ALBERT

Description: Introduction: Treatment of acute myeloid leukemia (AML) has remained largely unchanged for several decades despite the emergence of new agents. Long-term survival for patients aged 〉60 years is less than 10% (median survival 10.5 months). Targeting the proteasome in treating AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). Preclinical studies in leukemia cell lines revealed synergistic cytotoxicity when bortezomib, a proteasome inhibitor, was combined with the standard agents daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although neurotoxicity was noted among treated patients, 12% grade 3 sensory (Attar, …, Amrein, et al. Clin Cancer Res 2008, Attar, … Amrein, J Clin Oncol 2012). The next generation proteasome inhibitor, ixazomib, which is less frequently associated with neurotoxicity, was therefore selected for combination with conventional chemotherapy in this phase I trial. The primary objective was to determine the maximum tolerated dose (MTD) in the combination, initially in induction, and then in combination with consolidation in a subsequent portion of the overall study. We report here the results of the induction portion of the study, which has been completed. Methods: Adults 〉60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. The induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3; ixazomib orally at the cohort dose, Days 2, 5, 9, and 12 A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction and subsequently in consolidation. The dose of 3.0 mg/day was the maximum planned for this study. The determined MTD of ixazomib in the first portion of the trial would be used during induction in the second portion, which seeks to test dose escalation of ixazomib during consolidation. Secondary objectives included rate of complete remission and disease-free survival. Results: Fourteen patients have been analyzed for toxicity and activity during the induction portion of the study. There were 4 (28%) patients with either secondary AML or treatment related AML, 9 (64%) were male, and the median age was 67 years (range 62-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 3 thrombocytopenia) indicated at the highest dose level. There has been no neurotoxicity with ixazomib to date. Among the 14 patients, there have been 10 complete remissions (CR's) and 1 CRi for a remission rate of 79%. Conclusions: The highest dose level planned for this portion of the trial, 3.0 mg of ixazomib, was reached with 1 DLT and is the recommended dose for induction in the next portion of this study, which will seek to determine a safe ixazomib dose in combination with conventional consolidation therapy. That no neurotoxicity was encountered was reassuring, and the remission rate in this older adult population is favorable. Table. Table. Disclosures Amrein: Takeda: Research Funding. Attar:Agios: Employment, Equity Ownership. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Description: Introduction: AML and MDS are advanced myeloid malignancies more common among older adults and generally associated with poor outcomes. Allogeneic hematopoietic cell transplantation (HCT) may cure a proportion of affected patients, but disease relapse remains common and is associated with dismal survival. High doses of lenalidomide may modulate graft-vs-leukemia (GvL) effects, and have shown encouraging responses for relapsed AML. Bortezomib may also augment GvL and potentiate the effect of other chemotherapeutics. We conducted a phase I study of escalating doses of bortezomib added to high-dose lenalidomide in patients with AML and MDS, who had relapsed following HCT. Methods: We enrolled patients aged ≥ 18 years, with AML or MDS, relapsing after HCT in a '3+3' dose-escalation study. Patients with grade ≥3 GVHD, or chronic GVHD requiring 〉20mg/d of prednisone were excluded. Patients otherwise had to be off immunosuppressive therapy for 2 weeks. Lenalidomide 50mg/d was administered on days 1-21 of 28-day induction cycles. On days 2, 5, 9, and 12, subcutaneous bortezomib was administered at escalating dose levels: 0.7mg/m2, 1.0mg/m2, and 1.3mg/m2. Patients could receive up to two cycles of induction. After reaching the maximally tolerated dose (MTD), 9 patients were enrolled at the recommended phase II dose (RP2D) of bortezomib 1.3mg/m2. Dose limiting toxicities (DLTs) included G4 peripheral neuropathy, G3+ aGVHD, moderate/severe cGVHD, non-resolving G3/4 non-hematologic toxicities, and the inability to receive at least 50% of both drugs during induction. The DLT period spanned up to 2 induction cycles, but could be 1 cycle if a patient entered complete remission (CR) or complete remission with incomplete count recovery (CRi) after the first cycle. Response to induction was the best response after up to two cycles of induction and was assessed in those patients treated at the MTD/RP2D. Donor lymphocyte infusions (DLI) were allowed after induction per the treating physician. Results: A total of 21 patients were enrolled, with a median age of 66 years at study entry (range 23-74). The patients were predominately male (62%) and white (86%), while 2 patients (10%) identified as of Hispanic ethnicity. The majority had AML (19/21), with 10 of the AML patients having disease arising from prior CMML (1), MDS (7), or MPN (2). Three patients had del(5q); 2 patients had loss of 17p and 2 patients had complex cytogenetics. Three patients were enrolled at bortezomib dose levels of 0.7mg/m2 and 1.0mg/m2; at dose level 3, one patient experienced a DLT for receiving 〈 50% of doses and the cohort was expanded to 6 total patients. An additional 9 expansion patients were then treated at this dose level for a total of 15 patients treated with lenalidomide 50mg and bortezomib 1.3mg/m2. During dose expansion, grade 4 toxicities attributed to study drug included grade 4 neutropenia (n=5), thrombocytopenia (n=3), and febrile neutropenia (n=1), consistent with what was seen during dose escalation. Across