneumonia (n=3), atypical pneumonia (n=1), and scrotal abscess (n=1). Median days to engraftment of neutrophils (>500/dL) and to incomplete engraftment of platelets (>20000/dL) were 13 (range, 9-19) days, and 13 (7-30) days, respectively. Only 1 patient (2%) had primary graft rejection. Severe mucositis was observed in only 10% of the patients, and was mostly observed in the upper gut. 3 patients (7%) developed fungal pneumonia and 2 patients (5%) had blood stream infection during the neutropenic period. Only 2 patients (5%) developed sinusoidal obstruction syndrome.Complete remission was documented on day 30, in all but 1 patient. Cumulative incidences of grade 2-4 and 3-4 acute GVHD at day 100 were 40% and 20%, respectively. Cumulative incidences of overall chronic GVHD and moderate-severe chronic GVHD at 1 year after HCT were 76% and 52%, respectively. Cumulative incidences of relapse at 1 year and 2 years post HCT were 22% and 25%, respectively. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 7%, 10%, and 22%, respectively. Cumulative incidences of 1, 2,and 3 years overall survival were 66%, 60%, and 57% , Figure. Both older age and a mismatched donor were associated with decreased overall survival (HR=0.83, 95% CI=.335-.969, p=.02) and (HR=.25, 95% CI=.064-.954, p=.046), while time from 1st line regimen to HCT, uncontrolled infections at HCT, percentage of BM blasts prior to HCT, and type of the preparative conditioning were not predictive for survival.Conclusions - Sequential therapy in patients with primary refractory AML is safe and provides a remarakablre anti- leukemic effect. In patients with available donors, this strategy may be superior to repeating rounds of salvage chemotherapy and should be further studied in other settings (i.e. haploidentical donors and other diseases). Future protocols should focus on decreasing GVHD rate , maintaining the graft vs. leukemia effect. [Display omitted] DisclosuresScheid:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Safety and Clinical Activity of Combined Romidepsin and Azacitidine Therapy in High Risk Acute Myeloid Leukemia: Preliminary Results of the Romaza Trial

Introduction: Azacitidine (AZA) represents an important advance in the management of patients with acute myeloid leukemia (AML) in whom intensive chemotherapy (IC) is contra-indicated. However complete response (CR) rates are low and disease progression is inevitable. Romidepsin (ROM) is a potent Class I histone deacetylase inhibitors (HDACi) which demonstrates synergistic anti-leukemic activity with AZA in vitro and represents a plausible strategy by which its clinical activity can be increased. Despite this, the clinical impact of co-administration of ROM to AZA has not been evaluated in myeloid disorders. We therefore wished to both establish the maximum tolerated dose (MTD) of combined AZA/ROM therapy and determine the clinical activity of this novel combination in high risk AML.Patients and Methods: 46 patients with AML deemed ineligible for IC were studied. 16 patients had relapsed after previous IC, 15 after a previous allogeneic stem cell transplantation, 11 patients had de novo AML and 4 primary refractory AML. The median age of the treatment population was 68 years (range: 19-84). Patients were assessed for response, using modified Cheson criteria, after 3 and 6 cycles of therapy. The MTD of ROM/AZA combination therapy was estimated by using an escalating, de-escalating 3+3 cohort design in 13 patients and the clinical activity studied in an additional expansion cohort of 33 patients.Results: The MTD of combination ROM/AZA therapy was established as ROM 12 mg/m2 on days 8 and 15, in combination with AZA 75 mg/m2 administered for 7 days in a 28 day cycle. The most common grade 3-4 non-haematological serious adverse events experienced in patients treated at the MTD were: pulmonary infection (8%), vomiting (6%) and syncope (6%). 9 of 18 evaluable patients who had received at least three cycles of ROM/AZA combination therapy in whom an informative bone marrow was available achieved a major clinical response (CR/CRi n= 7, PR n=2). Survival was increased in patients achieving a major clinical response.Discussion: Combined ROM/AZA therapy is well tolerated and clinically active in patients with AML ineligible for intensive therapy. The observed response rates in this very high-risk patient population support further prospective evaluation of the role of ROM as a novel agent with the potential to increase clinical response rates to AZA monotherapy. DisclosuresTholouli:Pfizer: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Drummond:Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: 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, Speakers Bureau. Pavlu:Amgen Ltd: Consultancy; Jazz Pharma: Consultancy. Vyas:Celgene Corporation: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau.

Role of Allogeneic Reduced Intensity Conditioning Stem Cell Transplantation (RIC-SCT) in Older Patients with Acute Myeloid Leukemia (AML): Analysis of the ALFA-1200 Study

