ALBERT

Description: Key Points HIV-negative UCD and iMCD are heterogeneous at the clinical, immunophenotypic, and pathologic levels. Complete surgical resection is the primary option of treatment of UCD, while siltuximab is more effective for iMCD than rituximab.

Description: Introduction: Patients (pts) with histologically aggressive MCL (HA-MCL; blastoid or pleomorphic) including [de novo (dnMCL) or those transformed from classic morphology (t-MCL)], exhibit a poor prognosis. This analysis provides a comprehensive assessment of so far the largest patient cohort with HA-MCL treated with various modalities. Methods: We included all HA-MCL pts [blastoid (n=142) or pleomorphic morphology (n=26)] at MD Anderson Cancer Center from 12/1997 to 07/2018. Among the 168 pts, 99 were dn-MCL and 69 were t-MCL. Pt characteristics were collected at the time of initial diagnosis in dnMCL and at transformation in t-MCL. Overall survival (OS) was defined from the time of initial diagnosis of HA-MCL to death/last follow-up and failure free survival (FFS) - time of starting first-line treatment after diagnosis of HA-MCL to treatment failure. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed on specimens from 100 pts (among them, 27 tumor-normal pairs and 73 tumors without matched germline), this included CNT (classic never transformed=52), dnMCL=27, t-MCL=21. Two t-MCL pts had tumors sequenced at both classic and HA-MCL phase. Results: Median age for all 168 pts was 65 years (range, 39 to 95). Median time from initial diagnosis of classic t-MCL to HA t-MCL was 39 months (5 to 240 months). The median follow up after the diagnosis of HA-MCL was 19 months (0.1-168). Main clinical features of HA-MCL were - 72% pts had stage IV disease, 67% with marrow involvement, 27% leukemic phase, 20% with B symptoms, 6% had ECOG PS (3-4) and central nervous system involvement in 9% pts. Other features were, median Ki-67% 70% (10-100%), complex karyotype 11%, LDH 〉 upper limit of normal 44%, Sox-11 positive in 82%, median β2M of 2.9 mg/dL. In pt subsets, t-MCL were distinct from dnMCL in having significantly higher median age, higher Ki-67% and lower proportion of marrow involvement at diagnosis. All pts with t-MCL had prior treatment for MCL before transformation. Overall, the median OS after diagnosis of HA-MCL was 32.5 months (45 and 13 months for dnMCL and t-MCL respectively; p=0.001) and the median FFS was 12.5 months (22 and 5 months for dnMCL and t-MCL respectively; p=0.001). In univariate analysis, factors significantly associated with inferior OS in HA-MCL were older age, high Ki-67%, higher LDH, elevated WBC count, higher β2M, lower hemoglobin, lower platelet counts and advanced ECOG-PS, presence of B symptoms, CNS involvement, complex karyotype and t-MCL. Recursive partitioning analysis revealed that Ki-67% ≥50%, LDH ≥1282, β2M ≥ 4, hemoglobin

Description: BACKGROUND: Advanced age, AML arising from an antecedent hematologic disorder (AHD), and therapy-related AML (t-AML) are well established risk factors associated with poor outcome in AML. This subgroup of AML has been associated with lower rates of complete remission (CR) and shorter disease-free survival compared with de novo AML in younger patients (pts), when using standard therapy. Developing newer strategies to improve outcomes in this subgroup of pts is therefore a critical unmet need. Establishing baseline metrics from which to evaluate newer approaches is important. We sought to review our own experience with pts treated with different therapies at our institution to establish this baseline. METHODS: We retrospectively reviewed pts aged 60-75 years with newly diagnosed AML treated at our institution from 1990-2015 with one or more of the following characteristics: history of prior MDS, CMML, MPN, or aplastic anemia, the diagnosis of t-AML, or AML with karyotypic abnormalities characteristic of MDS as defined by the WHO. The pts were grouped into 5 study cohorts based on their treatment regimen: 1) High-dose Ara-C based intensive chemotherapy (HiDAC), 2) Hypomethylating agents (HMA)/HMA combinations, 3) Low-dose Ara-C combinations (LDAC), 4) Liposomal Ara-C:Daunorubicin (CPX-351), and 5) Other investigational agents (INV). Pts' karyotypes were divided into 4 categories: adverse karyotype (complex: defined by 〉2 chromosomal abnormalities, Del 5/5q, Del 7/7q, 11q, 3q abnormality); diploid karyotype, intermediate karyotype (karyotype other than adverse or diploid); and unknown/not available. Endpoints included complete response (CR) rate/CR with low platelets (CRp) and 8-week mortality rates. Both univariate and multivariate analyses were performed to examine the relationships between disease characteristics and outcomes (CR, Overall survival). RESULTS: