Shorter Remission Duration Research Articles

Ixekizumab-induced urticaria is associated with the short duration of remission in psoriasis by activation of mast cells

BackgroundMast cell degranulation plays a pivotal role in urticaria and is also an early histological characteristic of psoriasis. However, whether the activation of mast cells contributes to psoriasis recurrence after discontinuation of IL-17A blockers remains unclear. ObjectiveTo investigate the role of mast cells in ixekizumab treatment-associated urticaria (ITAUR) and assess the effect of urticaria eruption on psoriasis relapse. MethodsA retrospective analysis was performed on biopsies of patients who experienced psoriasis relapse after discontinuation of ixekizumab. Transcriptomic and histopathological features were assessed. Patterns were compared between patients with ITAUR and non-urticaria (NUR) as well as psoriasis-like mice with mast cell activation or inactivation. ResultsPatients with ITAUR experienced early relapse compared to NUR group after treatment withdrawal. Transcriptomic and histopathological analyses revealed that patients with ITAUR had an elevated proportion of mast cells in resolved skin. Especially, the proportion of IL-17A-positive mast cells was inversely correlated with the duration of remission. LimitationsThe mechanism of mast cell activation in ITAUR has not been precisely elucidated. ConclusionIxekizumab treatment increases IL-17A-positive mast cells in lesions of ITAUR, which is associated with early psoriasis relapse after ixekizumab withdrawal.

Covalent-103: A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study of Bmf-500, an Oral Covalent FLT3 Inhibitor, in Adults with Acute Leukemia (AL)

Background: FLT3 mutations occur in 25-35% of patients with AML and are associated with poor prognosis. FLT3 mutations are most frequently the result of an internal tandem duplication (ITD) of amino acids in the juxtamembrane region of FLT3 or point mutations in the tyrosine kinase domain (TKD). FLT3-ITD mutations are associated with increased incidence of relapse, shorter duration of remission, and decreased disease-free and overall survival. BMF-500 is a novel orally bioavailable, highly potent and selective covalent inhibitor of FLT3 including wildtype (WT), ITD, TKD, as well as a variety of additional resistance-conferring mutations such as the gatekeeper F691. BMF-500 has demonstrated high affinity for FLT3, lack of cKIT inhibition, and sustained cell-killing capacity despite drug washout (Law et al., ASH 2022 Abstract 2756). BMF-500 has shown sustained tumor regression and improved survival in both subcutaneous and disseminated xenograft models of mutant FLT3-driven AML. Study Design: COVALENT-103 (NCT05918692) is an open-label, non-randomized, multicenter, first-in-human Phase I study evaluating the safety, tolerability, and clinical activity of escalating doses of twice daily oral BMF-500 in patients with relapsed or refractory (R/R) AL, including AML, ALL, or MPAL, with or without FLT3 mutations. The trial has 2 arms that will undergo dose escalation in parallel: Arm A (without) and Arm B (with) concomitant use of a moderate or strong CYP3A4 inhibitor. Utilizing an accelerated titration design (ATD), doses of BMF-500 will be escalated in single-subject cohorts until 1 subject experiences either a Grade 2 or higher related-adverse event or dose-limiting toxicity (DLT). At that point, the cohort will switch to a classical “3 +3” design. Patients with WT FLT3 AL may be enrolled, up to a limit of 33% per arm. Treatment will continue in 28-day cycles until progression or intolerability. Expansion cohorts will enroll additional patients to obtain further safety and efficacy data. Patients must be refractory, relapsed or must have progressed on or following discontinuation of the most recent anti-cancer therapy or be ineligible for any approved standard of care therapies, including HSCT. Participants with FLT3-mutant AML must have received treatment with a FLT3 inhibitor approved for treatment of relapsed or refractory FLT3-mutant AML. Key inclusion criteria include ECOG PS ≤ 2, adequate organ function, and documented FLT3 mutation status. Key exclusion criteria include known CNS disease involvement, clinically significant cardiovascular disease, and WBC count >50,000/µL (uncontrollable with cytoreductive therapy). Objectives: The primary objective of the study is to evaluate safety and tolerability and to determine the optimal biological dose (OBD)/ recommended Phase 2 dose (RP2D) of BMF-500 oral monotherapy based on evaluation of available PK/ PD, safety and efficacy data. Secondary objectives include characterization of the pharmacodynamics and pharmacokinetics of BMF-500, and assessment of its antitumor activity per modified Cheson (2003) criteria or the NCCN Clinical Practice Guidelines (ALL Version 1.2022) as determined by the investigator. Endpoints include best overall response rate (ORR), complete remission (CRc), duration of response (DOR), relapse-free survival (RFS) and overall survival (OS). The study was initiated in July 2023 and will enroll ~110 participants at approximately 30 sites.

Phase 1 Trial of Orelabrutinib in Combination with Rituximab, Methotrexate, and Dexamethasone in Patients with Newly Diagnosed Primary CNS Lymphoma Implementing Bayesian Design for Dose-Seeking