Background - According to recommendations, AML patients with intermediate- or adverse-risk genetics are candidates for allogeneic SCT in first complete remission (CR1). In practice, only a minority of them undergoes SCT because of older age, comorbidities, poor tolerance of prior therapy, inability to achieve CR, or early relapse. The benefit associated with RIC-SCT is particularly difficult to assess in older patients, due to lower SCT numbers and strong selection biases.Patients & Methods - Between 2012 and 2016, 509 patients aged ≥60 years (median, 68 years [60-85]) were enrolled in the prospective older AML ALFA-1200 trial. Eighty-eight patients (17%) had secondary or therapy-related AML. ECOG performance status was 0/1/2/3/NA in 219/219/57/9/5 patients and comorbidity index (HCT-CI) was 0/1/2/3/4+/NA in 226/92/66/61/54/10 patients, respectively. Risk subgroup distribution was 76 favorable (15%), 347 intermediate (68%), and 86 adverse (17%), according to the ELN-2010 classification retaining double mutations only as favorable CEBPA mutations. Chemotherapy consisted of cytarabine (200 mg/m2/d CIV on day 1-7) and idarubicin (12 mg/m2/d on day 1-3) followed by 2 courses with intermediate-dose cytarabine at 1500 mg/m2/12h on days 1/3/5, reduced to 1000 mg/m2/dose in patients aged ≥70 years. Patients with intermediate- or adverse-risk AML and/or those who needed two courses to reach CR were eligible for allogeneic SCT in CR1 if a suitable donor (HLA-identical [id] sibling or 9-10/10 matched unrelated donor) and no acquired contra-indication.Overall Results - During first induction, 43 patients died before response evaluation, while 335 patients reached CR. Among the 131 patients with resistant AML, 71 received a second intensive course and 34 achieved CR (overall CR rate, 72.5%). The 60- and 100-day mortality rates were 9.4 and 13.0%, respectively. With a median follow-up of 26 months, 201/369 CR patients relapsed and 164 died, including 30 deaths in CR1. Median overall survival (OS) was 20.7 months (95% CI, 17.5-24.8) and OS was 46.8% (95% CI, 41.9-51.4) at 2 years. Median OS was 49.7, 22.5 and 9.4 months in the favorable, intermediate and adverse ELN-risk subgroup, respectively.Role of SCT - Among the 305 CR patients eligible for SCT, 93 proceeded to SCT in CR1. In addition, 22 patients with primary refractory AML and 25 patients relapsing prior to SCT eventually received SCT. Patients transplanted in CR1 were younger (median age, 64 [60-73] vs 70 [60-81] years; p<0.001) and had lower comorbidity index (HCT-CI≥3, 14 vs 26%; p=0.025) than the remaining eligible patients. We thus analyzed the role of SCT in CR1 in the 214 eligible patients aged 70 years old or less (ELN-risk: 2 favorable, 176 intermediate, 38 adverse). Ninety of them were actually transplanted in CR1 (ELN risk: 75 intermediate, 15 adverse; median time from CR to SCT, 113 days; stem cell source: 28 geno-id, 50 pheno-id, 8 haplo-id, 4 cord blood; conditioning regimen: 12 NMA, 66 RIC, 12 sequential-RIC). These 90 transplanted patients were still younger than the 124 non-transplanted patients (p=0.005) but their ELN-risk and HCT-CI distribution were similar. Among them, 22 patients relapsed and 29 died, including 18 deaths in CR1. At 2 years post-SCT, transplant related mortality (TRM) was 20.4% (95% CI, 13.2-30.9), cumulative incidence of relapse was 22.7% (95% CI, 15.0-33.4), and OS was 65.1% (95% CI, 52.9-75.0). Age, secondary AML, ELN-risk, type of stem cell source, or conditioning regimen did not significantly influence post-transplant survival. In a time-dependent SCT analysis, OS was not significantly prolonged in the SCT cohort (HR, 0.77 [95% CI, 0.49-1.21]; p=0.26). As illustrated on Figure 1, an OS benefit associated with SCT was only observed in the adverse ELN-risk subset (HR, 0.20 [95% CI, 0.07-0.63]: p=0.006), while not in the intermediate ELN-risk subset (HR, 1.08 [95% CI, 0.65-1.80]; p=0.76), with a significant interaction (p=0.005). Finally, SCT did not significantly prolonged OS in the 47 out of 319 patients with refractory/relapsed AML who eventually received SCT (HR, 0.69 [95% CI, 0.39-1.22]: p=0.21).Conclusion - In older AML patients, due to persistent high TRM and relapse incidence, RIC-SCT significantly prolongs survival in the adverse ELN-risk AML subset only. Even if a longer follow-up is needed, patients with intermediate ELN-risk AML do no seem to benefit from SCT in CR1 as compared to standard chemotherapy. [Display omitted] DisclosuresDe Botton:Servier: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Agios: Honoraria, Research Funding. Socié:Alexion Pharmaceuticals, Inc.: Consultancy.

CMV Status Predicts Survival in Refractory/Relapsed Myeloid Patients after a Clofarabine-Based Sequential Regimen: A Retrospective Study on Behalf of the SFGM-TC

Background: Recently, we have published the prospective results of a sequential regimen using a clofarabine (clo), cytosine arabinoside and reduced-intensity conditioning (RIC) regimen in 24 cases with primary refractory acute myeloid leukemia (AML) showing encouraging results with a very low non relapse mortality (Mohty, 2017). Here we report the outcomes after such sequential regimen in a larger cohort of patients.Methods: This was a retrospective study including all patients reported within the SFGM-TC registry having received a clo-based sequential conditioning regimen before allotransplant for active myeloid disease. Data were obtained through PROMISE, an internet-based system shared by all European transplantation centers. All patients gave informed consent allowing to collect their personal data from this data base.The sequential regimen consisted of clo (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by RIC combining cyclophosphamide (60 mg/kg), iv busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days.The primary objective of the study was to report the main outcomes at 1 year: overall survival (OS), disease free survival (DFS), relapse incidence (RI), NRM and GVHD Relapse free survival (GRFS). Secondary objectives were to identify prognostic factors for patient's survival.Results: Between January 2007 and December 2016, 131 patients (males n=75, median age: 52.6 years, range: 18-71) met the inclusion criteria. There were 111 AML patients, including 9 secondary AML, and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was as follows: primary refractory n=81, relapse 1 or 2 n=46, missing n=4. The majority of patients received peripheral blood stem cell as source of graft (n=127, bone marrow n=4). All patients received a graft from a matched donor (sibling n=64, unrelated n=67). Donor (D)/recipient (R) CMV status was as follows: D-/R-: n=55, D+/R-: n=14, D-/R+: 24, D+/R+: 38.Engraftment was observed in 105/122 assessable cases (86%) and patients achieving complete remission (CR) after transplant were 63% (n=72/114 evaluable cases). With a median follow-up of 12 months (range: 2.7-74.3) for alive patients, 1-year OS, DFS, RI, NRM and GRFS were 39.2% [30.2-48.2], 28.1% [19.8-36.5], 41% [32.1-49.8], 30.8% [22.7-39.3], and 22.2% [14.3-30], respectively.In univariate analysis, the only factor associated with lower survivals and GRFS and higher RI was unexpectedly a D-/R- CMV status at transplant: 1-year OS: 30% vs others status: 46.1%, =0.009; 1-year DFS: 18.1% vs 35.7%, p=0.015; 1-year GRFS: 11.9% vs 29.9%, p=0.009; 1-year RI: 53.2% vs 31.9%, p=0.004. In multivariate analysis, D/R CMV negative status remained independently associated with lower OS (HR: 1.74, 95%CI: 1.10-2.76, p=0.016), DFS (HR: 1.70; 95%CI: 1.09-2.66, p=0.018) and GRFS (HR: 1.76; 95%CI: 1.15-2.71, p=0.009) and higher RI (HR: 2.48; 95%CI: 1.37-4.50, p=0.002). D/R CMV status was not associated with NRM.Conclusion: Despite high CR achievement, this large cohort of patients confirmed the relatively poor outcome of patients with active myeloid disease at transplant and receiving a clofarabine-based sequential regimen. Post-transplant strategies should be proposed early to improve results and decrease incidence of relapse. The favorable impact on survivals of positive D or R CMV status may be related to a potential graft-vs-leukemia effect of CMV reactivation (thanks to NK or T cells stimulation) after transplant. The validation of this hypothesis is on-going. DisclosuresPeffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.