all cohorts (n=21), 4 patients achieved CR/CRi. Of the 15 patients treated at the MTD/RP2D, 4 patients had progressive disease after the first induction cycle, and 2 patients stopped therapy during induction cycle 2. A total of 9 patients completed both induction cycles. Of the 15 patients treated at the RP2D, 3 achieved a CR/CRi (20%, 90%CI 5.7-44.0%). Another 2 patients had stable disease. One additional patient achieved a CR in the first dose cohort (Figure 1). Chimerism during treatment tracked with disease response; one patient with persistent low chimerism achieved CRi and received DLI as well (patient 3, who also harbored a TP53 mutation). A total of 3/13 patients tested harbored TP53 mutations; 2/3 achieved CRi while the third (patient 2) came off treatment during induction. Conclusions: Lenalidomide may be safely combined with bortezomib in patients with AML and MDS relapsing after HCT, with an encouraging rate of complete remission (20%) in this poor risk population. Overall toxicities with this regimen were manageable, and largely related to cytopenias. Of note, 2 of the 4 CR/CRi responses on the trial were in patients with TP53-mutated disease, suggesting that this regimen should be further evaluated in this high-risk population, and combination with donor lymphocyte infusion may also merit investigation in larger studies. Figure 1. Figure 1. Disclosures Brunner: Takeda: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding. Rosenblatt:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding. Amrein:Takeda: Research Funding. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding.

Description: Background Recurrent mutations in the spliceosome complex are seen in myeloid malignancies, including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelodysplastic syndromes (MDS). Mutations are detected most frequently in SF3B1, SRSF2, or U2AF1, and are largely mutually exclusive. Recently, a novel SF3B1 modulator, H3B-8800, entered phase-I clinical trials. While the impact of spliceosome mutations at diagnosis and at the time of transplant has been described, there is limited data about the outcomes of patients with splicing factor-mutated disease after the initiation of standard frontline chemotherapies: induction chemotherapy (IC) or hypomethylating agents (HMA). Methods Patients with MDS, CMML, or AML with a spliceosome mutation and treated with chemotherapy were identified. Disease risk was assessed using standard criteria (IPSS-R for MDS, ELN for AML, and CPSS for CMML). Overall survival (OS) was defined as the time from start of treatment until death and censored at last known alive. Event free survival (EFS) was defined as the time from start of treatment until relapse, new therapy, or death. We identified the first therapy for newly diagnosed disease (induction chemotherapy, HMA, bone marrow transplant, or other), and grouped remissions as CR (complete remission) or CRi (complete remission with incomplete hematologic recovery). Outcomes were assessed by disease type, mutation, and initial therapy. EFS and OS were estimated by the method of Kaplan and Meier. Results We identified 88 patients diagnosed with AML, CMML, or MDS harboring a mutation in SF3B1 (n=24), SRSF2 (n=43), or U2AF1 (n=21). The median follow-up of the cohort was 637 days. The median age at diagnosis was 69.5 years (33-90), and there was no difference according to mutation (p=0.907). A diagnosis of AML was slightly more common among patients with SRSF2 mutations at the time of treatment, but this was not statistically significant (27/43, p=0.07). Patients with SF3B1 mutations were less likely to have co-mutated ASXL1 (12%, vs 42% with U2AF1 and 40% with SRSF2, p=0.0384). SRSF2 disease more often had co-mutated IDH2 (26%, vs 0% with U2AF1 and 4% with SF3B1, p=0.01). Other co-mutations did not vary significantly between U2AF1, SF3B1, or SRSF2-mutated disease (Figure 1). Patients who had a mutation in SF3B1 had a longer duration from diagnosis to first therapy (median 65 days, range 0-1159) than those with U2AF1 (median 39d) or SRSF2 (median 9d) mutations (p=0.045). A total of 31 patients received induction chemotherapy, while 50 received HMA as initial therapy; 3 patients were transplanted, and 5 received other chemotherapies (e.g. enasidenib). The remission rate for patients treated with induction was 55%, and there was no difference in rate of remission (CR+CRi) according to mutation type (U2AF1 50%, SF3B1 60%, SRSF2 53%, p=1.00). Patients treated with HMA had a remission rate of 22%, with a trend toward lower remission rates in SF3B1-mutated disease (0/11, vs. U2AF1 20% and SRSF2 33%, p=0.08). We performed a multivariate analysis for overall survival incorporating mutation type, initial treatment, disease risk group, age at the time of treatment, and disease (MDS, AML, or CMML). Compared to MDS, there was no difference in OS according to whether patients had splicing-factor mutated AML (p=0.45) or CMML (p=0.61) (Figure 2). Interestingly, although CR rates differed between all patients receiving induction or HMA, there was no difference in OS between these same groups (Figure 3, p=0.803). Conclusion In this study, there was no difference in response to frontline treatment for SF3B1-mutated myeloid malignancies compared to U2AF1- or SRSF2-mutated disease. Interestingly, there was no difference in survival according to whether patients had splicing-factor mutated AML, MDS, or CMML at the time of treatment; moreover, there was no difference in survival with induction compared to HMA therapy. Together, these point to a rationale to include AML, MDS, and CMML patients together on trials targeting these mutations, and the general need to improve on the poor outcomes with standard induction or HMA therapy. Disclosures Amrein: Takeda: Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Jazz: Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Brunner:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding.