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal subtype of non-Hodgkin's lymphoma (NHL). High-dose methotrexate (HD-MTX)-based regimens are the first-line treatment for PCNSL, but remain suboptimal due to response instability and short effective remission duration. Orelabrutinib is a novel, potent, highly selective BTK inhibitor with a high CSF concentration. This study aims to investigate optimal combination dose of Orelabrutinib in combination with Rituximab, Methotrexate, and Dexamethasone (ORMD) as well as safety and efficacy of the regimen. Methods: This was a phase 1, investigator-initiated, dose-escalation study of ORMD, being conducted at Huashan Hospital, Fudan University (NCT05036577). Eligible patients must have histopathologically confirmed PCNSL-DLBCL by biopsy of brain lesions and be aged 18-75 years with adequate organ functions. Patients were treated for 6-8 cycles of induction therapy with 21 days per cycle, receiving rituximab (375mg/m 2 on day 1), dexamethasone (10-15mg on d1-d4), MTX (d2, 3.5g/m 2 or 5g/m 2), and orelabrutinib (once daily, after MTX clearance, 150mg/d, or 200mg/d), followed by orelabrutinib maintenance up to one year among CR/CRu patients. The primary objective was to determine the maximum tolerated dose (MTD) of the combination of orelabrutinib and MTX with R and D and investigate the safety and tolerability of this regimen using Bayesian Optimal Interval (BOIN) waterfall design to determine rule of dose escalation and movement among dose combination matrix to identify MTD contour. DLT was defined by the occurrence of severe toxicities during the first cycle: any grade 4 hematologic toxicity, grade 3 febrile neutropenia and grade 3 thrombocytopenia with hemorrhage, or any grade 3 non-hematologic toxicity that failed to respond to supportive therapy and possibly related to orelabrutinib and/or MTX (assessed according to NCI CTCAE V5.0). The secondary objectives included ORR/CR（u） and PFS/OS. Results: From October 2021 to July 2023, the study completed enrollment of all 13 patients. The median age was 60 years, and other basic characteristics are shown in Figure 1. All the patients had completed at least one cycle of ORMD treatment and were evaluable for DLT. The median cycle of ORMD was seven (range: 2.5-8). No DLT occurred among first 3 patients in cohort 1 (Orelabrutinib: 150mg/MTX: 3.5g/m 2) and dose escalation was allowed to cohort 2 (Orelabrutinib: 200mg/MTX: 3.5g/m 2). In cohort 2, 5 patients were dosed in total, and Gr 3 lung infection was observed in patient #4 during cycle 1, was deemed as a DLT. Another four patients were enrolled in the same cohort according to BOIN design algorithm and no DLT was identified, allowing to escalate to cohort 3 (Orelabrutinib:200mg/MTX:5g/m 2). In cohort 3, 5 patients were dosed in total, and Gr 3 elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was observed in patient #9 during cycle 1, was deemed as a DLT. The causality of this AE was certain to methotrexate due to folate metabolic gene polymorphism in the assessment of the investigator. The toxicity probability from 3 dose combo cohort is 0.13, 0.13 and 0.21, all of which is below predefined threshold 0.3. So MTD is not reached and 200mg+5g/m 2 dose combo remains to be RP2D candidate. No Gr 4 AE had been observed. The most common adverse events were lymphopenia (Gr 3 in 8 case), neutropenia(Gr 3 in 2 case), Covid-19(Gr 3 in 2 case) and hyperglycemia (Gr 3 in 2 case). No atrial fibrillation or bleeding was observed by the cut-off date. ORR and CR/CRu in 12 patients possessed at least one efficacy evaluation were both 83.3%, the PFS and OS rate were 56.6% (95% CI, 29.6% ,100%) and 100%(95% CI, 100% ,100%) at 1 year. Among nine patients completed ≥6 cycles of induction therapy, ORR and CR/CRu were both 100%. PFS and OS rate were 75.0% (95% CI, 42.6% ,100%) and 100%(95% CI, 100% ,100%) at 1 year. All patients in remission achieved CR/CRu, the high rate of deep remission may be related to the addition of orelabrutinib. Conclusions: As a novel therapeutic combination of induction therapy, ORMD therapy has shown deep remission potential as well as a predictable and manageable safety profile in patients with newly diagnosed PCNSL. MTD contour not reached. The combination of this induction therapy with consolidation therapies such as ASCT deserves further investigation and may provide greater survival benefit for patients.

Disability and its correlates among persons with bipolar disorder: Exploratory findings from the bipolar disorder course and outcome study from India (BiD-CoIN study).

This study aimed to evaluate the disability and its correlates in persons with Bipolar Disorder during the remission phase. As part of the multicentric study, 773 patients with bipolar disorder, currently in clinical remission, were evaluated for disability on the Indian Disability Assessment Evaluation Scale. About one-fifth of the participants had some level of disability in the domain of self-care, one-third had some level of disability in the interpersonal domain, one-fourth had some level of disability in communication and understanding, and a maximum proportion (43.7%) had some disability in the domain of work. Overall, about one-fifth (18.4%) were considered to have a benchmark disability (i.e., disability >40%). In terms of correlates, those with a disability had a short duration of current remission, a higher number of manic and mixed episodes, a higher mean number of total episodes, spent more time in the episodes, had lower severity of the depressive episodes, higher residual depressive and manic symptoms, had overall higher manic affective morbidity, had a higher level of cognitive deficits, and had poorer insight. A significant proportion of patients with bipolar disorder have disability in work domain, and the presence of residual symptoms of either polarity are associated with higher level of disability.

Second hematopoietic stem cell transplantation as salvage therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after a first transplantation.

Second allogeneic hematopoietic stem-cell transplantation (HSCT2) is a therapeutic option for patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (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% confidence interval [95% CI]: 17-39%) and 50% (95% CI: 39-65%), respectively. The 5-year overall survival 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 (hazard ratio [HR]=0.31, P=0.001), short remission duration after HSCT1 (HR=2.31, P=0.05), acute graft-versus-host disease after HSCT1 (HR=2.27, P=0.035), HSCT2 from a haplo-identical donor (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 overall survival after HSCT2. Multivariate analysis of all patients including HSCT2 as a timedependent variable identified relapse within 6 months after HSCT1 (HR=2.32, P<0.001), acute graft-versus-host disease before relapse (HR=1.47, P=0.005), myeloablative conditioning in HSCT1 (HR=0.67, P=0.011), female gender (HR=0.71, P=0.007), relapse in earlier years (HR=1.33, P=0.031) and not having HSCT2 (HR=1.66, P=0.010) as predictive of overall survival after relapse. In conclusion, HSCT2 is associated with longer survival compared to non-transplant treatments and may be the preferred approach in a subset of patients with relapsed AML/MDS after HSCT1.