We evaluated a total of 931 pts with newly diagnosed AML meeting these criteria of age and secondary AML (s-AML). The baseline characteristics of pts in each group are summarized in table 1. The median age was 68 (60-75) years. Most pt characteristics were well balanced across the 5 treatment groups. Karyotyping was performed in 89% of the pts: 57.5% belonged to adverse risk profile and 31% belonged to intermediate risk profile (excluding diploid). The overall CR/CRp rates for the entire group was 39.5%. CR/CRp rates were lower in the HMA (36%) and INV (16%) groups compared to HiDAC (46%), CPX (45%) and LDAC (43%). Eight week mortality rate for the entire group was 20%: HiDAC (23%), HMA (12%), CPX (10%), LDAC (19%), and INV (27%). The median OS for the entire group was 6 months and by each treatment regimen is shown in Figure 1. There was a significant difference in OS between the 5 treatment groups. Pts receiving less intensive regimens [HMA + LDAC] had a superior median OS compared to those receiving HiDAC-based regimens (6.9 vs. 5.4; P=0.002, Figure 2). There was no difference in median survival in pts treated with CPX compared with conventional lower-intensity approaches (HMA + LDAC) (p=0.75). In the multivariate analysis, age 〉70yrs, adverse karyotype, and prior treatment for AHD were associated with a decreased OS. Similarly, use of HMA/INV treatment, adverse/intermediate risk karyotype, history of prior treatment for AHD were associated with lower CR rates. CONCLUSIONS: The outcomes of older pts with newly diagnosed s-AML are poor and reflective of their advanced age and poor-risk karyotype. Various treatment approaches have been attempted to improve outcomes. Lower-intensity approaches such as HMA and LDAC-based regimens have response rates similar to HiDAC regimens, but are associated with lower early mortality and improved overall survival. While the investigational liposomal formulation CPX-351was associated with favorable CR rates and low early mortality, the median OS was similar to pts treated with low intensity therapy. The unsatisfactory outcomes using other investigational agents in the INV group underscores the need for more effective therapies for these patients. Table 1 Baseline study population characteristics and disease outcomes Table 1. Baseline study population characteristics and disease outcomes Figure 1 OS in pts by the treatment regimen group Figure 1. OS in pts by the treatment regimen group Figure 2 OS comparison in pts who received IC/HiDAC vs less intensive (LDAC + HMA) therapies Figure 2. OS comparison in pts who received IC/HiDAC vs less intensive (LDAC + HMA) therapies Disclosures Kantarjian: BMS, Pfizer, Amgen, Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. DiNardo:Celgene: Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding. Jain:Celgene: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Description: INTRODUCTION: Ponatinib is a pan-tyrosine kinase inhibitor (TKI) with proven efficacy in multi-refractory CML patients (pts) who have failed other TKIs and approved in all CML stages after failure to other TKIs and for pts with T315I mutation. Despite excellent response rates, resistance or intolerance may develop in some cases. Treatment options in these pts are limited and the outcomes have not been described. METHODS: We conducted a retrospective review of the outcomes of pts with refractory chronic (CP) and accelerated (AP) phase CML who discontinued ponatinib in the salvage setting. Pts were assessed for the cause of ponatinib discontinuation, therapies (Rxs) received after discontinuation, response to such Rx, and survival post-ponatinib discontinuation. RESULTS: Among 55 pts treated (32 treated in CP, 23 in AP), 36 (65 %) have discontinued ponatinib at the time of this analysis. Nineteen pts were either lost to follow up (F/U) or died on Rx and excluded from this analysis. Of the 36 pts analyzed, 19 were in CP and 17 in AP at initiation of ponatinib. Pts had received a median of 4 Rxs (2-6) prior to ponatinib. Median age at discontinuation was 67 yrs (22-94). Median duration on ponatinib Rx was 17 mo (1-61). Of 19 CP pts, 5 discontinued due to toxicity (pancreatitis = 2, stroke = 1, headache = 1, thrombocytopenia = 1), 13 for lack of response, 1 per pt choice. At discontinuation, 14 were still in CP [complete cytogenetic response (CCyR) = 3, no/minor CyR (NR/mCyR) = 10, major molecular response (MMR) = 1]; 3 had progressed to AP, and 2 to blast phase (BP). Subsequent therapy for those still in CP included stem cell transplant (SCT) = 4, supportive care only (NT) = 3, dasatinib = 2, omacetaxine = 2, and bosutinib + decitabine (DAC), nilotinib, and imatinib (1 each); the 3 pts that progressed to AP received dasatinib + DAC, low-dose Ara-C (LDAC), and NT = 1 each, respectively; and BP pts received Hyper - CVAD + dasatinib followed by SCT = 1, ponatinib + LDAC = 1. Of the 3 CP pts in CCyR, 1 died from sepsis 1 mo after discontinuing ponatinib due to thrombocytopenia; 1 pt received SCT and died in MMR 11 mo post SCT; 1 developed 7q- /Ph- on ponatinib and received SCT (MMR at 47 mo F/U). The CP pt in MMR discontinued ponatinib after a stroke and lost MMR 38 mo later (still in CCyR off Rx). Two CP pts improved to CCyR after SCT (1 died in 8 mos; 1 in MMR at 25 mo). Thirteen pts (CP 9, AP 3, BP 2; all non-SCT Rx) did not improve their responses post ponatinib (remained in NR/mCyR). The Median survival (OS) post ponatinib discontinuation of the 19 CP pts was 26 mo [Fig 1]. Twelve pts have died: 5 disease related (CP 2, BP 2, AP 1), 4 cause unknown (CP 3, AP 1), 3 from sepsis (CP 2, AP 1). Of 17 AP pts who discontinued, 15 stopped due to poor response and 2 for toxicity (stroke = 1, nausea = 1). At discontinuation, 14 were still in AP [NR/mCyR = 13, partial CyR (PCyR) = 1], 3 had progressed to BP. Subsequent therapy included NT = 5, dasatinib = 4, dasatinib + DAC = 2, SCT = 2, hydroxyurea = 1 for those still in AP, and SCT = 1, BIDFA = 1, mitoxantrone + etoposide + ponatinib = 1 for those in BP. The pt with PCyR at discontinuation died 3 mos after discontinuation of heart failure. Three pts (AP = 2, BP = 1) received SCT: 1 BP pt achieved MMR but died 12 mos post SCT of unknown cause; 1 AP pt maintains MMR 63 mos after SCT; the other AP pt did not respond and relapsed in AP, then received Rx with dasatinib + DAC and died of progressive disease 5 mos later. The remaining 14 pts (AP 12, BP 2; all non-SCT Rx) did not improve their responses post ponatinib (remained in NR/mCyR). The OS post ponatinib discontinuation (17 AP) was 9 mo [Fig 1]. Twelve pts have died: sepsis 3 (AP 3); progression 4 (AP 3, BP1), unidentified 5 (BP 1, AP 4); other 1 (BP 1). The OS for all 36 pts was 16 mos [Fig 2]; OS by stage at discontinuation was 31mo in CP, 9 mo in AP, 13 mo in BP [Fig 3]. The 12-mo survival probabilities for individual post-discontinuation Rx cohorts were: TKI 74%, SCT 56%, supportive 30%, other 50%. The OS for pts who stopped ponatinib because of toxicity vs resistance was 60 mo and 11 mo respectively. CONCLUSIONS: Long term outcomes of pts with ponatinib failure are poor with estimated 1-year OS and EFS rates of 54% and 40% respectively. Lack of response to ponatinib, after failing other TKIs, predicts a considerable risk for subsequent Rx failure. New Rx options are required for this small subset of patients. Figure 1 OS post ponatinib by stage at start of ponatinib Figure 1. OS post ponatinib by stage at start of ponatinib Figure 2 OS after failure for pts treated in CP or AP Figure 2. OS after failure for pts treated in CP or AP Figure 3 OS post ponatinib by stage at the time of ponatinib dc Figure 3. OS post ponatinib by stage at the time of ponatinib dc Disclosures Kantarjian: Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Daver:Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Ariad: Research Funding. Kadia:BMS: Research Funding; Novartis: Honoraria. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Jain:Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Infinity: Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger:Gilead: Research Funding; Portola: Consultancy; Roche: Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Description: Introduction: A fraction of pts with classic variant MCL can transform to an aggressive histology (blastoid/pleomorphic) MCL. Outcomes of transformed pts are inferior to that of denovo blastoid variant MCL and classic variant MCL who never transformed (CNT) Jain P et al ASH 2018. Application of routinely available clinical variables at initial diagnosis to predict the future risk for transformation or time to transformation is an unmet need in MCL. Methods: We analyzed charts from 369 pts with MCL (293 were CNT and 76 were transformed MCL). Statistical analysis was performed from baseline pt characteristics collected from the time of initial diagnosis in CNT group and at the time of initial diagnosis of classic variant MCL who later transformed (t-MCL). Time to transformation (TTT) was calculated from initial diagnosis to the date of transformation in those who transformed and last follow up in those who never transformed. Univariate and multivariate logistic regression modeled the risk of transformation. Classification and regression tree (CART) analysis was performed to identify optimal cut off in categorical variables predictive of TTT. Results: Among the 369 pts, the median age was 62 yrs (range 34-90), 79% were males. Ki-67% values were available in 133 pts (36% of total) and median Ki-67% was 25% (range 1-80). 