Description: Introduction: Myelodysplastic syndromes (MDS) are neoplasms characterized by cytopenias, high risk of leukemic progression, and poor overall survival. Chemotherapy for MDS is not curative, and no new drugs have been approved for the treatment of MDS in over a decade. Clinical trials should be considered at any time during the management of patients with MDS, but enrollment criteria may be barriers that limit accrual. In this study, we extracted MDS clinical trial data from clinicaltrials.gov, and compared study indications and characteristics, including inclusion and exclusion criteria. Methods: We identified MDS clinical trials via clinicaltrials.gov (accessed: April 16, 2018). Studies were included if they allowed "MDS," "Myelodysplastic syndromes," "Preleukemia," and/or "Myelodysplasia," based on the pre-defined 'related terms' criteria in the database. We included interventional studies open in the United States that were listed as recruiting or not yet recruiting, for adults (age 18-64) and older adults (age 65+). We excluded studies that were observational in nature, involved a transplant-based intervention, or did not use a pharmacological intervention. We coded inclusion and exclusion criteria based on those provided by study authors in the database. Results: 83 interventional clinical trials enrolling patients with MDS were identified. Studies started enrollment between 4/1/2013 and 3/27/2018, and anticipated reaching the primary objective between 5/1/2017 and 6/1/2025. The median planned study duration was 38 mo (range 10-95). In total, studies sought to enroll 8866 patients over 273 study-years; the median study enrollment estimate was 1.7 patients/month, or across all trials 247 patients/month. Clinical trials could be exclusive to MDS patients (n=28), include MDS patients and other myeloid malignancies e.g. AML (n=44), or include MDS patients and other cancers including solid tumors (n=11). For clinical trials exclusive to MDS, the total enrollment goal was 1966 patients over 96 study-years, with a median rate of 1.4 patients/month (range 0.3-13.2) or total of 63 patients/month across all studies. 33 trials were phase 1 studies, 17 were phase 1/2, 26 were phase II, 1 trial was phase 2/3, and 6 were phase III studies. The primary endpoint was typically MTD (n=50) or ORR (n=22), while 5 studies had an OS endpoint. Most trials specified "higher risk" MDS (n=44); 8 specified "lower risk" MDS and 31 allowed all MDS risk or did not specify risk (Figure 1). Lower risk MDS studies were all exclusive to MDS patients. Inclusion criteria related to MDS risk varied significantly according to whether a study was MDS-specific or not (p=0.021): 82% of MDS-specific trials had risk exclusions, compared to 72% of myeloid trials, and only 36% of trials open across cancers. Of 52 trials specifying MDS risk, 20 included IPSS criteria, 24 included IPSS-R criteria, and 27 had blast count criteria. Lower risk MDS criteria was variably defined as IPSS low or INT-1 disease (n=3), IPSS-R very low or low risk (n=1), IPSS-R VL, L, or intermediate risk (n=4), or blast counts 〈 5% (n=1), 〈 10% (n=2), or 5% (n=12) or 〉10% blasts (n=12). Most studies specified exclusion of CNS disease, even though CNS involvement is exceptionally rare in MDS. 43 trials excluded concurrent cardiovascular disease; most often (n=18) requiring 6mo since a cardiovascular event. 46 trials had language excluding concurrent cancers, including 4 that did not allow any prior cancer, and 17 required ³24mo disease free. Exclusions for prior cancers did not vary according to primary outcome (MTD or PK, vs ORR/OS, p=0.16). 20 of 56 studies with MTD or early outcomes (e.g. PK) required cancer-free intervals of ³1y, while 7 allowed concurrent cancers if not on active therapy. Discussion: Currently enrolling MDS clinical trials show significant variation in their inclusion and exclusion criteria. Heterogeneous definitions of basic entry criteria, such as the definition of higher- and lower-risk MDS, may cause barriers to enrollment. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Garcia:Celgene: Consultancy.

