Abstract: 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.

Abstract: Abstract 1554 Background: MSC1936369 is a selective non-competitive inhibitor of MEK1/2 with anti-proliferative activity in leukemia cell lines and in human tumor xenograft models with activation of mitogen-activated protein kinase (MAPK) signaling. We present the preliminary data of the safety run-in part of the phase II trial, in which the primary objective is to determine the maximum tolerated dose (MTD) for different dosing schedules (S). Methods: MSC1936369 was administered orally twice per day (BID), either on days 1–5, 8–12, 15–19 and 22–26 (S1) or on days 1–21 (S2) of a 28-day cycle. Dose escalation within each S followed a modified Fibonacci scheme with 3+3 cohorts. PK samples and peripheral blood leukemia blasts for the measurement of phosphorylated extracellular signal-regulated kinase (pERK) were collected for all pts. Results: 48 pts have been treated, 25 in S1 (8–42 mg BID) and 23 in S2 (8–60 mg BID). Pt characteristics, treatment exposure, and safety signals were similar in both Ss. The median age was 67 years (range 22–80), 66% were male and the Eastern Cooperative Oncology Group Performance Status was 0/1/2 in 25%/58%/17% of pts, respectively. Underlying HMs were: acute myeloid leukemia (AML, n=41), myelodysplastic syndrome (MDS, n=3) and other (n=4). Cytogenetics were known for 42/44 pts with MDS (n=3) and AML (n=39): 3 were favorable, 21 intermediate and 18 unfavorable. RAS mutation was present in 5 pts (not reported in others), of whom 2 also carried a FLT3 mutation. Six additional pts had a FLT3 mutation. The median duration of treatment was 3.7 weeks (range 0.1–77). The MTD has not been reached in either S. One dose-limiting toxicity (DLT) of grade 2 angioedema was seen in S1 at 42 mg BID. The most common non-hematological adverse events (AEs): infections (56%), diarrhea (46%), skin rash (38%), nausea (27%), pyrexia (25%), peripheral edema (21%), dizziness (21%), aspartate aminotransferase increase (21%) and transient visual disorders (with underlying serous retinal detachment in most cases) (21%). Plasma concentrations increased proportionally with dose. Sustained pERK inhibition during the dosing period was observed in blasts and lymphocytes starting at 23 mg BID. Transient clearance or 50% decrease of blasts in bone marrow and peripheral blood have been detected in 6 pts (MDS n=2, AML n=4), 2 RAS mutated. Conclusions: MSC1936369 in intermittent Ss is well tolerated with reversible mild or moderate AEs, PD effect during dosing and signals of activity have been seen. Dose escalation continues in intermittent Ss. Continuous dosing is being introduced. Molecular genotyping is ongoing. Disclosures: Ravandi: EMD Serono Inc: Research Funding. Luepfert:Merck KGaA: Employment. Asatiani:Merck Serono SA: Employment. Donica:Merck Serono SA: Employment. Kantarjian:Novartis, Pfizer, BMS: Consultancy, Research Funding. Smith:infinity, genzyme, synta, celator, BMS, novartis: Research Funding; celgene, BMS, novartis: Membership on an entity's Board of Directors or advisory committees.