Extended Follow up of a Phase 2 Study of Ibrutinib in Hairy Cell Leukemia

INTRODUCTIONHairy cell leukemia (HCL) is a rare B-cell malignancy where there is a need for treatment options for patients who do not benefit from purine nucleoside analogs (PNA) due to short remission duration or other conditions making them unsuitable to receive them. Ibrutinib is an oral inhibitor of Bruton Tyrosine Kinase (BTK) that is effective in a variety of B-cell malignancies and tolerable for indefinite extended administration. As inhibitors of BTK have been successful in other B-cell cancers it was a rational therapeutic approach in HCL. We conducted a phase 2 study of ibrutinib in both classic and variant HCL and have previously reported outcomes for the first 37 patients treated. We now report the primary endpoint for the entire cohort (n=44) as well as extended follow up. METHODS This phase 2 multisite study is funded by the National Cancer Institute (NCI) with ibrutinib supplied by Pharmacyclics. The protocol was IRB approved at all participating sites. Adults (≥18 years old) with both classic and variant HCL were eligible if they met criteria for requiring treatment. They had to have received prior treatment with a PNA or be unsuitable to receive one. Patients with the HCL variant could have no prior treatments. Patients were initially treated with ibrutinib at either 840mg daily or 420mg daily. Based on concerns for toxicity 420mg was selected as the dose for more recently enrolled patients and those started at 840mg were allowed to reduce to 420mg. Response was assessed at 32 and 48 weeks after starting treatment as well as any time after that at the discretion of the investigator. The study was open to accrual in April 2013 and completed enrollment in March 2021. Data reported include follow up as of May 25, 2022. Response rates were calculated for each time point and were compared by HCL subtype with Fisher's exact tests. Kaplan Meier methods were used to assess progression-free (PFS) and overall survival (OS), with log-rank tests used to compare the outcomes by subtype. RESULTS A total of 44 patients were included with characteristics in Table 1. The median follow up is 3 years (range 2 weeks to 8.6 years) and 16 (36%) patients remain on treatment. There were 13 patients initially treated with 840mg and 31 with 420mg. All except 1 patient continued treatment with 420mg. Reasons for discontinuing treatment were progressive disease (n=12), adverse events (n=9), elective withdrawal (n=5), and death (n=2). There were 6 deaths in the study, 2 during treatment from pneumonia, 2 from progressive disease, and 2 from infections after discontinuing ibrutinib. The primary endpoint was overall response at 32 weeks and was 29% (12/42, 2 missed due to COVID-19) and improved to 41% (18/44) at 48 weeks and 59% (26/44) at any time. 7 (16%) achieved a best response of complete remission and 19 (43%) partial remission. Response rate was not different between patients with classic or the variant subtype. The median PFS and OS were not reached (Figure 1). The estimated 60-month PFS and OS were 68% (95% CI: 50%-81%) and 87% (95% CI: 71%-94%) months, respectively. There were no significant differences in PFS and OS between classic and variant subtypes. The most frequent adverse events (AEs) regardless of attribution to study treatment were diarrhea (59%), fatigue (52%), myalgias (52%), nausea (48%), thrombocytopenia (45%), upper respiratory infection (45%), bruising (41%), cough (41%), headache (41%), and hypertension (41%) which are all established AEs observed with ibrutinib in other diseases. The most frequent grade ≥3 AEs were hematologic with thrombocytopenia (23%), leukopenia (23%), lymphopenia (20%), neutropenia (18%) with grade ≥3 lung infection (16%) and hypertension (11%) also noted. CONCLUSIONS With a median follow-up length of 3 years, patients with HCL continue to benefit from ibrutinib with an estimated 60-month PFS of 68%. In this evaluation of 44 patients the rate of response to ibrutinib at any time was 59% which is similar to 54% in the initial report with 37 patients (Rogers et al., Blood 2021). The durable PFS in this difficult to treat population makes ibrutinib an effective therapy for select patients with HCL who are not expected to benefit from a PNA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review.

Mantle cell lymphoma (MCL) accounts for nearly 2-6% of all non-Hodgkin lymphoma (NHL) cases, with a steady incidence increase over the past few decades. Although many patients achieve an adequate response to the upfront treatment, the short duration of remission with rapid relapse is challenging during MCL management. In this regard, there is no consensus on the best treatment options for relapsed/refractory (R/R) disease, and the international guidelines demonstrate wide variations in the recommended approaches. The last decade has witnessed the introduction of new agents in the treatment landscape of R/R MCL. Since the introduction of Bruton's tyrosine kinase (BTK) inhibitors, the treatment algorithm and response of R/R MCL patients have dramatically changed. Nevertheless, BTK resistance is common, necessitating further investigations to develop novel agents with a more durable response. Novel agents targeting the B-cell receptor (BCR) signaling have exhibited clinical activity and a well-tolerable safety profile. However, as the responses to these novel agents are still modest in most clinical trials, combination strategies were investigated in pre-clinical and early clinical settings to determine whether the combination of novel agents would exhibit a better durable response than single agents. In this report, we provide an updated literature review that covers recent clinical data about the safety and efficacy of novel therapies for the management of R/R MCL.

The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.

Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.

Radiation Therapy for Patients with Diffuse Large B Cell Richter's Syndrome of CLL

Introduction: The transformation of chronic lymphocytic leukemia (CLL) into a highly aggressive B-cell lymphoma histology, known as Richter's syndrome (RS), is associated with rapid progression and remains a serious treatment challenge. Standard chemoimmunotherapy approaches often yield poor response rates, short remission durations, and limited overall survival. The role of radiation therapy (RT) in the management of RS has not been explored, and decision making regarding the use of RT in RS is extrapolated from the de novo diffuse large B cell lymphoma (DLBCL) literature. Herein, we report, to the best of our knowledge, the largest case series of patients with RS who received RT.Methods: We conducted a retrospective review of all patients Memorial Sloan Kettering Cancer Center diagnosed with DLBCL RS between April 2002 and August 2020 who received RT at any time following RS diagnosis. Baseline characteristics, information regarding CLL- and RS-directed therapy, RT characteristics including its therapeutic intent, and outcomes were collected. Progression free and overall survival (PFS, OS) were estimated using Kaplan Meier method. All other analyses were descriptive. Analyses were performed using STATA 17.0.Results: 34 RS patients who received RT were identified. Twenty-one received RT as part of a definitive therapeutic strategy while 13 received RT solely for palliation. Baseline characteristics for the entire cohort, as well as divided by RT therapeutic intent, are described in Table 1. Patients received a median of 1 (range 0-5) prior line of CLL-directed therapy prior to RS diagnosis; 24% had prior ibrutinib while 9% had prior venetoclax. Patients received a median of 2 (range 0-5) lines of RS-directed therapy prior to RT; chemoimmunotherapy was first-line RS-directed therapy for 82%. Figure 1 depicts a swimmer's plot for all patients from time of RS diagnosis and includes timing of RT and cellular therapy (CAR-T or allogeneic stem cell transplant, alloSCT).Heterogeneity in the parameters of radiation utilized reflected diverse clinical situations in this cohort. Across the cohort, most commonly irradiated areas included head and neck sites (n=11), abdomen (n=5), paraspinal (n=4) and pelvis/groin (n=4). Median delivered dose was 30.6 Gy (range: 18-54) and 25 Gy (range: 4.5-45) for the definitively and palliatively-treated patients, respectively. Four patients (3 palliative, 1 consolidative) did not complete prescribed course of RT.We subsequently focused on 21 patients treated with RT as part of a definitive therapeutic strategy. With a median follow-up time of 5.8 (range 0.2 - 18.5) years, median OS was estimated to be 6.8 years from RS diagnosis. Fourteen patients (67%) experienced DLBCL progression following RT.A subset of 12 patients received RT following chemoimmunotherapy without immediate cellular therapy in the front-line setting (58%; 7/12) or relapsed/refractory setting (42%; 5/12). Response at the time of RT was CR/clinical CR in 7 patients (58%), PR in 3 (25%), and PD in 1 (8%); response at the time of RT was unknown for 1 patient. In this subset, four (33%) experienced RS disease relapse with 2 occurring within the prior radiation field and 2 occurring distantly. Two patients received RT as an up-front therapy prior to any chemoimmunotherapy in the setting of localized disease. One of these two subsequently had a DLBCL relapse within the prior radiation field.RT was used as a bridging strategy to cellular therapy in 7 patients including alloSCT (n=4) and CAR-T (n=3). Four patients experienced RS relapse. Estimated median PFS was 1.1 years and median OS was 1.9 years from time of cellular therapy.Conclusion: In the largest single-institution series to describe the use of RT in RS, patients who received RT for the diagnosis of RS experienced favorable long-term survival when used as part of a definitive therapeutic strategy, including consolidation following chemoimmunotherapy and as bridging to cellular therapy. These data suggest a role for RT in the management of RS to be further explored through multicenter collaborations and prospective studies. [Display omitted] DisclosuresThompson: VJHemOnc: Honoraria; Curio Science: Honoraria; MJH Life Sciences: Honoraria. Mato: Acerta/AstraZeneca: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; Sunesis: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; DTRM BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; MSKCC: Current Employment. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company.