High-Dose Melphalan-Based Sequential Conditioning Chemotherapy Followed By Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)

Introduction: The majority of patients with newly diagnosed AML fail to achieve long-lasting remission, even after initial complete remission (CR). Response rates to common salvage regimens reach up to 50% in patients with late relapse and decrease to 10-15% in patients with refractory AML or early relapse. Without allogeneic HSCT the long-term overall survival (OS) for patients with refractory AML hardly reaches 5%. Survival rates of AML patients post allogeneic HSCT are significantly higher for patients transplanted in CR as compared to those transplanted with active leukemia. Common conditioning regimens followed by allogeneic HSCT of patients with active AML have shown disappointing results. Therefore, others and we developed the concept of sequential therapy as a preparative regimen for allogeneic HSCT to optimize the balance between treatment-related toxicity and antileukemic efficacy.Methods: From April 2005 to May 2016, 292 patients with R/R-AML received an allogeneic HSCT at the BMT centers of the German university hospitals of Muenster and Essen. The median age was 56 years (range 17 -74). The remission status prior to transplant was primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). All patients were treated with a single infusion of high dose melphalan, followed by dose-adapted conditioning consisting of fludarabine (120 mg/m2) and 8 Gy TBI or followed by fludarabine (150 mg/m2) and treosulfan (42 g/m2). Median time between melphalan and continuation of the therapy was 5 days (range 1-18 days), resulting in an overall duration of conditioning prior to HSCT of 11 days in most patients. Additional pretreatment with antithymocyte globulin (ATG) was applied to 157 of 222 patients with an unrelated donor and in 44 of 70 patients with a HLA-identical sibling donor. Most patients (except 2) received cyclosporine as acute GvHD prophylaxis in combination with methotrexate (89 patients) or mycophenolate mofetil (197 patients) or both (4 patients).Results: Median follow-up after allogeneic HSCT of all patients alive at last follow-up was 4.8 years. OS rates at 3 years were 34% for primary refractory patients, 29% for secondary refractory patients, and 41% for patients with untreated relapsed AML. Factors associated with an inferior OS were older age, a time interval of 5-9 months between first diagnosis and allogeneic HSCT, and transplantation from an HLA-mismatched unrelated donor. Most importantly, leukemic burden was associated inversely with a 3-year OS of 51%, 31%, and 22% for patients with leukemic blast infiltration of <20%, 20-50%, and >50%, respectively (p <.001). Particularly patients transplanted from HLA-mismatched unrelated donors had a significantly higher non-relapse-related mortality (NRM) rate of 55% (95%CI 27 to 56%) at one year, compared to those transplanted from HLA-matched related (34%, 95%CI 24 to 48%) or unrelated donors (28%, 95%CI 22 to 37%). In addition, adverse risk factors for NRM were older age, pre-existing infection prior to start of conditioning therapy and a higher comorbidity index (HCT-CI >3). Multivariate analysis of risk factors revealed that high disease burden before conditioning (p <.001), longer time interval between first diagnosis and transplantation (p .039), and transplantation from an HLA-mismatched unrelated donor (p .049) were independently associated with inferior overall survival. High risk disease according to cytogenetic and molecular genetic aberrations as an adverse risk factor showed a trend in this analysis (p .052).Conclusion: Allogeneic HSCT remains the most potent treatment option for patients with R/R-AML. High-dose melphalan based sequential conditioning chemotherapy followed by an allogeneic HSCT allows for achieving long-term remission in a substantial proportion of patients with active R/R-AML with otherwise detrimental prognosis. Since allogeneic HSCT is superior to other alternative treatment strategies evaluated in the past, direct allogeneic HSCT should be evaluated prospectively against remission induction therapies followed by an allogeneic HSCT in patients with R/R AML. DisclosuresLenz:Celgene, JJ, Hexal, Roche, BMS, Novartis, Bayer: Consultancy; AstraZeneca, Gilead, JJ, Celgene, Novartis, Bayer: Research Funding.

Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation from HLA-Identical Siblings Versus Unmanipulated Haploidentical Donors in Relapsing or Refractory Acute Myeloid Leukemia: A Retrospective Study from the ALWP of the EBMT