84% had initial bone marrow involvement and 12% had leukemic phase at diagnosis. The median follow up was 58.5 months and the median overall survival (OS) was 94.8 months and 47% were alive at the time of this analysis. Compared to pts in the CNT group, pts in t-MCL group exhibited differences in following baseline characteristics - higher values of median Ki-67% (30% vs 20% in t-MCL; p=0.04), higher LDH levels, higher proportions of pts with high risk simplified MIPI risk score, leukemic phase at initial diagnosis, complex karyotype and lower hemoglobin and lower proportion of pts achieving complete remission (CR) after first line treatment (78% in t-MCL vs 86% in CNT). In addition, first line treatments received by both groups were similar - R-HCVAD based, R-chemo based, ibrutinib based, chemotherapy alone and miscellaneous. Logistic regression model showed factors associated with the risk of transformation. In univariate analysis, higher risk was significantly associated with Ki-67% as a continuous variable - OR 1.03 (95% CI 1.01-1.05; p=0.006), leukemic phase at diagnosis, high risk MIPI score, complex cytogenetics. First line treatment with ibrutinib compared to R-HCVAD, autologous stem cell transplant SCT at any time point and higher number of nodal sites were associated with decreased risk of transformation. In multivariate analysis (MVA), higher number of nodal sites and SCT were associated with decreased risk of transformation. The median time to transformation in months for those who transformed was 39 (range 5-240 months) while in CNT it was 51 months (1-257 months). We further identified that incremental Ki-67% was significantly associated with TTT and OS (Figure-1A-B). Using CART analysis we identified Ki-67% ≥60 is significantly associated with shorter TTT (HR, 6.26; 95% CI 2.58-15.21; p

Description: PURPOSE Pain for sickle cell patients occurs on a daily basis, but this becomes magnified during a sickle cell crisis (SCC). The mainstay of treatment during hospitalization is intravenous fluids and opiates however this can be a nidus for an opiate addiction long term, especially in the ongoing opiate epidemic. Marijuana has been used in a variety of chronic pain disorders including those from cancer. It is known that within the sickle cell population, smoking tobacco increases the risk of acute chest syndrome. Marijuana use or its derivatives used to treat pain has not been studied on a large scale within the sickle cell population. We propose the question of whether marijuana use affects SCC admissions as well as acute chest syndrome (ACS). METHODS The National Inpatient Sample (NIS) dataset was queried from 2005 to 2014 to identify the primary diagnosis of SCC with the International Classification of Disease (ICD) Code 282.42, 282.62, 282.64 and 282.69, as has been done in the literature. We then identified those with marijuana use, excluding those used in the past and not currently with the ICD code 304.30, 304.31 and 304.32. Additionally we identified those with ACS with the ICD code of 517.3. We then used multivariate analysis along with Chi-square for non-continuous variables using the statistical software SAS. RESULTS Between the years of 2005 and the 2014, there were a total of 798,313 hospitalizations for sickle cell crisis in the United States. Around 0.08 % of these patients had marijuana use. When stratified by race marijuana use was predominantly documented among African Americans (95.2%) followed by Hispanics (3.8%). Length of stay was statistically the same among marijuana users at 4.65 vs 5.28 days without use (p = 0.11) when compared to non-users. Total charges at the end of hospitalization were also the same at $23134.2 vs $24662.7 (p=0.60) with marijuana users and non-users respectively. Marijuana patients did that lower proportions of ACS at 5.46% vs 8.48% without (p= 0.004) and a relative risk of 0.64. Proportion of death was the same with marijuana users of 0% and non-users 0.28% (p=0.16). The age at admission was higher at 30.77 when compared to 27.25 among non-users (p=0.0009). CONCLUSIONS: Marijuana use was associated with lower instances of ACS with a relative risk of 0.64. Additionally patients presented on average 3 years later than non-users. The fact that mortality, length of stay and total charges were the same amongst the two groups may indicate that during a crisis, the disease process is the same, however outside of having a crisis, marijuana use may help with pain control given later presentation. CLINICAL IMPLICATIONS: Further research should be done to look at marijuana use as an alternative to pain control for sickle cell patients in the community setting. Disclosures No relevant conflicts of interest to declare.