Description: Background: Core binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22) or inv(16)(p13.1q22)/t(16;16)(p13.1;q22) and is associated with a favorable outcome, particularly if treated with repetitive cycles of high-dose cytarabine as post-remission therapy. Long-time 10-year overall survival (OS) rate was reported of 58% in FLT3-ITD negative patients (pts; Allen et al. Leukemia 2013). Nevertheless, 30-40% CBF-AML pts experience relapse. FLT3-ITD mutations occur in roughly 5-10% of adult CBF-AML. However, their prognostic relevance is still controversial. Aims: To characterize CBF-AML with FLT3-ITD and compare outcomes according to their genetic background. Methods: We retrospectively studied 65 AML pts with CBF-AML and FLT3-ITD (median age at diagnosis, 54 years; range, 22-81 years) diagnosed between 1996 and 2018 within seven study groups/institutions of the US and Europe. Results: Thirty-two (49%) of the 65 pts harbored t(8;21). Median white blood cell and platelet counts at diagnosis of patients with t(8;21) and inv(16) were 18.3/nl (range, 1.8-202/nl) and 31/nl (range, 7-372/nl), respectively. AML diagnoses were de novo in 61 (94%) and therapy-related in 4 (6%) of the pts. Thirty (46%) pts were female. Cytogenetic analysis revealed additional abnormalities (abn) in 38 (58%) pts, most frequently loss of X or Y (n=13; n=12 associated with t(8;21)), complex karyotype (≥3 abn; n=12; n=7 occurring in t(8;21)), trisomy 22 (n=7, all associated with inv(16)) or trisomy 8 (overall n=6, n=5 occurring in inv(16)). Four pts were positive for both mutations, FLT3-ITD as well as FLT3-TKD. Median ITD allelic ratio were 0.44 (range, 0.003-50) and median ITD size 60 bp (range, 3-120 bp). Three older pts (median age, 75.5 years) were treated with either azacitidine + sorafenib, azacitidine + venetoclax or with etoposide + tipifarnib. All three patients receiving non-intensive therapy died within one year and were excluded from further analysis. Complete remission (CR) after anthracycline-based induction therapy was achieved in 98% (n=61/62) of patients fit for intensive treatment including two pts treated with 7+3 ± midostaurin within the RATIFY trial. One patient died during induction. Fifteen (24%) pts underwent allogeneic hematopoietic cell transplantation. Of those, 10 pts were transplanted in 1st and 5 pts in 2nd CR. Median follow-up for the entire cohort was 4.43 years (95%-CI, 3.35-8.97 years). Median and 4-year relapse-free survival (RFS) rates were 3.41 years (95%-CI, 1.26 years - not reached) and 44.9% (95%-CI, 32.9-61.4%). Median and 4-year overall survival rates (OS) were 4.48 years (95%-CI, 2.26 years - not reached) and 51.8% (95%-CI, 39.6.2-67.9%). Neither type of CBF-AML (p=0.60), nor additional chromosomal abn (p=0.80), nor presence of a complex karyotype (p=0.50) had a prognostic impact on OS. Higher age (≥60 years) was an in trend negative prognostic factor on RFS and OS (p=0.07, each). High allelic ratio (≥0.5) had no impact on RFS (p=0.3), but in trend on OS (p=0.10). Conclusions: Despite a high remission rate pts with FLT3-ITD had an inferior outcome as compared to previously published data on CBF-AML without FLT3-ITD. Thus, CBF-AML with FLT3-ITD should not be classified within the low-risk category. CBF pts with FLT3-ITD warrants further study and should be included in FLT3-inhibitor trials. Disclosures Brunner: Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Novak:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel,Accommodations; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel,Accommodations; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stoelzel:Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding; JAZZ Pharmaceuticals: Consultancy. Thiede:Daiichi Sankyo: Honoraria; AgenDix GmbH: Employment, Equity Ownership; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Diaceutics: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Levis:Agios: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo Inc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Description: Background: Induction therapy for newly diagnosed AML pts can be classified as intensive or non-intensive. Non-intensive therapies are increasingly used in pts aged 〉65 years due to concerns about their ability to tolerate intensive chemotherapy. However, the relative benefit-risk ratios associated with intensive versus non-intensive therapies in AML pts is likely affected by age, comorbidities, and disease-related characteristics, such as cytogenetic and molecular features. Here, we examine these relationships. Methods: Data from 1295 newly diagnosed AML patients, given induction therapy between 2008 and 2012 at six participating academic centers, were retrospectively collected. We used two previously validated models to define distinct prognostic groups, and within each, compared 2-year mortality rates according to whether pts received intensive or non-intensive therapy. Non-intensive therapy principally included