AML-468: Outcomes of FLT3-Mutated Acute Myeloid Leukemia Patients: A Single-Center, Real-World Experience

Background:Internal tandem duplications (ITDs) within the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common driver mutation and confers a poor prognosis in patients (pts) with acute myeloid leukemia (AML) due to proliferative presentation, short remission durations and early relapse. The addition of midostaurin to induction therapy has become standard therapy in newly diagnosedFLT3-mutated (FLT3-mu) AML. Next-generation FLT3 inhibitors (FLT3i) as gilteritinib and quizartinib are more specific, more potent, and may have fewer toxicities associated with off-target therapies but are only available in clinical trials or for salvage therapy. Real-world experience in smaller academic institutions is scanty. Methods:We reviewedFLT3-ITD mu AML pts at our institution from October 2016-December 2019. FLT3i were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low intensity therapy (LIT) (hypomethylating agents). AllFLT3-ITD DNA was subjected to PCR amplification using primers targeting the juxtamembrane domain of FLT3, and products were analyzed by capillary electrophoresis. We analyzed the characteristics of these pts, responses to therapy, and outcomes. Results:Sixteen pts with newly diagnosedFLT3-ITD mu AML were identified. The median age was 47 years [range, 17-76 years] and the median follow-up was 9.3 months [range, 1.2-29.5 months]. The median time from AML diagnoses to FLT3 detection was 4 days [range, 3-5 days]. Patient characteristics are shown in Table 1. The most common co-occurring mutations wereNPM1(44%) andNRAS(31%); 2 pts (12%) had both mutations. Five pts (31%) received CCT and 11 pts (69%) received CCT+FLT3i. The most frequently used FLT3i was midostaurin 25 mg twice daily on days 8 through 21 (14 days) (10 pts, 63% of all pts); 1 pt received sorafenib (6% of all pts). The complete remission rate (CR) and the overall response rate (ORR) (CR+CR with incomplete hematologic recovery [CRi]) were 31% and 88%, respectively. The two pts who did not achieve a remission were older than 65 years. Among the pts who received CCT+FLT3i, CR and OOR were 50% and 100%, respectively. The median number of cycles to remission was 1 [range, 1-2 cycles], and the median number of consolidation cycles was 0 [range, 0-3 cycles]. Overall, the median duration of response in frontlineFLT3-ITD pts who did not receive allogeneic hematopoietic stem cell transplantation (Allo-HSCT) was 5 months [range, 1-9 months] (all of them received CCT+FLT3i). There was no statistically significant difference in response in pts with NPM1 mutation compared with pts with NRAS mutation (P=0.7), or with no additional mutations. Seven pts (44%) received an Allo-HSCT (6 after CCT+FT3i, and 1 after CCT alone): 2 (28%) from matched unrelated donor, 1 (14%) from a haploidentical transplant, 1 (14%) from dual cord transplant, and the remaining (44%) from matched related donors. Two patients relapsed after Allo-HSCT (28%). Both of these patients had received FLT3i before Allo-HSCT; one of the two relapsed pts received ivosidenib and azacitidine (IDH1 mutation) after Allo-HSCT, achieved remission then received the 2nd Allo-HSCT with subsequent remission. Two pts (29%) received maintenance therapy after Allo-HSCT, one with midostaurin, and the other with azacitidine + gilteritinib; both pts are still on remission (24 and 6 months after CR, respectively). All 7FLT3-ITD pts who did not receive Allo-HSCT relapsed. Gilteritinib was used as a single agent (n=3) or in combination with LIT (n=1) in these pts after relapse. CR rate was 25% and CRI 50%; one pt relapsed (33%). All pts who responded are still receiving gilteritinib. Conclusion:Combination of FLT3i based therapy with CCT is effective therapy inFLT3-ITD frontline pts in real-world setting. Duration of response is short in the absence of Allo-HSCT. Download : Download high-res image (299KB) Download : Download full-size image Disclosures Cortes:Arog:Research Funding;Pfizer:Consultancy, Research Funding;Amphivena Therapeutics:Research Funding;Daiichi Sankyo:Consultancy, Research Funding;Astellas:Research Funding;Telios:Research Funding;Novartis:Consultancy, Research Funding;BioPath Holdings:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Merus:Research Funding;Bristol-Myers Squibb:Research Funding;Takeda:Consultancy, Research Funding;Sun Pharma:Research Funding;BiolineRx:Consultancy, Research Funding;Immunogen:Research Funding;Jazz Pharmaceuticals:Consultancy, Research Funding.

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Clinical Relevance of Minimal Residual Disease Monitoring in NPM1 Mutated AML: A Study of the AML Study Group (AMLSG)

Inhibition of Carbonic Anhydrase-IX As a Novel Strategy to Overcome Hypoxia Mediated Drug Resistance in FLT3/ITD Mutated Acute Myeloid Leukemia