Description: Background: HLH is a systemic condition characterized by inflammatory storm and immune-mediated organ damage. Adult M-HLH is particularly challenging with median overall survival (OS) 5000, 〉10000, 〉25000, and 〉50000 mg/L, respectively. 23/32 (72%) pts had high sIL2R (med 7010; range 749-127000). Tissue hemophagocytosis was seen in 18 (50%) pts. Other features at diagnosis: fever (n=33; 92%), splenomegaly (n=26; 72%), new ≥ 2 cytopenias (n=26; 72%), triglycerides ≥265 mg/dL (n=23; 64%), fibrinogen 5xULN at diagnosis in 33 pts (92%) with med of 6420 (range 833-42000+); 16 (47%) pts at LDH ≥10000. Clinical hepatitis, coagulopathy and nephritis were seen in 28 (78%), 25 (69%) and 20 (56%) pts, respectively. 27 (75%) pts had central nervous systems symptoms; 12/18 (67%) evaluated pts had lymphocytic pleocytosis suspicious for CNS HLH on lumbar punctures. Potential secondary infectious triggers were identified in 16 pts (44%): 5 pts were EBV positive by PCR in blood and bone marrow, 4 had positive CMV PCR in blood, and 7 were found to have various disseminated fungal infections. 17 (47%) pts were tested for hypomorphic mutations and 4 (24%), all male with med age of 55 yrs (range 33-59), tested positive for known HLH mutations including STXBP2 (n=2), BIRC4 (n=1), and PRF1 genes (n=1). 34 (94%) pts received HLH-directed therapy for a med of 2.3 weeks (range 1-16): 4 (11%) received dexamethasone (D) alone at 10 mg/m2 BID (med 1 week; range 1-2); 14 (39%) received D+etoposide (E) with med of 4 (range 1-12) E doses, and 16 (44%) received D+E+tocilizumab (T) with med of 4 (range 1-10) E doses and med of 1.5 (range 1-4) T doses (Fig 1C); 2 (6%) pts declined therapy. 14 (39%) pts received concomitant systemic therapy for their underlying malignancy including 6 with D+E, 7 with D+E+T, and 1 with D only . Pts received broad-spectrum antimicrobials, intrathecal chemotherapy, renal replacement therapy and polyvalent immunoglobulins (when indicated). Overall, 11/34 (32%) pts responded: 5/14 (36%) in D+E group (all had complete response (CR) of whom 1 received allogeneic stem cell transplant (ASCT)) and 6/16 (38%) in D+E+T group (2 CR; 4 partial response (PR)). At med follow-up of 19 mos, med OS of the cohort was 1.6 mo (95% CI: 0.2-23.9), with 1-yr OS of 20%. The 30- and 60-day mortality was 44% and 64%. Med OS for the 11 responders was 6.2 mos vs 0.6 mos in non-responders (p=0.001). Conclusion: M-HLH has poor outcomes with med OS

Description: INTRODUCTION The TET2 (Ten‐Eleven Translocation 2) gene, located at chromosome 4q24.1, belongs to TET family of proteins that possesses the capacity of catalyzing the conversion of 5‐methylcytosine into 5‐hydroxymethylcytosine. It is considered to be a putative tumor suppressor gene during cancer initiation and development. TET2 mutations are extensively studied and reported in a variety of human hematological malignancies including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), suggesting a crucial role of TET2 in the pathogenesis of blood cancers. The landscape of rare TET2 variants which may be of potential clinical relevance is not fully described. The landscape of TET2 variants from a large cohort of MDS and AML patients was explored. METHODS We analyzed data from bone marrow samples of 2634 patients with AML or MDS who presented at MD Anderson between the years 2012-2016. Seven hundred seventy seven patients were found to have TET2 variants that were not classifiable as known mutations. Two hundred sixty-three patients were diagnosed with MDS, 144 with secondary AML transformed from MDS, and 370 with AML without prior history of MDS. The coding regions of TET2 gene was analyzed by next-generation sequencing in the molecular diagnostics laboratory. Non-mutation variants were classified into 2 groups: 1) those reported as germline polymorphisms (GP) in population studies, literature or matched tumor-normal