▪Introduction: Primary refractory or relapsing acute myeloid leukemia (R/R-AML) has very poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) may be the only chance of cure. Therefore a suitable donor should be rapidly searched for, in this setting. In those patients (pts) lacking an HLA-matched sibling donor (MSD), mismatched family donor (haploidentical, Haplo) may represent a valid and rapidly available option.Methods: Herein, we compared the outcomes of pts with R/R-AML undergoing first HSCT from either a MSD (n=1654) or Haplo (n=389) in the period 2007-2015. The Haplo group included pts receiving a T-repleted graft with post-transplant cyclophosphamide (PTCY, n=278), in vivo T-cell depletion (TCD, n=95), or both (n=16).Results: Median age at HSCT was 52 (range 18-74) years. Median follow-up was 16 and 22 months for MSD and Haplo recipients, respectively (p=0.11). At time of HSCT, 41% and 56% presented a primary refractory AML in Haplo and MSD groups, respectively (p<0.01). Compared to MSD, Haplo HSCT were performed more recently (median year 2013 versus 2011, p<0.01) with a higher number of pts having a poor Karnofsky performance status (22% versus 16%, p<0.01) and a positive serology for CMV (83% versus 71%, p<0.001) at time of HSCT, respectively. The latter also had more frequently undergone a previous autologous HSCT (8% vs 3%, p<0.01), had a longer interval from diagnosis to HSCT (7 versus 5 months, p<0.01), received more frequently bone marrow as stem cell source (47% vs 8%, p<0.01), a reduced intensity conditioning regimen (50% vs 43%, p<0.03), and a graft from a male donor (59% versus 53%, p<0.03) as compared to MSD recipients. Compared to Haplo, cumulative incidence (CI) of neutrophil engraftment was higher (93% versus 83%, p<0.01) and associated to a shorter median time to engraftment (15 versus 18 days, p<0.01) in MSD recipients. According to donor type, no differences were found in univariate analysis for the CI of grade II-IV acute graft-versus host disease (aGVHD)(28% versus 27%, p=0.37), while a lower CI of chronic GVHD (cGVHD) (27% versus 42%, p<0.01) and extensive cGVHD (12% and 19%, p<0.01) was observed in HSCT from Haplo compared to MSD, respectively. At two years, overall survival (OS) was 25% and 32% (p<0.01), leukemia-free survival (LFS) 19% and 27% (p<0.01) and GVHD/relapse-free survival (GRFS) 18% and 26% (p<0.01) in HSCT from Haplo and MSD, respectively. Relapse incidence (RI) was similar following HSCT from Haplo and MSD (50% vs 51%, p=0.60), while non-relapse mortality (NRM) was higher for Haplo transplants (31% vs 22% in HSCT from MSD, p<0.001), respectively. In a multivariate analysis adjusted for the differences between the two groups, Haplo HSCT was associated with lower OS (HR 1.19, p<0.04), LFS (HR 1.17, p<0.05) and GRFS (HR 1.22, p<0.02). Higher grade II-IV aGVHD was observed in Haplo recipients. Neither cGVHD (any grade) nor RI differed according to donor type (p=ns). Compared to MSD, Haplo recipients experienced a higher NRM (HR 1.4, p<0.02) mainly related to a higher incidence of infections (41% versus 25%, p<0.01). Regardless of donor type, age as a continuous variable was associated with lower RI (HR 0.99, p<0.01), lower OS (HR 1.01, p<0.01) and higher NRM (HR 1.02, p<0.01). The use of peripheral blood as stem cell source was independently associated with a higher risk of cGVHD (HR 1.64, p<0.01).Conclusions: Our results indicate that for pts with R/R-AML outcome is better with HSCT from a MSD compared to unmanipulated Haplo donor, mainly due to the higher NRM associated with transplants from Haplo and most probably related to a higher incidence of infections and grade II-IV aGVHD. Chronic GVHD as well as RI are similar, indicating once again that despite the broader HLA disparities with Haplo HSCT the graft versus leukemia effect is probably not stronger than after HSCT from MSD (Ringden O, on behalf of the ALWP; Leukemia 2016). In the absence of a MSD, Haplo HSCT may represent a valid alternative, with nearly one quarter of the R/R-AML pts surviving at 2 years from transplant. Future goals in the Haplo setting should be to reduce NRM and rate of infections in order to further improve outcomes. DisclosuresCiceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.

Comparison of Mitoxantrone-Based Salvage Therapies (MEC vs CLAG-M) in Relapsed or Refractory Acute Myeloid Leukemia

Introduction:Primary refractory and early relapsed acute myeloid leukemia (RR-AML) continue to pose a therapeutic challenge. There are currently a number of treatment strategies for RR-AML, with performance status, cytogenetics, and availability of appropriately matched allogenic hematopoietic cell transplant (HCT) donors all influencing that clinical decision. Salvage therapy treatment regimens for refractory and relapsed disease are not standardized but include mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M), among many others. While previous studies have established the roles of MEC, and CLAG-M independently and have retrospectively compared MEC vs CLAG; no retrospective analysis of MEC vs CLAG-M has been published to date, though both remain commonly used regimens in practice. In this retrospective single-center analysis we compare the outcomes of patients receiving MEC or CLAG-M as salvage therapy for RR-AML.Methods:The study included 55 patients with RR-AML who received MEC or CLAG-M between 09/01/2009 and 12/31/2016. Information about sociodemographics, disease and transplant characteristics and clinical outcomes were obtained by medical record review. The probabilities of overall survival (OS) and relapse-free survival (RFS) were estimated according to the Kaplan Meier method and log-rank test was used to compare outcomes between patients who received either of the two regimens.Results:Fifty five consecutively treated patients with RR-AML were included in this analysis, 44 patients received MEC and 11 patients received CLAG-M. The median age of patient was 58.5 years (18-75) among MEC recipients and 54 years (23-64) in the CLAG-M group, with 53% being males. The majority of patients had relapsed disease (n=38, 69%). High risk subtypes of AML, as determined by cytogenetics and molecular studies, predominated with 87% (48/55) being high risk.Cytoreduction was achieved in 30 (68%) of patients who received MEC, and 8 (73%) patients who received CLAG-M achieved cytoreduction. HCT was pursued in 33 (75%) of patients who received MEC and 9 (82%) who received CLAG-M. Median follow-up after transplant was 30 months from treatment with either MEC or CLAG-M (5 - 60 months), 17 (52%) and 3 (27%) were alive from the MEC and CLAG-M groups respectively. In the follow-up interval for transplanted patients, 9 (27%) from the MEC group and 6 (55%) from the CLAG-M group relapsed, with a median time to relapse from the date of transplant of 9.1 months (0.4 -30 months) and 2.9 months (1.8 - 11 months), respectively.Median time to relapse for patients who received HCT was 12 months (0-76 months) for the MEC group and 5.5 months (2-35 months) for the CLAG-M group. Relapse free survival at 24 months between the MEC and CLAG-M treatment groups that went to HCT were 67% (51-87%) and 11% (1.8-71%), respectively with an associated hazard ratio (HR) of 3.86 (1.55-9.59, CI 95%, p 0.0016). Similarly, overall survival analysis at 24 months was 66% and 11% for MEC and CLAG-M respectively, with a HR of 3.85 (1.51 - 9.81, 95% CI, p=0.002).Discussion:While induction therapies for AML are fairly standard, there are numerous potential salvage therapies that serve to bridge a person to transplant in RR-AML. With allowances that a degree of agent availability and provider familiarity with treatment likely biases the selection of one regimen over another, our results would suggest a treatment benefit both in terms of RFS and OS in patients with RR-AML who receive MEC over CLAG-M and ultimately go to HCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Towards the Next Generation CAR T Cells with TEGs: In Vivo Efficacy — Toxicity Profile in Xenografts of Primary Human AML Disease and Healthy Bone Marrow