azacitidine, decitabine, or low-dose cytarabine, while intensive therapies primarily included the standard 7+3 regimen or "high-dose" cytarabine combinations with anthracyclines or purine analogs. The first model (Blood 2015; 126:532) was a composite of the prognostic effects of age, comorbidity index, and cytogenetic/genetics risks per European Leukemia Net (ELN) classification. The second (JCO 2011; 29(33): 4417) was a treatment related mortality (TRM) index including 8 pt- and AML-specific risk factors. Results: Age distribution of the pts were ≤49 (23%), 50-59 (20%), 60-69 (33%), and ≥70 (24%) years old. Median follow-up for currently alive pts was 41 (range, 0-99) months. Cytogenetic-molecular risks per ELN classification were favorable (18%), intermediate I and II (39%), or unfavorable (43%). Induction treatments were intensive in 77% and non-intensive in 23% of pts. The proportion of patients receiving non-intensive therapy increased with increasing age (Table 1). Almost all pts (99%) with the lowest composite scores (1-3) received intensive therapies and were therefore omitted from the comparisons with either model. Per the composite model grouping, pts had better survival rates if they received intensive therapy, although the differences were not statistically significant in pts with composite scores ≥10 (Table 2). Pts with TRM scores of 0-4 and ≥5, with a score of 5 corresponding to the median score, statistically significantly benefitted from intensive therapies (Table 2). Among all pts aged 70-79 years old (n=242), 41% received intensive therapy, while 59% received non-intensive therapy. The intensively treated pts in this age range had statistically significantly higher survival rates at 2 years (26% versus 13%, HR: 0.73, 95% CI: 0.54-0.98, P=0.04, Figure). Conclusion: After accounting for underlying prognosis using 2 validated models, we found pts with newly diagnosed AML generally had better survival if they received intensive therapy. This survival benefit was not statistically proven for pts with the highest composite scores (≥10). Early mortality was not increased in older pts given intensive versus non-intensive therapy (Figure), likely due to improvements in supportive care which allowed the greater anti AML effect of intensive therapy to become manifest over time. While we cannot exclude the effects of selection bias, absent a randomized trial our results suggest intensive therapy could be considered for most pts, up to the age of 80 years, regardless of their comorbidity burden. Although results seem better with intensive therapy, less than 50% of patients with composite scores 〉3 given such therapies were predicted to be alive at 2 years, suggesting the need for randomized clinical trials between novel intensive and non-intensive therapies to achieve better survival. Table 1 Regimen intensity per pt age groups Table 1. Regimen intensity per pt age groups Table 2 Comparisons of hazard ratios (HR) and 2-year rates of survival between intensive and non-intensive initial therapies Table 2. Comparisons of hazard ratios (HR) and 2-year rates of survival between intensive and non-intensive initial therapies Figure. Intensive versus non-intensive therapies among pts aged 70-79 years with AML Figure. Intensive versus non-intensive therapies among pts aged 70-79 years with AML Disclosures Fathi: Bexalata: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Research Funding. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Introduction: Pts with AML often present with hyperleukocytosis, defined with a white blood cell count (WBC) of 〉50 or 〉100 × 109/L. Hyperleukocytosis is associated with higher rates of complications and death especially when associated with clinical leukostasis. There are no clear guidelines outlining the best cytoreductive strategy and the use of leukapheresis is based on institutional practice. Limited data is available regarding characteristics of AML pts with hyperleukocytosis, treatment patterns, short and long-term clinical outcomes. Methods: Data were collected retrospectively from 12 centers in the United States and Europe. Eligible pts had newly diagnosed AML, WBC 〉 50 × 109/L, and had received intensive chemotherapy (IC). Pts with hyperleukocytosis who did not receive IC are described in a separate abstract. Kaplan-Meier methods estimated overall survival (OS) from time of presentation till death or end of follow-up. Clinical evidence of leukostasis was defined as new onset hypoxia, chest pain, headache, focal neurological symptoms, priapism, intestinal ischemia and acute renal failure attributed to hyperleukocytosis by the primary provider of the pt. Results: Among 1050 pts with AML and hyperleukocytosis whose data were collected, 787 were reported to have received intensive chemotherapy and were included in this analysis. The median age was 55 years (range [R], 15-86), and 51% were male (Table 1). Median WBC at presentation was 109 × 109/L (R, 47-561) and 57% had WBC 〉 100 × 109/L. Median hemoglobin was 9.2 g/dL (R, 3.6-126) and median platelet count was 31 x 109/L (R, 3-1268). A good, intermediate and poor risk karyotype were present in 31%, 51% and 18% of pts, respectively. Clinical leukostasis, tumor lysis syndrome (TLS) and disseminated intravascular coagulation (DIC) were present in 27%, 28% and 18% of pts at time of presentation, respectively (Table 1). Organs affected by leukostasis were the lung, CNS, retina, heart, kidney and GI tract in 44%, 36%, 6%, 6%, 5% and 4%, respectively. Leukapheresis was administered in 117 pts (15%) (Figure 1). Four centers did not use leukapheresis. 31% of pts with clinical leukostasis underwent leukapheresis and 10% of pts without clinical leukostasis received leukapheresis (p