Background: FLT3/ITD mutated (FLT3/ITD+) acute myeloid leukemia (AML) is an aggressive form of blood cancer that carries a poor prognosis due to short remission durations and high relapse rates. Several studies suggest that this poor outcome is due to a small fraction of leukemic cells (LCs) that elude treatment and survive in hypoxic niches of the bone marrow (BM) where they lead to relapse. The identification of molecules capable to target LCs under hypoxic conditions is therefore of utmost importance on the way to find a cure for AML. Our study addresses the effects of pharmacological inhibition of carbonic anhydrase-IX (CA9), a transmembrane protein which functions to maintain a neutral intracellular pH - a key survival mechanism for tumor cells to escape cell death in the hypoxic environment - on AML cells. Targeting CA9 is of particular interest as its expression is confined to only a few normal tissues. CA9 inhibition may therefore show relatively few side effects compared to standard chemotherapies. Methods: Molm14 (M14), M13, OCI-AML3, THP-1 and primary cells (PC) from FLT3/ITD+ AML patients were incubated under normoxic (21% O2) and hypoxic (1% O2) conditions in the presence or absence of Quizartinib (Quiz), Cytarabine (Cy) or the CA9 inhibitors FC531 (FC) or SLC-0111 (SLC). After 48h proliferation and apoptosis assays were performed using MTT assays, annexin V/PI staining and FACS analysis. Cells were also assessed for CA9 and CA12 mRNA expression as well as intracellular pH levels via RT-PCR and fluorescent imaging, respectively. FLT3/ITD+ AML xenografts were generated by injecting M14 cells in the tail vein of NSG mice. Tissue samples were fixed in 10% NBF, embedded in paraffin and stained with H&E and CA9 for pathologic evaluation. Results: CA9 mRNA was upregulated in M14 cells (3.8±1.1-fold; n=3, p<.05) and FLT3/ITD+ AML PCs (215.4±142.7-fold, n=7, p=NS) under 1% compared to 21% O2. Consistently, immunohistochemical staining of M14 xenograft tissues showed multifocal CA9 staining of LCs in the BM and spleen. In M14 cells, inhibition of CA9 with FC conferred substantial, dose-dependent growth inhibitory effects under 1% O2 (IC50=4.04µM) and was significantly more effective than clinically achievable doses of Quiz or Cy in this regard. Under 1% O2, flow cytometry revealed significant induction of apoptosis in FC, but not in Quiz or Cy treated cells (p<.01 vs Cy, p<.01 vs Quiz; n=3). Similar results were obtained in M13 cells. Treatment of M14 cells with 5µM FC under 1% O2 resulted in substantial intracellular pH acidification (ΔpH=-2.7±0.6, p<.05 vs 1% O2, n=3) within 48h. FC synergistically inhibited M14 cell growth when combined with Cy (CI=0.78). To investigate the effects of CA9 inhibition against non-FLT3 mutated cells we incubated OCI-AML3 and THP-1 cells to increasing doses of FC (1-10µM) under 1% O2. We observed that both cell lines were less sensitive to FC (IC50>10µM) compared to M14 and M13 cells. Interestingly, these cell lines displayed higher levels of CA12 mRNA (CA9/12 ratio=0.68 [OCI-AML3] and 0.54 [THP-1]) compared to the FC sensitive cell lines M14 and M13 (CA-9/12 ratio=2.5 and 4.6, respectively). Next, we assessed the effects Cy (1µM), Quiz (100nM) and FC (200µM) against FLT/ITD+ PCs. As expected, Cy and Quiz did not confer cytotoxic effects under 1% O2. Surprisingly, FC was only mildly effective against FLT/ITD+ PCs, which harbored low CA9/12 ratios (<0.5). In contrast, treatment with equimolar doses of SLC, a different class CA9 inhibitor, exhibited substantial anti-leukemic activity under 1% O2 conditions (78.8±1.9% growth inhibition, n=3, p<.05 vs FC, p<.001 vs Cy or Quiz). Conclusions: 1. CA9 is upregulated in FLT3/ITD+ cell lines and PCs under hypoxic conditions. 2. CA9 is expressed in LCs residing in the BM and spleen of FLT/ITD+ AML xenografts. 3. The CA9 inhibitor FC531 confers marked anti-leukemic activity against FLT3/ITD+ AML cells under hypoxic conditions via intracellular pH acidification and acts synergistically with cytarabine. 4. Upregulation of other carbonic anhydrase isoforms, such as CA12, might represent a resistance mechanism against FC531 that can be overcome by different class CA9 inhibitors. 5. Our data suggests that CA9 inhibition has the potential to specifically target LCs residing in hypoxic niches and may be of value as an adjunct to chemotherapy for FLT3/ITD+AML treatment. 6. Our ongoing work evaluates the effects of CA9 inhibition in AML xenografts. DisclosuresNo relevant conflicts of interest to declare.

XPO1 Inhibition Targets Transcriptional Vulnerability of FLT3-ITD+D835 Double Mutant AML through p53 Accumulation and Inhibition of Oncogenic Transcription Factors: Lesson Learned from Cage Sequencing of Primary AML Cells

Acute myeloid leukemia (AML) with Fms-like tyrosine kinase 3 / the internal tandem duplications (FLT3 /ITD mutations) present a major clinical challenge, because of short remission duration and higher relapse rates. FLT3-targeted therapies using tyrosine kinase inhibitors (TKIs) often promote acquisition of additional point mutations in the tyrosine kinase domains (TKD) mutations, most commonly at D835 within the activation loop.To elucidate the alterations of transcriptome signatures of FLT3 /ITD-D835 mutants in AML, we performed cap analysis of gene expression (CAGE) sequencing of 14 AML patient samples with FLT3 /ITD and 12 patient samples with FLT3 /ITD-D835 mutations. CAGE identifies and quantifies the 5' ends of capped mRNA transcripts, which enables the identification of transcription start sites (TSS) necessary for gene expression. The TSS of genes altered in AML samples with FLT3 /ITD-D835 compared with FLT3 -ITD were mapped. CAGE detected upregulation of 378 and downregulation of 77 genes, respectively (false discovery rate; FDR < 0.05). Ingenuity Pathway Analysis (IPA) highlighted the activation of transcription factors NFKBIA (IκBα), RELA (NFκB subunit), HIF1α, EP300 (co-activator of HIF1α), TP73, PRDM1 (regulator of TP53 activity), NUPR1 (regulator of p21 relocalization), and FOXO3 (post-transcriptional regulators of MYC) in FLT3 /ITD-D835 mutant primary patient samples compared to FLT3 /ITD primary samples (Z score >1.9).To validate these transcriptional changes, we utilized paired isogenic FLT3 /ITD or FLT3 /ITD-D835Y transfected Ba/F3 cell lines. CAGE detected upregulation of 523 and downregulation of 373 genes, respectively, in FLT3 /ITD-D835 compared to FLT3 /ITD cells (FDR < 0.05). IPA indicated activation of HIF1α and MYC and inhibition of TP53 in FLT3 /ITD-D835 compared to FLT3 /ITD cells. Immunoblot analysis confirmed higher expression of c-Myc, IκBα and HIF1α and lower expression of TP53 in FLT3 /ITD-D835 compared to FLT3 /ITD cells. In turn, FLT3 downstream targets phospho- (p-) ERK, p-AKT, and p-STAT5 were significantly lower in FLT3 /ITD-D835 than in FLT3 /ITD cells. These results indicate that secondary FLT3 -D835 mutations activate oncogenic transcription factors c-Myc, IκBα and HIF1α, inhibit tumor suppressor TP53, and downregulate FLT3 downstream signaling pathways ERK, AKT, and STAT in FLT3 /ITD mutated AML cells.Exportin 1 (XPO1) mediates the nucleo-cytoplasmic transport, and is overexpressed in AML cells with FLT3 /ITD mutations (Kojima, Blood, 2013) . TP53 and IκBα are XPO1 cargos, and XPO1 inhibitors are known to upregulate TP53 and block c-MYC and NFκB signaling. We therefore examined the anti-leukemia activity of clinically available XPO1 inhibitor selinexor in FLT3 /ITD and FLT3 /ITD-D835 Ba/F3 cells. As expected, selinexor effectively inhibited cell proliferation in both FLT3 /ITD and FLT3 /ITD-D835 mutated cells at IC50 of 0.3 μM and 0.1 μM, respectively (48 hrs). CAGE detected upregulation of 1,590 and 2,220 genes and downregulation of 1,238 and 2,640 genes, respectively by selinexor treatment in FLT3 /ITD and FLT3 /ITD-D835 Ba/F3 cells, (FDR < 0.05). IPA analysis highlighted TP53, NUPR1 and CDKN2A (ARF; stabilizer of TP53) as the top three activated transcription factors by selinexor both in FLT3 /ITD and FLT3 /ITD-D835 cells. Immunoblot assay detected that selinexor significantly upregulated TP53, and downregulated IκBα and HIF1α both in FLT3 /ITD and FLT3 /ITD-D835 Ba/F3 cells. Selinexor treatment suppressed c-Myc and increased cleaved caspase 3 more prominently in FLT3 /ITD-D835 cells, but also upregulated p-ERK, p-AKT, p-STAT5 and p-STAT3, more notable in FLT3 /ITD cells. MCL1 and mTOR downstream p-4EBP1 and p-pS6 were repressed by selinexor in FLT3 /ITD-D835 but not in FLT3 /ITD cells.Collectively, the primary mechanism underlying the sensitivity to XPO1 inhibition of FLT3 /ITD-D835 cells is intolerance to the accumulation of nuclear TP53 and inhibition of multiple oncogenic transcription factors, including c-Myc, IκBα and HIF1α, which confer pro-survival activity independent of FLT3 downstream signaling. These findings indicate that XPO1 (CRM1) inhibition is a promising therapeutic strategy for AML patients with FLT3 /ITD and secondary acquired D835 mutations. DisclosuresHarada:Celgene: Research Funding; NIPPON SHINYAKU CO.: Speakers Bureau; NOVARTIS: Research Funding. Andreeff:Daiichi Sankyo: Consultancy.