T.S. and I.J.G. contributed equally</spanBackgroundγδT cells mediate essential cancer immune surveillance by sensing transformation-dependent metabolic changes through their γδT cell receptors (TCRs). This process is independent ofMHC-restricted antigen presentation, making these innate-like receptors valuable additions to current treatment strategies. The γδTCR alone is instrumental to distinguish between healthy and leukemic stem cells. This concept led to the development of next generation CAR T cells, so-called TEGs: αβT cells Engineered to express a defined γδTCR. A particular γ9δ2TCR, isolated from “clone 5”, has been selected as the candidate for clinical testing (TEG001). A purification strategy was introduced that combined maximal interference of γδTCR chains with endogenous TCR chains with a GMP-grade anti-αβTCR-bead-based depletion strategy to obtain a pure population of engineered immune cells (Straetemans et al. Clin Can Res 2015). TEG001 cells showed a strong and broad recognition of hematological malignancies against both cell lines and primary AML in vitro and limited the tumor outgrowth in cell line-based mouse xenograft models (Marcu-Malina et al. Blood 2011, Gruender et al. Blood 2012). To further prepare clinical implementation of this novel strategy we here investigated the in vivo efficacy and toxicity profile against primary leukemic blasts and healthy hematopoietic cells, respectively.ResultsIn order to evaluate the biodistribution and safety profile of TEGs we developed patient derived xenograft (PD-X) in vivo models by establishing primary malignant AML blasts, which tested positive in an in vitro assay for recognition by TEGs, in NSG mice. In addition, healthy stem cells from human cord-blood were in parallel engrafted in a separate set of NSG mice. This allowed us to study the homing capacity, tumor-targeting efficacy and off-target toxicity of TEGs by following the outgrowth of malignant and healthy human cell fractions in the peripheral blood. Healthy hematological cellular compartments remained unharmed by TEGs, in spite of effector cell persistence for over 50 days. In contrast, AML blasts could be eliminated as measured by frequencies of blasts in peripheral blood.ConclusionWithin the limitations of humanized PD-X models, TEGs target acute myeloid leukemia but do neither interfere with engraftment of hematopoietic progenitors nor harm matured subsets of the hematopoiesis. In addition, no additional signs of off-target toxicity were observed in mice. TEGs are a promising addition to the currently available immune therapeutic strategies as they target cancer as a metabolic disorder. A GMP-compliant production procedure has now been established in order to evaluate TEG001 in a phase I open label dose escalation study to assess the safety of TEGs in patients with primary refractory or relapsed acute myeloid leukemia as well as patients with multiple myeloma. DisclosuresSebestyen:University Medical Center Utrecht: Patents & Royalties: inventor on the recognition mechanism of clone 5. Kuball:Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gdT cells and receptors and isolation strategies , Research Funding; Miltenyi: Research Funding.

Efficacy of 5-Azacitidine on IDH1/2 Acute Myeloid Leukemia/Myelodysplastic Syndromes and Correlation with 2-Hydroxyglutarate Production

Background. Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations are found in 10 and 15% of acute myeloid leukemia (AML) patients, respectively. IDH1/2 mutants' proteins produce high 2-hydroxyglutarate (2HG) levels that inhibit α-ketoglutarate-dependent dioxygenases including histone and DNA demethylases, as TET2 proteins. Furthermore, serum 2HG can act as a biomarker predictive of the presence of IDH1 and IDH2 mutations at diagnosis (cut-off value >2µM) but also correlate with response after intensive chemotherapy. 5-azacitidine (AZA) is a DNA methyltransferase inhibitor that demonstrated significant clinical benefit not only in high-risk MDS but also in AML. Hypomethylating agents yield higher response rate in the context of CpG island hypermethylation phenotype induced by TET2 mutations in myelodysplastic syndrome (MDS). Thus, we evaluate AZA response in the context of IDH1/2 mutations and the effect of AZA on serum 2HG production.Patients and methods. The present study retrospectively focused on IDH1/2 mutant AML/MDS patients treated in our center with at least 1 cycle of AZA. IDH1/2 mutational status was evaluated in all patients with Sanger or Next-Generation sequencing before therapy. All patients received subcutaneous AZA 75mg/m2/d for 7 days every 28 days. Response to therapy was evaluated according to modified 2003 IWG criteria's for AML. Hematological improvement (HI) was evaluated according to IWG 2006 criteria's for MDS. Overall survival (OS) was censored in case of IDH1/2 inhibitor therapy after AZA. Serum samples were analyzed for total 2HG by reverse-phase liquid chromatography coupled to mass spectrometry.Results. Thirty-six patients (34 AML, 2 MDS) were retrospectively analyzed. Initial characteristics of the patients are shown on Table 1. Median age was 74.3 years (range, 48.4-86). Thirteen patients (36%) had IDH1 mutations (R132C: 10, R132H: 2, R132G: 1) and 22 patients (61%) had IDH2 mutations (R140Q: 19, R172K: 3). One patient had both IDH1 R132H and IDH2 R140Q mutations. Twenty-nine patients had intermediate cytogenetic (including normal karyotype in 20 patients) and 6/36 unfavorable. IDH1/2 mutations were associated with SRSF2 mutations in 13 patients, DNMT3A in 11 patients, NPM1 mutation in 9 patients, ASXL1 in 5 patients and FLT3 -ITD in 5 patients. Ten patients (28%) were treated frontline with AZA while the others received AZA as second line (50%, including 6 patients with primary refractory AML to intensive chemotherapy) or subsequent lines (22%). Five patients received IDH1/2 inhibitors (AG221: 3, AG120: 2) prior to AZA treatment. Patients received a median of 4.5 cycles of AZA (range, 1-23). Four patients (11%) achieved complete remission (CR) and 7 (19%) obtained HI with persistent excess of blasts (overall response rate: 30%). Median OS was 9.5 months (FU range, 0.2-41.6) with a trend toward shorter OS in IDH1 mutant AML patient (6.4 vs 10.1; p≤0.0764) (Figure 1). No difference was observed between patients in 1st or subsequent treatment lines (p≤0.7265).Median 2HG concentration (available in 25/36 patients) before the onset of AZA treatment was 9.7µM. Seventeen patients had available serum during follow-up (median: 2 measures/patient). When 2HG values in responding and non-responding patients were compared at different time-points, 2HG values remained elevated in responders (median 2HG: 6.8µM; range 0.99-13.5) without significant difference compared to baseline or relapse values (Figure 2). All responders to AZA ultimately relapsed or progressed during follow-up. IDH1 or IDH2 mutations persisted at relapse along with elevated 2HG levels (median 2HG: 4.5µM).Discussion. In the present series, IDH1/2 mutations were not associated with an increased sensitivity to AZA, as opposed to TET2 mutations. AZA may decrease production of 2HG in responders compared to diagnosis values. However, unlike intensive chemotherapy, AZA is unable to normalize 2HG values in responding patients. This suggests that 2HG cannot be used as a surrogate marker of AZA response and AZA efficacy might not be related to inhibition of 2HG production in IDH1/2 AML/MDS patients. Thus, combinations of AZA with IDH1/2 mutant proteins inhibitors might lead to an additive or synergistic antitumor effect. [Display omitted] DisclosuresRenneville:CELGENE: Research Funding. Ribrag:Roche: Honoraria, Other: travel, accommodation, expenses; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Pharmamar: Consultancy; Esai: Honoraria, Research Funding; ArgenX: Research Funding; Servier: Consultancy, Honoraria. de Botton:Celgene Corporatation: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Agios Pharmaceuticals, Inc.: Honoraria, Research Funding.