Description: Abstract 3063 Background: Dying mammalian cells release danger signals that stimulate antigen presenting cells (APCs) to promote an immune response. It has been demonstrated that uric acid released from injured cells alerts the immune system to cell death, acts as a danger signal to stimulate cytotoxic T cell responses and that elimination of uric acid in mouse models reduces this immune response (Ref: Nature 2003; 425:516–521). Rasburicase is a recombinant urate-oxidase enzyme that catalyzes oxidation of uric acid into an inactive soluble metabolite and is currently used to prevent tumor lysis syndrome. We hypothesized that rasburicase administered during myeloablative conditioning prior to allogeneic HCT will reduce the serum levels of uric acid and thereby may decrease the incidence of acute GVHD via inhibition of danger signal-mediated activation of host APCs. Methods: In this pilot trial at the Massachusetts General Hospital, between 2007 and 2010, 23 patients (median age: 41 years, range: 19–59) with hematologic malignancies in complete remission (AML, n=13; ALL, n=8; MDS, n=1; MPD, n=1;) received myeloablative preparative regimens (Bu/Cy, n=14; Cy/TBI, n=7; Bu/Flu, n=2) followed by GCSF-mobilized HLA-matched (MRD, n=18; MUD, n=5) peripheral blood HCT. GVHD prophylaxis consisted of cyclosporine or tacrolimus and methotrexate for MRD transplants and tacrolimus/MTX and anti-thymocyte globulin (Thymoglobulin) for MUD transplants. Rasburicase was administered beginning on the first day of conditioning therapy, at a dose of 0.20 mg/kg intravenously daily for 5 consecutive days. Outcomes were compared to 44 controls at this institution from the same time period identified using retrospective chart review. Patients in the control group received allopurinol during the conditioning as a part of the institutional guidelines. Associations between categorical variables were evaluated using Fisher's exact test. Overall and disease-free survival (OS and DFS) were estimated using the method of Kaplan and Meier. Results: The mean serum uric acid concentration was 0.2 mg/dl (range, 0–1.7) on 6 consecutive days, beginning the day after the first dose of rasburicase. Engraftment was achieved in all patients, and the median times to neutrophil (at least 0.5 × 109/ul) and platelet engraftment (at least 20 × 109/ul) were 18 days (range, 7–26 × 109/ul) and 16 days (range, 8–57 × 109/ul), respectively. The only serious toxicity caused by rasburicase was intravascular hemolysis in one patient who was found to have G6PD deficiency; this patient received only 2 doses of rasburicase. Greater than or equal to grade II-IV acute GVHD occurred in 5 out of 23 patients (22%), 4/18 in MRD and 1/5 in MUD recipients: grade II, n=1; grade III, n=2; and grade IV, n=2. When compared with 44 patients (AML 28, ALL 5, MDS 4, NHL 5, MPD 1, CML 1), comparable to rasburicase-treated patients with respect to age, gender, disease status, donor sources, conditioning and GVHD prophylaxis, who received myeloablative HCT (MRD, n=32; MUD, n=12) at the MGH during the same time period as the patients in the rasburicase-treated group, there was significantly less grade II or higher aGVHD in the rasburicase group (rasburicase: 22% vs. institutional control: 48% [total 21/44, 13/32 in MRD and 8/12 MUD recipients], Fisher's exact test, p=0.033). There was no significant difference in the incidence and severity of chronic GVHD between the two groups (rasburicase, 61%, control 48%; Fisher's exact test, p=0.721). At 3 years, there was no significant difference in disease-free survival (DFS) or overall survival (OS) between the rasburicase-treated and control groups (DFS: rasburicase vs. control 51.2% vs. 40.4%, p=0.97; OS: rasburicase vs. control 55.3% vs. 44.9%, p=0.88). Conclusion: Rasburicase can be safely administered during myeloablative conditioning, results in a profound lowering of serum uric acid levels and has the potential to reduce the incidence of acute GVHD. Based on these data a prospective randomized phase II trial is planned in order to verify whether rasburicase inhibits acute GVHD after myeloablative HCT and to study the possible mechanisms of protection from GVHD. Disclosures: Off Label Use: Rasburicase for GVHD prevention in allo-HSCT.