Outcomes after Third Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Acute and Chronic Leukemias

Background: A subset of patients with acute and chronic leukemia have received more than one allogeneic hematopoietic stem cell transplant (alloSCT) to achieve a durable remission. A very small proportion of these patients have received a third alloSCT (alloSCT3), and very little is known about their outcome.Methods: We identified 18 patients with acute or chronic leukemia who had relapsed or failed to engraft after their second alloSCT, and received alloSCT3 at our institution. Primary objectives were to evaluate relapse-free (RFS) and overall survival (OS). RFS was the time from SCT3 to relapse, death or censored at last follow up date. OS was defined as the time from alloSCT3 to death from any cause or censored at last follow up.Results: Eleven of the 18 patients, 11 (61%) had acute myeloid leukemia (AML). Patient characteristics are listed in Table 1. Sixteen (18%) patients were considered for SCT3 after disease relapse and 2 (11%) for SCT2 engraftment failure. Five of 11 (55%) AML patients had adverse risk cytogenetics prior to alloSCT3. In the entire cohort (n=18), seven (39%) were in complete remission (CR) at alloSCT3, and 6 patients with AML had active disease with a median bone marrow blast % of 16 [range, 7-40]. Neutrophil and platelet engraftment occurred in 94% and 83% of the cases, respectively. The most common preparative regimen was fludarabine + melphalan that was used in 10 (55%) patients. Other preparative regimens used were fludarabine + cyclophosphamide + rituximab, 2 (12%); decitabine, 2 (12%); others, 4 (23%). Ten (55%) alloSCT3 were from matched-related donors, 6 (33%) from matched-unrelated and 2 (11%) from umbilical cord blood. Median time for neutrophil and platelet count recovery was 18 and 21 days, respectively. Thirteen (72%) patients had a different donor from SCT2 to alloSCT3. Acute and chronic GVHD occurred in 3 (19%) and 5 (31%) of 16 evaluable patients, respectively. Nine of 15 (60%) evaluable patients relapsed after alloSCT3. Two patients, both with AML, experienced delayed relapses at extramedullary sites (breast at 9.5 months; skin at 11.5 months). At a median follow up of 7.5 (range, 0.8-678) months, one-year RFS and OS probabilities were 39% (Figure 1) and 38% (Figure 2), respectively. Both patients transplanted with umbilical cord blood graft experienced short remission durations lasting < 3 months from the receipt of transplant. Two patients (CML 1, CLL 1) are still alive and in remission, beyond 5 years post-alloSCT3.Conclusions: Our study results suggest that alloSCT3 is a feasible option in a small subset of patients with leukemia and can offer durable remissions in selected cases. [Display omitted] DisclosuresPemmaraju:novartis: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; roche diagnostics: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; cellectis: Research Funding. Kantarjian:Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; Novartis: Research Funding. De Lima:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Continuation of Antidepressants vs Sequential Psychological Interventions to Prevent Relapse in Depression

Depression frequently recurs. To prevent relapse, antidepressant medication is often taken in the long term. Sequentially delivering a psychological intervention while undergoing tapering of antidepressant medication might be an alternative to long-term antidepressant use. However, evidence is lacking on which patients may benefit from tapering antidepressant medication while receiving a psychological intervention and which should continue the antidepressant therapy. A meta-analysis of individual patient data with more power and precision than individual randomized clinical trials or a standard meta-analysis is warranted. To compare the associations between use of a psychological intervention during and/or after antidepressant tapering vs antidepressant use alone on the risk of relapse of depression and estimate associations of individual clinical factors with relapse. PubMed, the Cochrane Library, Embase, and PsycInfo were last searched on January 23, 2021. Requests for individual participant data from included randomized clinical trials (RCTs) were sent. Randomized clinical trials that compared use of a psychological intervention while tapering antidepressant medication with antidepressant monotherapy were included. Patients had to be in full or partial remission from depression. Two independent assessors conducted screening and study selection. Of 15 792 screened studies, 236 full-text articles were retrieved, and 4 RCTs that provided individual participant data were included. Time to relapse and relapse status over 15 months measured via a blinded assessor using a diagnostic clinical interview. Individual data from 714 participants (mean [SD] age, 49.2 [11.5] years; 522 [73.1%] female) from 4 RCTs that compared preventive cognitive therapy or mindfulness-based cognitive therapy during and/or after antidepressant tapering vs antidepressant monotherapy were available. Two-stage random-effects meta-analysis found no significant difference in time to depressive relapse between use of a psychological intervention during tapering of antidepressant medication vs antidepressant therapy alone (hazard ratio [HR], 0.86; 95% CI, 0.60-1.23). Younger age at onset (HR, 0.98; 95% CI, 0.97-0.99), shorter duration of remission (HR, 0.99; 95% CI, 0.98-1.00), and higher levels of residual depressive symptoms at baseline (HR, 1.07; 95% CI, 1.04-1.10) were associated with a higher overall risk of relapse. None of the included moderators were associated with risk of relapse. The findings of this individual participant data meta-analysis suggest that regardless of the clinical factors included in these studies, the sequential delivery of a psychological intervention during and/or after tapering may be an effective relapse prevention strategy instead of long-term use of antidepressants. These results could be used to inform shared decision-making in clinical practice.