Updated results from DIAMOND-01 (CLI24-001) trial: A phase I/II study of SEL24/MEN1703, a first-in-class dual PIM/FLT3 kinase inhibitor, in acute myeloid leukemia.

7023 Background: SEL24/MEN1703, a dual PIM/FLT3 kinase inhibitor, in the dose escalation (DE) DIAMOND-01 trial (CLI24-001, NCT03008187), showed an acceptable safety profile up to the recommended dose (RD) of 125 mg along with initial evidence of single agent activity and meaningful target engagement in heavily pre-treated patients (pts) with AML (Solomon et al, EHA 2020; Tomirotti et al, ASH 2020). Here we present updated data including pts enrolled in the Phase II, cohort expansion (CE) of the study. Methods: DIAMOND-01 trial enrolled pts unsuitable for chemotherapy having relapsed or refractory (R/R) (DE and CE) or previously untreated (DE) AML. Previous targeted therapies – except PIM inhibitors – were allowed. SEL24/MEN1703 was given orally, QD, 14 days ON / 7 days OFF until progression/unacceptable toxicity. The DE tested MEN1703 escalating doses from 25 to 150 mg, whereas in the CE the RP2D (125 mg) was administered. The key objectives of the CE were the confirmation of the safety profile determined in the DE along with further investigation of single agent activity. Adverse events (AEs) were graded according to NCI-CTCAE v.4.03; responses assessed as per ELN 2017 criteria. Results: As of January 21, 2021 (cut-off date), n = 48 pts were treated across DE (n = 25) and CE (n = 23). Median age was 69 (25-84) years. Overall, 20 (43%) and 15 (32%) pts had non de novo AML and primary refractory AML, respectively. Adverse karyotype was reported in 7 (15%) pts. Most frequently reported mutations were FLT3/ITD (23%, n = 11), DNMT3A (15% n = 7), NPM1 (15%, n = 7), IDH1 (13%, n = 6) and IDH2 (4%, n = 2), CEBPA (4%, n = 2), FLT3/TKD (2%, n = 1). Median number of cycles was 2 (1-8). At the RD (n = 30), most frequent serious treatment-emergent AEs (serious TEAEs) were pneumonia (23%), sepsis and febrile neutropenia (13%) and pulmonary mycosis (10%) whereas most frequent G≥3 TEAEs were febrile neutropenia and pneumonia (23%), leukocytosis (20%) and neutrophil count decrease, platelet count decrease, lymphocyte count decrease and sepsis (13%). Responses occurred in 2 pts in the CE, both with IDH1 mutant disease (naïve to IDH inhibitors) who achieved complete remission with incomplete hematologic recovery (CRi). Both responses occurred by Cycle 3, with a duration of 79 (ongoing at cut-off date) and 43 days, respectively. Across DE and CE, 4 CR/CRi occurred, three of which in pts with IDH mutations. A total of 3 out of 6 pts with IDH mutations treated at doses ≥75 mg achieved CR/CRi, including a CR in a patient with IDH2 mutant AML relapsed on Enasidenib. Conclusions: SEL24/MEN1703 confirmed a manageable safety profile at RD and showed preliminary single agent efficacy in R/R AML, particularly clustering in pts with IDH mutant disease either naïve or previously exposed to IDH inhibitors. These results warrant further investigation of SEL24/MEN1703 in AML, with potential focus in the IDH mutated subset. Clinical trial information: NCT03008187.

Hematologic Predictors of Outcomes in Patients Undergoing Intensive Induction Chemotherapy for Newly Diagnosed Acute Myeloid Leukemia