Description: Background: Heterozygous somatic mutations in the genes encoding RNA splicing factors SF3B1, U2AF1, SRSF2 or ZRSR2 induce aberrant splicing in cancer cells and are among the most common mutations in patients with MDS, AML or CMML. H3B-8800 is an orally available small molecule that binds to the SF3b complex and induces alternative splicing changes in cells. Because splicing factor mutant cells depend on residual wild-type function of splicing factors for survival, we hypothesized that H3B-8800 would induce preferential cell killing of mutant cells by further perturbing splicing to synthetic lethality. In pre-clinical models, H3B-8800 preferentially kills spliceosome mutant cells and induces antitumor activity in xenograft leukemia models with core spliceosome mutations (Seiler M et al Nature Medicine 2018). Therefore, we conducted a phase I clinical trial (NCT02841540) of H3B-8800 in patients with MDS, AML or CMML. Here we describe the safety profile and clinical outcomes of the dose escalation cohorts in this phase I trial. Methods: This phase I trial explored the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of H3B-8800 in patients with myeloid cancers. Dose escalation cohorts, employing a standard 3+3 design, examined 2 different once daily dosing regimens (schedule I: 5 days on/9 days off; schedule II: 21 days on/7 days off) in a 28-day cycle, with stratification based on lower-risk (LR) versus higher-risk (HR) myeloid neoplasms. Results: As of June 16th, 2019, 84 patients were enrolled at 24 centers in the US and Europe. Dose ranged from 1-40 mg among 65 patients on schedule I, while 19 patients were enrolled with dose ranging from 7-20 mg on schedule II. The patient population included AML (n=38), CMML (n=4), HR-MDS (n=20), LR-MDS (n=21) and 1 MDS with unknown risk level. Most patients (88%) had spliceosome mutations of interest. The most common mutations were in SRSF2 (p.P95H in 17, p.P95L in 9, p.P95_R102Del in 4), SF3B1 (p.K700E in 11, p.R625C in 4), and U2AF1 (p.Q157P in 6, p.S34F in 4). Patients remained on treatment from 7 to 819 days; 25 patients (30%) had time on treatment greater than 180 days, 20% more than 1 year and 2% over 2 years. The median therapy duration for LR-CMML/MDS, HR-CMML/MDS, and AML patients were 216, 62, and 47 days respectively. Most observed treatment related treatment-emergent adverse events (TEAEs) were Grade 1 or 2. The most common treatment-related (as judged by the investigator, 〉10% frequency) TEAEs in the patients treated on schedule I were diarrhea (75%), nausea (37%), fatigue (28%) and vomiting (27%). The most common treatment-related TEAEs in the patients treated on schedule II were diarrhea (68%), vomiting (42%), QTc prolongation (21%), nausea (16%), and fatigue (16%). The most common dose limiting toxicity was prolongation of the QTcF interval 〉500 msec (n=2, 40 mg on schedule I and n=1, 20 mg on schedule II, all ≥Grade 3) and bradycardia without other arrhythmias (n=1, 14 mg on schedule II, ≥Grade 3). No ophthalmic AEs were observed; 1 patient (LR-MDS) experienced durable marrow aplasia. The maximum tolerated dose (MTD) has not been confirmed for either Schedule I or Schedule II. PK analysis indicates that H3B-8800 is rapidly absorbed and exhibits dose-proportional increase in plasma exposure. Consistent dose-dependent target engagement (i.e., alteration in mature mRNA transcripts) was observed in blood mononuclear cells from patients enrolled in the 2 mg up to 40 mg dose cohorts on both schedules. Despite this splicing modulation, no objective complete responses (CR) or partial responses (PR) meeting International Working Group criteria were observed. One patient with CMML had a durable platelet response that began in Cycle 1 and persisted through Cycle 13. Nine red blood cell (RBC) transfusion-dependent patients with MDS or CMML and 2 patients with AML did not require RBC transfusions for ≥8 weeks (up to 28 weeks) while on study. One platelet transfusion-dependent patient with LR-MDS did not require platelet transfusions for ≥8 weeks. Conclusion: Results from this first-in-human multicenter prospective clinical trial of a splicing modulator in myeloid neoplasms demonstrate dose-dependent target engagement and predictable PK profile of H3B-8800, and safety even with prolonged dosing. Although