analysis on patients at MDACC; and 2) variants for which a germline versus somatic origin could not be determined unequivocally (variants of uncertain origin, VUO). Very common GP variants (defined as those with a population frequency of over 20% in laboratory sample cohort) were not evaluated. Variants' predicted frequency in the population according to gnomAD Exomes 2.0.2, and classification according to American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants, were assessed using the VarSome platform by Saphetor. RESULTS Two-hundred and twenty-eight unique variants were identified. The amino acid substitutions from missense variants were widely distributed throughout TET2. Fifty-four unique variants were classified as GP and several of these recurrent variants were found to be present in our population at a significantly higher frequency (p

Description: Introduction: Additional cytogenetic clonal evolution (CE) is a known risk factor for a poor prognosis in chronic myeloid leukemia (CML). However, its prognostic significance in the setting of new tyrosine kinase inhibitor (TKI) remains unclear. We sought to analyze the baseline characteristics and clinical outcome in chronic phase (CP) CML pts with or without CE treated on frontline TKI clinical trials in a single institution. Methods: Patients (pts) with Ph-positive CML in CP with or without CE at the time of diagnosis receiving initial therapy with imatinib 400 mg/d, imatinib 800 mg/d, dasatinib 100 mg/d, nilotinib 800 mg/d or ponatinib 30 or 45 mg/d in consecutive or parallel clinical trials at a single institution were analyzed. Overall survival (OS), transformation free survival (TFS), event free survival (EFS), failure free survival (FFS) were analyzed from the start of therapy by Kaplan-Meier method. Clonal evolution (CE) was defined by the presence of any cytogenetic abnormality other than a single Ph, variant Ph chromosome or loss of Y chromosome. Also we analyzed CML pts with CE with regard 'major route' abnormalities vs other. The major route abnormalities includes trisomy 8 (+8), trisomy 19 (+19), isochromosome 17q10 (i17q) and additional Ph chromosome. Results: A total of 603 pts were analyzed including 579 pts in CP without CE and 24 pts with CE. Pts in CP without CE received initial therapy with imatinib-400 (n=70), imatinib-800 (n=200), dasatinib (n=138), nilotinib (n=122), or ponatinib (n=49), and pts with CE received imatinib-400 (n=2), imatinib-800 (n=7), dasatinib (n=10), nilotinib (n=4), and ponatinib (n=1). Pts with CP were usually older, female and have a higher WBC (P 〈 0.001). There was a statistically significant higher Complete cytogenetic response (CCyR) at 6 mo in pts without CE (P = 0.012), however the cumulative and 3-month rates of complete hematologic response (CHR), and the cumulative rates of CCyR and MMR were not different (Table). Similarly, the rates of MR4.0 and MR4.5 were similar for the two groups. At 5 years, the presence of additional cytogenetic findings at diagnosis does not seem to affect the rate of transformation, failure-free, event-free and overall survival. Acknowledging the small sample size for subset analysis, response rates and survival outcomes were comparable in CP with CE irrespective of whether chromosomal abnormalities were 'major route' or other (n=12 in each arm). Conclusion: Additional cytogenetic CE at the time of diagnosis among patients with CML in CP is associated with a similar favorable outcome as those without CE when treated with TKI. The type of additional CE (major route vs other) does not seem to impact outcome. Patients with CML-CP with CE at the time of diagnosis can thus be treated with TKI as all other pts with CP with no need for consideration for SCT unless there is clear evidence of failure. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. DiNardo:Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.