A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma

Refractory/relapsed B cell lymphoma patients who received the available anti-CD19 chimeric antigen receptor (CAR) T cells may still experience a short duration of remission. Here in this study, we evaluated the safety and efficacy of a novel dominant-negative programmed cell death-1 (PD-1) armored anti-CD19 CAR T cells. A total of 9 patients (including 4 diffuse large B cell lymphomas, DLBCL, 2 transformed follicular lymphomas, TFL, and 3 follicular lymphomas, FL) received the novel CAR T cells infusion at a dose of more than 1 × 106/kg. Grade ≥ 3 cytokine release syndrome (CRS) and neurotoxicity were observed in 11.1% (n = 1/9) and 11.1% (n = 1/9) of patients, respectively. The overall response rate (ORR) was 77.8% (n = 7/9) and complete response (CR) rate was 55.6% (n = 5/9). Two patients have ongoing CR (all at 20+ months). CAR T cells expanded after infusion and continued to be detectable at 12+ months in patients with ongoing CR. This novel CD19-CAR T cell was safe and effective with durable remissions in patients with refractory/relapsed B cell lymphoma.

CPX351 Has Short Remission Duration but Is an Effective Bridge to Allogeneic Transplant in High Risk AML: Results from Canadian Real-World Multi-Centre Study

Background and objectives: CPX-351 is a liposomal formulation of daunorubicin and cytarabine in a fixed synergistic ratio of 5:1. It has been approved by both the FDA and EMA for use in high risk AML including therapy related AML (t-AML) and AML with myelodysplastic related change (AML-MRC). When compared with '3+7', CPX-351 resulted in superior OS (9.56 vs 5.96 months) and overall response rate (47.7% v 33.3%; P = .016; Lancet JCO 2018). However, this is little data of CPX-351 in a real world setting. The primary objective of our multi-centre study was to assess outcomes and associated toxicities of CPX-351 in these high risk AML patients. Methods: Patients aged 18 and over who were treated with CPX-351 and who met the WHO criteria for t-AML and AML-MRC were included in the study. Retrospective data was collected from 6 centres throughout Canada. Targeted sequencing was performed on DNA samples using the TruSight Myeloid Sequencing Panel isolated from peripheral blood or bone marrow samples at diagnosis. Overall survival (OS) and progression free survival (PFS) rates were calculated using the Kaplan-Meier method. Results: Fifty patients treated with CPX-351 were identified from six centres. Baseline characteristics are seen in Table 1. Cytogenetics was available in 45 (90%) patients and an abnormal karyotype was seen in 30 (60%) patients. Monosomal (33%) and complex (28%) karyotype were the most common chromosomal abnormalities seen. Targeted sequencing was performed on 64% patients (32/50) and the average number of mutations was 2(0-7). RUNX1 was the most commonly mutated gene found in 22% (7/32), followed by SRSF2 in 19% (6/32) with ASXL1 and NRAS both at 16% (5/32). Other commonly mutated genes were NPM1, IDH2, DNMT3a and TP53 all occurred at a frequency of 12% (4/32). Of the 10 patients (20%) that were FLT3 mutated (80% ITD and 20% TKD), 5 patients received the FLT3 inhibitor midostaurin in combination with CPX-351. Assessing treatment responses, 50% (25/50) of patients achieved a complete remission (CR) or a complete remission with incomplete recovery (CRi). Median neutrophil recovery (≥500/μl) was 32 days (range 18-68) and median platelet recovery (≥50 000/μl) was 34 days (range 19-70). Proven or probable fungal infection was seen in 10 (20%) patients. 30 day mortality was 4% (2/50) and 60-day mortality was 10% (5/50). The median CR duration was short at 7.17 months. Of the 25 patients who did not achieve a CR, 6 (24%) had prior azacitidine use for MDS suggesting CPX-351 may not have activity in this group of patients. Median follow up was 7.43 months (range 0.2 to 18 months). OS was 44% at 12 months (0.28-0.58 95% CI) and 29% at 18 months (Fig 1; 0.13-0.46 95% CI). PFS was 28% at 12 months (0.15-0.43 95% CI) and 18% at 18 months (0.06-0.39 95% CI). There were no differences in OS when stratified by ELN risk (p=0.25), adverse risk cytogenetics (p=0.1485), or poor risk mutations such as FLT3-ITD (p=0.29), RUNX1 (p=0.123) or ASXL1 (p=0.06). This is consistent with previous studies, which suggest that CPX-351 overcomes the poor prognosis associated with these mutations. 18 (36%) patients received an allogeneic stem cell transplant (ASCT) in CR1. Patients who received a allogeneic transplant had significant improvement of OS of 62% at 18 months compared to those who did not receive a transplant of 14.5% at 18 months (Fig 2; p=0.0008). Conclusion Our study reveals that CPX-351 produces high remission rates in patients with AML with a similar efficacy and toxicity profile seen in the Phase 3 trial data (Lancet JCO 2018). However, response rates are short and therefore CPX-351 is most effective when used as a bridge for allogeneic stem cell transplantation in this high risk population. Disclosures Assouline: AbbVie: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding. Brandwein:Celgene: Honoraria; Astellas: Honoraria; Taiho: Honoraria; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Gupta:Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer: Consultancy; Takeda: Research Funding; Novartis: Honoraria. McNamara:Novartis: Honoraria. Sanford:Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Schimmer:Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria.

Outcomes of FLT3-Mutated Acute Myeloid Leukemia Patients: A Single Center Real-World Experience