no objective CR or PR were achieved, decreased RBC or platelet transfusion requirements were observed in 12 (14%) of enrolled patients. Disclosures Steensma: H3 Biosciences: Other: Research funding to institution, not investigator.; Pfizer: Consultancy; Aprea: Research Funding; Stemline: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Astex: Consultancy; Onconova: Consultancy. Wermke:Novartis: Honoraria, Research Funding. Greenberg:Notable Labs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; H3 Biotech: Research Funding; Aprea: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Komrokji:Agios: Consultancy; JAZZ: Speakers Bureau; DSI: Consultancy; JAZZ: Consultancy; Incyte: Consultancy; Novartis: Speakers Bureau; celgene: Consultancy; pfizer: Consultancy. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Brunner:Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Ades:Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Coombs:H3 Biomedicine: Research Funding. Foran:Agios: Honoraria, Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Micol:AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy. Perez De Oteyza:Celgene: Speakers Bureau. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Buonamici:H3 Biomedicine: Employment. Kim:H3 Biomedicine: Employment. Gourineni:H3 Biomedicine: Employment. Marino:H3 Biomedicine: Employment. Rioux:H3 Biomedicine: Employment. Schindler:H3 Biomedicine: Employment. Smith:H3 Biomedicine: Employment. Yao:H3 Biomedicine: Employment. Yuan:Eisai: Employment. Yu:H3 Biomedicine: Employment. Platzbecker:Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: H3B-8800 (experimental, unapproved)

Description: Introduction: Hyperleukocytosis, defined as a white blood cell count (WBC) of 〉50 × 109/L or 〉100 × 109/L, is seen in newly diagnosed AML and often results in leukostasis, increased risk of complications, and potentially early death. Those pts often require urgent evaluation and therapy. Leukapheresis is also sometimes used despite limited evidence supporting its use. There is limited data regarding the impact of time (day/night) and day (weekday/weekend) of admission and time to initiation of IC on outcomes in pts with hyperleukocytosis. Methods: Data were collected from 12 centers in USA and Europe (EU). Eligible pts had newly diagnosed AML, presented with a WBC 〉 50 × 109/L, and received IC. Univariate and multivariable logistic regression models stratified by centers (EU vs. USA) estimated odds ratios for death during induction (30-day mortality) and achievement of composite complete response (CRc) defined as CR+CR with incomplete count recovery (CRi). Univariate and multivariate Cox proportional hazard models stratified by centers (EU vs. USA) estimated hazards ratios (HR) for overall survival (OS). We evaluated the impact of leukapheresis, day of presentation (weekend vs. weekday), time of presentation (nighttime = 6pm-6am vs. daytime=6am-6pm), and time to initiation of IC. Studied covariates included age, Eastern Cooperative Oncology group performance status (ECOG PS), cytogenetics and molecular abnormalities, WBC, hemoglobin, platelet count, bone marrow and blood blast percentage, and presence of clinical leukostasis, tumor lysis syndrome (TLS) or disseminated intravascular coagulation (DIC) at presentation. Results: Among 1050 pts with AML and hyperleukocytosis whose data were collected, 787 were reported to have received IC and were included in this analysis. Of 787 pts receiving IC, 16.6% (95%CI, 13.9-19.3%) died during the first 30 days of IC. Leukapheresis was used in 117 pts (15%) in 8 of the 12 centers. In univariate analyses, neither weekend nor nighttime presentation nor use of leukapheresis impacted odds of death in the first 30 days. In multivariate analysis, higher odds of death during first 30 days were associated with age ³ 55 years (OR 3.2, p=0.015), ECOG PS ³ 2 (OR 4.4, 0.004), WBC 〉 100 × 109/L (OR 6.0, p=0.01) and presence of leukostasis (OR 4.5, p=0.005) and TLS (HR, 3.2, p=0.049). However, neither initiation of IC beyond 48 hours of presentation (vs. less than 48 hours) or use of leukapheresis significantly affected the odds of death in first 30 days (Figure 1A). Median OS of the entire cohort was 12.6 months (95%CI, 11.5-14.9) (Figure 2A). In multivariate analyses, age ³ 55 years (HR 2.6, p