Background Presently, acute myeloid leukemia (AML) risk stratification is estimated prior to treatment by incorporating patient and disease characteristics. However, apart from the limited use of minimal residual disease measurement, few methodologies assess AML relapse risk post-treatment. In attempts to correlate pre- and post-treatment blood cell counts with hematologic disease outcomes, the ratio, LNR, between absolute lymphocyte count (ALC) and neutrophils (ANC) has been utilized to approximate the relationship between the lymphoid system and the myeloid microenvironment (in particular myeloid-derived suppressor cells), and increased LNR is prognostic in myeloma and lymphoma. Similarly, increased LMR (lymphocyte to monocyte ratio), utilized as a crude marker of tumor-infiltrating lymphocytes and tumor-associated macrophages, predicts better outcomes in Hodgkin's disease (Romano et al. Ann Hematol2018). However, analyses correlating such ratios with AML outcomes have not been performed. Here we specifically investigate whether LNR, LMR, or neutrophil-monocyte (NMR) ratios, measured at multiple time-points, correlate with outcomes. Methods We identified patients &amp;gt;18 yrs receiving induction chemotherapy at our institution between 1/1/2005 - 12/31/2019. Data collected included demographics, comorbidities (Charlson Comorbidity Index [CCI]), AML subtype, cytogenetics/molecular data, ELN risk stratification, and response to therapy. We recorded patients' total WBC, ANC, ALC and AMC both prior to treatment, at first ANC recovery (ANC &amp;gt; 1.0 x 109/L with ALC and AMC &amp;gt; 0), and just prior to next therapy. We also identified a subset of patients who received consolidation chemotherapies with curative intent and collected their first WBC counts ~100 days post-therapy completion (range 50-150 days). The calculated LNR, LMR, and NMR at these time-points were correlated with Event-Free Survival (EFS), defined as time to relapse, death from any cause, or last follow-up. Data was censored on 6/1/2020. WBC ratios were categorized into tertiles. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, survivor functions estimated using Kaplan-Meier and the equality of survivor functions tested using stratified log-rank tests. Outcomes were adjusted for CCI, age, sex, race, subtype, presence of inflammation/infection, and ELN risk. Results 145 patients met eligibility criteria, however 23 with primary refractory AML were excluded from EFS analysis. Using WBC ratios at first ANC recovery, both intermediate and high LNR trended towards a lower HR for EFS: HR 0.54 (95% CI 0.24-1.23,p= 0.142) and 0.68 (95% CI 0.32-1.33,p= 0.329), respectively, however differences were not statistically significant (Table 1 and Figure 1). A high NMR also trended towards a worse EFS: HR 1.71 (95% CI 0.74-3.99,p= 0.212), though it was also not statistically significant. LMR did not correlate with improved EFS. Notably, pre-induction ratios and the ratios measured just prior to next treatment were not associated with any differences in EFS. In a subset of patients who received curative intent consolidation chemotherapies (generally ELN favorable risk), a t-test correlating for relapse was performed, though limited by small numbers (16 without, 8 with relapse). Patients in this group who did not relapse trended toward a numerically higher LNR and LMR, 0.57 vs 0.50 (p =0.36) and 4.33 vs 3.97 (p= 0.39), respectively. Discussion In our patient population, high LNR after induction chemotherapy trended towards predicting an improved EFS. Thus, recovery WBC ratios, although crude approximations of the immune system and the tumor microenvironment, may predict patients at higher risk of relapse, however, more patients are clearly needed to show whether a statistically significant association exists. The optimal time to evaluate these counts is also not clear. Nonetheless, as blood counts are obtained routinely post-treatment, these ratios may represent a low-cost strategy to predict relapse risk, potentially allowing for earlier treatment and donor searches for allogeneic transplantation. We propose to repeat these analyses using a multi-center approach - we are especially interested in ratios measured at the 100 days post-therapy mark, as we suspect these may better reflect the immune system at steady state and, potentially, risk of relapse. Disclosures Arain: Astellas:Other: Spouse is employed.Calip:Flatiron Health:Current Employment.Khan:Takeda:Research Funding;Celgene:Consultancy;Incyte:Honoraria;Amgen:Consultancy.Patel:Amgen:Consultancy;Janssen:Consultancy;Celgene:Consultancy.Quigley:Amgen:Other: Advisory board;Agios:Speakers Bureau;Alnylam:Speakers Bureau.

A Phase I Clinical Trial Testing the Safety of IL-21-Expanded, Off-the-Shelf, Third-Party Natural Killer Cells for Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Allogeneic transplantation (allo-HCT) is an effective treatment for many patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). With HCT the long term disease free survival (DFS) rate is approximately 60% for patients transplanted in first remission. After relapse, the rate falls to approximately 40% if the patients are in remission at the time of HCT. However, many patients present with refractory chemo-resistant disease, relapse during or shortly after induction therapy, or develop complicating comorbidities due to prolonged induction. For most such relapse-refractory (R/R) AML patients, allo-HCT is not an option. These patients have a dire prognosis with only 5-10% long term DFS. Natural Killer (NK) cells are cytotoxic lymphocytes that are able to identify tumors and exert an anti-tumor effect in an MHC-I independent manner. However, NK cells from patients with cancer can be dysfunctional and reduced in number. To overcome that, NK cells expanded ex vivo to yield high numbers of cells could provide a cellular therapeutic option for cancer patients, including patients with AML/MDS. The therapeutic potential of ex vivo membrane-bound IL-21 expanded NK cells (FC21-NK) from a haploidentical donor has been established in patients with poor prognosis AML/MDS undergoing a haploidentical HCT. Besides obtaining sufficient cell numbers, having them readily available for patients is another major obstacle for adoptive NK cell immunotherapy. Patients with aggressive disease need prompt intervention yet the manufacture of patient-specific NK cells exceeds three weeks. As NK alloreactivity plays a critical role in mediating anti-tumor effects, we identified KIR and HLA-mismatched 'ideal' donors (selected through "Be The Match Biotherapies"). Using lymphocytes from these donors, we have established a third-party NK cell bank to ensure readily-available immune cell therapies that allows scalable, affordable mass-production of large numbers of NK cells suitable for banking &amp; immediate 'off-the-shelf' administration to a broad population of recipients. This trial is to determine the safety of FC21 expanded Off-the-shelf (OTS), Third-party donor-derived NK cells for relapsed/refractory AML patients. Methods: This phase 1 study follows a 3+3 design to investigate the safety of FC21-expanded, third-party, OTS NK cells for treatment of patients with primary refractory or relapsed AML or myelodysplastic syndrome. Active GvHD is excluding. Patients aged ≥18 or ≤80 years are enrolled into two cohorts: those &amp;lt;60 yrs &amp; able to tolerate intensive chemo &amp; sensitive to Cytarabine will receive Fludarabine 30 mg/m2/day (days -6 to -2) &amp; Cytarabine 2 g/m2/day (days -6 to -2). Patients &amp;gt;60 yrs or &amp;lt;60 yrs &amp; unable/unwilling to tolerate intensive chemo or disease insensitive to Cytarabine will receive Fludarabine 30 mg/m2/day (days -5 to -2) &amp; Decitabine 20 mg/m2/day (days -6 to -2). All patients subsequently receive a total of 6 infusions of NK cells administered thrice weekly for two weeks (between day 0-21). Three NK cell dose-levels: 1x107, 3x107 &amp; 1x108 cells/kg/dose will be explored to determine MTD (maximal tolerated dose). Between 3-18 patients/cohort/dose for MTD determination, plus an additional 10 patients/dose in an expansion phase may be enrolled (maximum 28/cohort = 56 total subjects). Patients will be followed up to day 56 from first NK cell infusion. Primary objectives are to determine the recommended phase 2 dose and overall response rate (CR, CRi &amp; MLFS). Secondary objectives will explore PFS, OS &amp; MRD negativity, cell counts, infectious complications, and patients proceeding to transplant. Enrollment in both cohorts is ongoing. Clinical trial information: NCT04220684. Disclosures Vasu: Kiadis Inc: Other: Kiadis has obtained exclusive licensing requirements from The OHio State University; Janssen: Membership on an entity's Board of Directors or advisory committees; Omeros: Membership on an entity's Board of Directors or advisory committees. Bhatnagar:KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Blachly:AbbVie, AstraZeneca, KITE Pharma: Consultancy. O'Donnell:Kiadis Pharma: Other: Licensing of intellectual property. Lee:Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties.