Background:Internal tandem duplications (ITDs) within the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common driver mutation and confers a poor prognosis in patients (pts) with acute myeloid leukemia (AML) due to proliferative presentation, short remission durations and early relapse. The addition of midostaurin to induction therapy has become standard therapy in newly diagnosedFLT3-mutated (FLT3-mu) AML. Next-generation FLT3 inhibitors (FLT3i) as gilteritinib and quizartinib are more specific, more potent, and may have fewer toxicities associated with off-target therapies but are only available in clinical trials or for salvage therapy. Real-world experience in smaller academic institutions is scanty. Methods:We reviewedFLT3-ITD mu AML pts at our institution from October 2016-December 2019. FLT3i were given as a single agent or in combination with cytotoxic chemotherapy (CCT) or low intensity therapy (LIT) (hypomethylating agents). AllFLT3-ITD DNA was subjected to PCR amplification using primers targeting the juxtamembrane domain of FLT3, and products were analyzed by capillary electrophoresis. We analyzed the characteristics of these pts, responses to therapy, and outcomes. Results:Sixteen pts with newly diagnosedFLT3-ITD mu AML were identified. The median age was 47 years [range, 17-76 years] and the median follow-up was 9.3 months [range, 1.2-29.5 months]. The median time from AML diagnoses to FLT3 detection was 4 days [range, 3-5 days]. Patient characteristics are shown in Table 1. The most common co-occurring mutations wereNPM1(44%) andNRAS(31%); 2 pts (12%) had both mutations. Five pts (31%) received CCT and 11 pts (69%) received CCT+FLT3i. The most frequently used FLT3i was midostaurin 25 mg twice daily on days 8 through 21 (14 days) (10 pts, 63% of all pts); 1 pt received sorafenib (6% of all pts). The complete remission rate (CR) and the overall response rate (ORR) (CR+CR with incomplete hematologic recovery [CRi]) were 31% and 88%, respectively. The two pts who did not achieve a remission were older than 65 years. Among the pts who received CCT+FLT3i, CR and OOR were 50% and 100%, respectively. The median number of cycles to remission was 1 [range, 1-2 cycles], and the median number of consolidation cycles was 0 [range, 0-3 cycles]. Overall, the median duration of response in frontlineFLT3-ITD pts who did not receive allogeneic hematopoietic stem cell transplantation (Allo-HSCT) was 5 months [range, 1-9 months] (all of them received CCT+FLT3i). There was no statistically significant difference in response in pts with NPM1 mutation compared with pts with NRAS mutation (P=0.7), or with no additional mutations. Seven pts (44%) received an Allo-HSCT (6 after CCT+FT3i, and 1 after CCT alone): 2 (28%) from matched unrelated donor, 1 (14%) from a haploidentical transplant, 1 (14%) from dual cord transplant, and the remaining (44%) from matched related donors. Two patients relapsed after Allo-HSCT (28%). Both of these patients had received FLT3i before Allo-HSCT; one of the two relapsed pts received ivosidenib and azacitidine (IDH1 mutation) after Allo-HSCT, achieved remission then received the 2nd Allo-HSCT with subsequent remission. Two pts (29%) received maintenance therapy after Allo-HSCT, one with midostaurin, and the other with azacitidine + gilteritinib; both pts are still on remission (24 and 6 months after CR, respectively). All 7FLT3-ITD pts who did not receive Allo-HSCT relapsed. Gilteritinib was used as a single agent (n=3) or in combination with LIT (n=1) in these pts after relapse. CR rate was 25% and CRI 50%; one pt relapsed (33%). All pts who responded are still receiving gilteritinib. Conclusion:Combination of FLT3i based therapy with CCT is effective therapy inFLT3-ITD frontline pts in real-world setting. Duration of response is short in the absence of Allo-HSCT. Disclosures Cortes: Arog:Research Funding;Pfizer:Consultancy, Research Funding;Amphivena Therapeutics:Research Funding;Daiichi Sankyo:Consultancy, Research Funding;Astellas:Research Funding;Telios:Research Funding;Novartis:Consultancy, Research Funding;BioPath Holdings:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Merus:Research Funding;Bristol-Myers Squibb:Research Funding;Takeda:Consultancy, Research Funding;Sun Pharma:Research Funding;BiolineRx:Consultancy, Research Funding;Immunogen:Research Funding;Jazz Pharmaceuticals:Consultancy, Research Funding.

AML-211: Active Galectin 3/CD74 Axis is Associated with Poor Survival Outcome in AML

Context Galectin 3 (LGALS3) participates in diverse survival pathways that support many pro-tumor molecules, especially RAS. However, the role of LGALS3 in acute myeloid leukemia (AML) is not clear. Objective We previously found suppression of LGALS3 in AML cell lines sensitized cells to chemotherapy drugs. Here, we examine protein expression of LGALS3 in 511 AML patients and identify an active LGALS3 protein network. We used reversephase protein analysis for the study. Patients Peripheral blood and bone marrow specimens were collected from 511 patients with newly diagnosed AML. Samples were acquired in accordance with the regulations and protocols (Lab 01-473) approved by the IRB of MDACC. Results LGALS3 was significantly elevated in AML blast cells compared to normal CD34+ counterpart cells and highest in monocytic AML patients. Pearson correlation of LGALS3 with other proteins identified a distinct set of 23 proteins positively and 13 proteins negatively correlated with LGALS3 expression levels. LGALS3 positively correlated with the anti-apoptotic BCL2 family member MCL-1. RPPA also identified novel positive association of LGALS3 with CD74. Pearson correlation with the other proteins analyzed identified 23 proteins, including LGALS3, that were positively correlated with CD74, and 8 proteins that were negatively associated with CD74. The protein associations of LGALS3 and CD74 were used to assemble protein clusters that were used for analysis of patient survival. LGALS3 and CD74 were collectively analyzed as part of a group of T-cell regulating proteins analyzed on this array. Within that group, 4 different expression patterns (clusters) were defined by hierarchical clustering with LGALS3 being active in 2 of them. The protein cluster identifying active LGALS3 was prognostic for shorter remission duration. AML patients who exhibited both LGALS3 and CD74 active clusters exhibited very poor survival characteristics. For AML patients with both LGALS3 and CD74 active protein cluster, median overall survival was only 24.3 weeks, median remission duration was 17.8 weeks, and no patient survived beyond one year. Conclusions These data suggest that LGALS3 supports AML cell survival via diverse pathways, including positive regulation of MCL-1, and support of a CD74 protein network that identifies a new at-risk AML population.

IL-10 enhances T cell survival and is associated with faster relapse in patients with inactive ulcerative colitis

Ulcerative colitis (UC) is characterized by a relapsing and remitting pattern. The remission phase may last weeks to years. It remains unclear what specific factors can cause the disease to exist the remission phase and enter an activated state. IL-10 is a cytokine best known for its anti-inflammatory roles. We hypothesized that IL-10 might have a role in suppressing disease flares in UC remission patients. Unexpectedly, we found that UC remission patients with higher serum IL-10 levels presented faster progression to disease flares. Subsequently, we found that exogenous IL-10 could significantly reduce the level of CD4 and CD8 T cell proliferation. On the other hand, IL-10 significantly elevated the viability of activated CD4 and CD8 T cells. Interestingly, it appeared that the IL-10-mediated pro-survival effects were more pronounced in CD8 T cells than in CD4 T cells and were able to promote the survival of activated T cells when administered prior to cell activation. To examine whether IL-10 in the serum of UC patients was able to enhance T cell survival, we separated UC remission patients into Low, Intermediate, and High groups based on the serum IL-10 level. The native serum from High IL-10 patients, but not the native serum from Low IL-10 patients, could significantly increase the viability of activated T cells. In conclusion, we demonstrated that high IL-10 level at the remission phase was associated with shorter duration of remission, possibly due to IL-10-mediated effects on T cell survival.