Abstract: Abstract 1550 Background: Clofarabine is a second generation nucleoside analogue with activity in adults with AML. A recent randomized phase III study in AML relapse showed higher response rates and better event-free survival with the combination of clofarabine and cytarabine (CA) compared to cytarabine alone. We have also reported the feasibility and safety of the addition of idarubicin to CA (CIA) in a previous phase I and II study. To explore this combination further, we conducted a phase II study of CIA in pts 〈 /= 60 years with previously untreated AML. Patients and Methods: Patients (Pts) were eligible if they were 〈 /=60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS 〉 2, cardiac ejection fraction 〈 45%, or active and uncontrolled infection. For the first 30 pts, induction therapy consisted of Clofarabine 22.5 mg/m2 iv daily (days 1–5), Idarubicin 6 mg/m2 daily (days 1–3), and Cytarabine 0.75 g/m2 daily (days 1–5). From pt 31 onward, induction doses were amended to Clofarabine 20 mg/m2 × 5, Idarubicin 10 mg/m2 × 3, and Cytarabine 1 g/m2 × 5. Pts who have not achieved a complete remission following the induction could receive one re-induction course. Pts in CR or CRp continued with up to 6 consolidation cycles with Clofarabine 22.5 mg/m2 × 3, Idarubicin 6 mg/m2 (days 1–2), and Cytarabine 0.75 g/m2 × 3, subsequently amended to Clofarabine 15 mg/m2 × 3, Idarubicin 8 mg/m2 × 2, and Cytarabine 0.75 g/m2 × 3. Supportive care was standard. Pts ≥ 50 yrs were admitted to a laminar air flow room for the duration of the induction. Results: From April 2010 until August 2011, 51 pts have been accrued with a median age of 49 yrs (range 19–59): 33 pts (65%) with de novo AML and 18 pts (35%) with secondary AML (18 related to MDS, 7 related to therapy). Three pts (5%) had a PS of 2. Median WBC at diagnosis was 3.4 × 109/L (0.6-92.3). Thirty-three (65%) pts had abnormal cytogenetics (21/33[64%] poor risk and 5/33 [15%] intermediate risk). Molecular profile: 6 pts (11%) had FLT3/ITD, 3 pts (6%) CEBPA, and 8 pts (16%) NPM1 mutations. Thirty-five pts (69%) achieved CR and 1 (2%) CRp for an overall response rate (ORR) of 71%. 61% pts (31/51) achieved CR following one induction cycle. 18% (9/51) pts required a re-induction and 44% (4/9) of them responded after the re-induction. Responding pts received a median of 2 courses (1–8) courses. With a median follow-up of 23 weeks (3–36+) median remission duration has not been reached with a 1-yr remission probability of 85%. Ten pts (19%) died on study including 2 (4%) who died 〈 28 days from treatment start (one from septic shock and multi-organ failure, and one from Steven Johnson syndrome). Median overall survival (OS) for responding pts has not been reached (2–36 weeks). One-yr survival probability is 65%. Sixteen pts (31%) proceeded with an allogenic stem cell transplant in CR1. Most toxicities were 〈 /= grade 2 and included rash (41 %), nausea (29%), diarrhea (23%), elevated transaminases (21%), and elevated bilirubin (17%). Toxicities 〉 grade 2 included elevated bilirubin (4%), hypokalemia (4%), cellulitis (4%) and seizure (1%). Myelosuppression was ubiquitous but prolonged myelosuppression 〉 42 days was infrequent. 76 % (39/51) pts had neutropenic fever. Conclusion: Clofarabine, Idarubicin and Cytarabine achieve a response rate of 71% in patients 〈 /=60 yrs with previously untreated AML. Induction mortality was low and the toxicity profile was expected and manageable. Longer follow up and comparisons with standard induction therapy will be needed to further assess the role of this combination in AML therapy. Disclosures: Off Label Use: Clofarabine, use of Clofarabine in AML. Ravandi:Genzyme: Research Funding. Kantarjian:Genzyme: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Abstract 3851 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, debilitating symptoms, cytopenias and progressive bone marrow fibrosis. Survival in MF is poor, and effective therapy is lacking. Ruxolitinib (INCB18424) is a JAK1 and JAK2 inhibitor with established clinical benefit in patients (pts) with MF (Verstovsek S. J Clin Oncol 29: [suppl; abstr 6500], 2011) by reducing spleen size and improving MF symptoms & quality of life. Objective: Aim was to identify potential correlates of overall survival (OS) of MF pts receiving ruxolitinib. This study was based on a subset analysis of an open-label single-arm phase I/II trial (INCB18424–251; NCT00509899). Methods: 158 adult pts with primary or secondary MF were enrolled in the parent trial; most received ruxolitinib at doses of 10–25 mg PO twice daily. This updated analysis focuses on 107 pts enrolled at MDACC: 63 were high, 34 intermediate (int)-2 and 10 int-1 risk, according to the International Prognosis Scoring System (IPSS), and assesses their survival and correlates thereof. For log-rank survival analysis, events were censored at the later