A Phase I/IIa Study of Lemzoparlimab, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS): Initial Phase I Results

Background Lemzoparlimab (also known as TJC4 or TJ011133), a novel, RBC-sparing CD47 antibody with a unique epitope, is in early phase clinical development in both the U.S. and China. Like other anti-CD47 antibodies, lemzoparlimab blocks the interaction of CD47 and SIRPα, leading to phagocytosis of various CD47+ tumor cell lines and primary AML cells. Mono-treatment of lemzoparlimab inhibited tumor growth completely and extended the overall survival of treated mice in a patient-derived AML xenograft model. Here we report initial findings in the ongoing phase I trial which is to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lemzoparlimab in relapsed and/or refractory (r/r) AML and MDS patients. Methods The trial (NCT04202003) adopted a modified 3+3 dose escalation design with weekly lemzoparlimab at dose levels of 1, 3, 10, 20 and 30 mg/kg. The initial two lower dose cohorts (1 mg/kg and 3 mg/kg) was designed to enroll one patient each, and the study would escalate to the next level (10 mg/kg) if no DLT and no predefined toxicity events (e.g. grade 2 or above drug-related non hematologic toxicity, except for isolated lab abnormality with no clinical manifestation) were observed. If the first DLT or predefined toxicity event was observed, the cohort size would be expanded at the current dose level and the study would revert to the standard 3+3 design. Safety, PK/PD parameters, and preliminary efficacy were evaluated. Results As of 24 July 2020, 5 r/r AML patients (pts) including 1 relapsed, 1 relapsed/refractory and 3 primary refractory, were enrolled across 3 dose cohorts (1 at 1 mg/kg, 1 at 3 mg/kg and 3 at 10 mg/kg). Patients had 2-4 prior therapies. Median age was 45 years (range 25-66). Four of 5 pts developed treatment emergent AEs. Most of the AEs were grade 1 or 2. Treatment-related AEs that occurred in &amp;gt; 1 patient included thrombocytopenia (2/5 pts, 1 with grade 1 and 1 with grade 3) and positive anti-erythrocyte antibody (2/5 pts). No dose dependent hematologic toxicities have been observed so far. There was no treatment-related dose interruption or dose discontinuation. No patient developed treatment-related SAE or death. The maximum tolerated dose (MTD) has not yet been reached and the drug was well tolerated in r/r AML pts in the background of significantly impaired hematopoietic function with or without supportive blood transfusion. The anti-CD47 interferences on the blood bank testing were mitigated before blood transfusion. With doses from 1 mg/kg to 10 mg/kg, lemzoparlimab exhibited a supraproportional increase in exposure, which can be attributed to target (CD47) mediated drug disposition at low doses. CD47 receptor occupancy (RO) was evaluated as a PD marker. The mean RO on peripheral T cells at Cmax was 74.0%, 82.0% and 84.9% for 1, 3 and 10 mg/kg, respectively. The mean RO on CD33+ tumor cells at Cmax was 45.9%, 75.8% and 82.2% for 1, 3 and 10 mg/kg, respectively. Of note, one patient with primary refractory AML achieved morphologic leukemia-free state (MLFS) after 2 cycles of lemzoparlimab treatment at 1 mg/kg. Conclusion Lemzoparlimab was well tolerated in r/r AML pts in the doses tested and importantly, consistent with preclinical data, there were no serious hematological AEs so far. No DLTs or MTD was observed up to 10 mg/kg weekly dosing so far. The PK/PD profile of lemzoparlimab is also consistent with preclinical findings. The preliminary efficacy observed was encouraging. Dose escalation will continue until MTD or RP2D is reached. Disclosures No relevant conflicts of interest to declare.

Tandem Allogeneic Hematopoietic Stem Cell Transplantation for Salvage Treatment of Acute Myeloid Leukemia Refractory to Induction Chemotherapy: A Case Report

BackgroundPrimary refractory acute myeloid leukemia (AML) is associated with dismal prognosis. No standard treatment options are available, and it remains an unmet clinical need. Here, we report a case of a tandem allogeneic hematopoietic stem cell transplantation (allo-HSCT) performed in a patient who did not achieve remission after 2 courses of induction chemotherapy. Methods Case reportThe treatment was approved by the Bioethical Commission of the Medical University of Warsaw and was performed in accordance with the Declaration of Helsinki. The patient gave informed consent. ResultsA 41-year-old woman was diagnosed with AML, high cytogenetic risk, with concomitant skin and central nervous system involvement, bone marrow necrosis, and hemophagocytic lymphohistiocytosis. She received “3+7” induction and HAM (cytarabine, mitoxantrone) reinduction, after which she did not achieve remission and hematopoietic recovery. Tandem allo-HSCT was performed from the same HLA-identical brother---the first after reduced intensity conditioning (cladribine, cytarabine, mitoxantrone, melphalan) and the second after myeloablative conditioning (BuCy--busulphan, cyclophosphamide). The patient obtained complete remission after the first allo-HSCT and remains disease-free after the second for 5 years ConclusionTandem allo-HSCT may be a treatment option for primary refractory AML.

Relapsed or primary refractory AML: moving past MEC and FLAG-ida.

Purpose of reviewTreatment of relapsed and refractory acute myeloid leukemia (AML) is still very challenging, with poor response rates and low chance for cure. This is especially true when treating patients who are elderly, have multiple comorbidities, or who are too unfit for traditional salvage chemotherapy regimens.Recent findingsRecently, advances in the treatment of relapsed/refractory AML utilizing novel chemotherapy combinations, hypomethylating, and targeted therapies have shown promising results.SummarySeveral early-phase studies with novel targeted therapy combinations have demonstrated encouraging results warranting larger, comparative studies. This has expanded the access of treatment for patients with relapsed/refractory AML who cannot receive traditional salvage chemotherapy. These newer treatments have the potential to outperform traditional chemotherapy as well.

Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart® Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients

Flotetuzumab, an Investigational CD123 x CD3 Bispecific Dart® Protein, in Salvage Therapy for Primary Refractory and Early Relapsed Acute Myeloid Leukemia (AML) Patients

Outcomes of Relapsed or Refractory Acute Myeloid Leukemia after Frontline Hypomethylating Agent with Venetoclax Regimens

Outcomes of Relapsed or Refractory Acute Myeloid Leukemia after Frontline Hypomethylating Agent with Venetoclax Regimens