Yi, Cecilia Arana

Abstract Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, ∼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).

Abstract Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed by many hematologic malignancies. SL-401 is currently being advanced through clinical trials in patients with a variety of CD123+ malignancies including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML) in remission with high relapse risk, and multiple myeloma. CD123 has been shown to be expressed on myeloproliferative neoplasm (MPN) cells as well as microenvironmental immune cells, namely plasmacytoid dendritic cells (pDCs), in the bone marrows of some patients with MPN including chronic myelomonocytic leukemia (CMML). Microenvironmental pDCs have been implicated in promoting plasma cell disorders and preliminary data suggest that pDCs could play a related role in some myeloid neoplasms. Accordingly, a therapy directed at both CD123-expressing myeloid cells and neighboring CD123-expressing pDCs could provide therapeutic benefit. SL-401 is being evaluated in patients with advanced, high-risk MPN, including systemic mastocytosis (SM), myelofibrosis (MF), primary eosinophilic disorders (PED), and CMML. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of patients with advanced, high risk MPN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients receive SL-401 as a daily IV infusion at 7, 9, 12 ug/kg/day, or higher for days 1-3 of a 21-28 day cycle in a 3x3 design. In stage 2, patients receive SL-401 at the dose determined in stage 1. Study objectives include characterization of the safety profile, including determination of the maximum tolerated or tested dose, and detection of preliminary efficacy signals including evaluation of tumor response and progression free survival by standard criteria. As of 7/20/16, 6 patients with MPN (MF, n=3; CMML-2, n=2; CMML-1, n=1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3). The median age was 66 years (range: 42-81 years). Patients treated at all doses received 1+ to 2+ cycles (ongoing) of SL-401. The most common treatment-related adverse events (AEs) were thrombocytopenia (2/6; 33%) and fatigue (2/6; 33%); the most common ≥ Grade 3 treatment-related AEs were thrombocytopenia (2/6; 33%) and anemia (1/6; 17%); there has been no DLT. Efficacy assessments are ongoing. Patients are currently enrolling in the 12 ug/kg/day cohort. Conclusions: Initial dosing of SL-401 appears to be well-tolerated in patients with MPN and CMML, with no unexpected AEs observed. Given CD123 expression on myeloid neoplastic cells as well as microenvironmental immune cells (namely, pDCs), SL-401 may offer a novel, targeted therapeutic approach in patients with high-risk MPN and CMML of unmet medical need. Enrollment continues in stage 1 of this ongoing Phase 2 trial and updated safety and efficacy data will be presented. Clinical trial information: NCT02268253. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Baxalta: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Schiller:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. McCloskey:Novartis: Speakers Bureau; Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Lee:Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer Inc: Consultancy. Yacoub:Alexion: Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau. Ali:Incyte Corporation: Research Funding. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

AbstractBackgroundAlthough the prognosis of core‐binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.MethodsEleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).ResultsComplete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease‐free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper‐ or hypodiploidy were included in a scoring system (named I‐CBFit). DFS rate at 2 years was 76% for patients with a low‐risk I‐CBFit score compared with 36% for those with a high‐risk I‐CBFit score (P < 0.0001). Low‐ vs high‐risk OS at 2 years was 89% vs 51% (P < 0.0001).ConclusionsI‐CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low‐risk I‐CBFit score).