of last dose, last visit, or last follow-up date. Results: Efficacy and safety findings of the parent trial have been published (Verstovsek S. N Engl J Med 363:1117, 2010): ruxolitinib treatment led to a rapid and sustained reduction in splenomegaly and improvements in MF symptoms; anemia and thrombocytopenia were the most common adverse events. After a median follow-up of 32 months, 58 of 107 pts (54%) were still receiving therapy. The corresponding overall survival (OS) was 69% (33 pts died, none due to therapy-related reasons: 14 while on therapy/within 30 days (d) of discontinuation (dc), and 19 off-study). Accounting for deaths occurring on the study, the 2-yr actuarial survival of int-2 and high-risk pts was 92% and 88%, respectively. However, the 2-yr survival of 13 int-2 and 21 high-risk pts who had discontinued therapy and were subsequently followed was 32% and 21%, respectively. MF transformed to acute leukemia in 9 pts: 5 while on therapy/within 30 d of dc, and 4 off-study; the transformation rate was 0.036/pt years. Pts with normal baseline cytogenetics did not have better survival than those with aberrations (Hazard ratio [HR]=1.52; p=0.24). However, pts with a baseline bone marrow fibrosis score of 2 had greater survival than those with a score of 3 (HR=2.21; p=0.031). Other evaluable baseline pt characteristics (gender, age, anemia, WBC and splenomegaly, did not affect survival. Surprisingly, high-risk pts (per either IPSS or dynamic IPSS [DIPSS] ) did not have significantly worse survival than int-2 pts. Importantly, reduction in palpable spleen length while on ruxolitinib was noted to be the most robust predictor for survival: pts who had a ≥50% reduction in spleen size (n=62) had significantly prolonged survival vs. those with a 〈 25% reduction (n=20) (Fig. 1; HR=4.94; p 〈 0.0001). Conclusions: Most MDACC pts with advanced MF in the phase I/II ruxolitinib study are still receiving therapy, demonstrating an OS of 69% after a median of 32 months. The 2-yr survival of pts who remained on therapy was 3–4-fold greater than those who discontinued therapy. Among baseline pt characteristics, only a lower bone marrow fibrosis score correlated with better survival. Conversely, achievement of ≥50% reduction in spleen size while on ruxolitinib resulted in greater survival (vs. 〈 25% reduction). Our data suggest that the most important factors that influence survival of MF pts receiving ruxolitinib are continuous active therapy and a degree of the spleen response, not pt pretherapy characteristics. Disclosures: Verstovsek: Incyte Corporation: Research Funding.

Abstract: Abstract 2613 The hypomethylating agents are standard of care in patients with higher risk MDS and used frequently in older AML. A number of strategies, including combination approaches, are being developed to improve results of single agent hypomethylating agent. For instance the combination of 5-azacitidine and lenalidomide (LEN) has been shown to be safe and active in a phase I trial (Sekeres JCO 2010; 28:2253–8). Recently the use of high dose LEN (50 mg orally daily) has been reported to have significant activity in older AML (Vij Blood. 2011;117:1828–33). We hypothesized that sequential combination of 5-azacitidine followed by LEN could be safe and active in patients with higher risk MDS and AML. To test this concept, we developed a phase I/II protocol of such combination. Here, we present results from the completed phase I portion of the study. Patients with refractory or relapsed AML and MDS (bone marrow blasts more than 10%) of any age or untreated patients older than 60 years with AML or MDS who refused or were not eligible for frontline therapy were eligible. Adequate performance status, liver function and renal function were requiered. All study participants were registered into RevAssist® program. Females of childbearing potential were required to have a negative pregnancy test. 5-azacitidine was administered at 75 mg/m2 IV daily for 1 to 5 day on a 28 day cycle. LEN was administered on day 6 for 5 or 10 days. The phase I portion of the study design followed a classic “3+3” design and only LEN was dose escalated. 28 patients were registered in the study. The following doses of LEN were used: 10 (N=5), 15 (N=3), 20 (N=3), 25 (N=3), 50 (N=4), 75 mg (N=3) orally for 5 days and 75 for 10 days (N=7). Median age was 65 (range 31 to 79); 19 patients had AML and 9 had MDS or CMML. Median baseline WBC was 1.95 K/μL (range 0.1 to 19.1), median platelet count 68 K/μL (4 to 328), median bone marrow blasts 23% (range 11% to 84%), 8 had diploid cytogenetics and 20 others including 5q- (8 patients), monosomy 5 (5 patients) and monosomy 7(7 patients), del 17 (4 patients), t(9:11)(2 patients) and t(3;5)(2 patients). FLT-3 and N-RAS mutations were seen in 2 patients each and NPM-1 mutation in 1 patient. 22 patients had received prior therapy. A total of 88 cycles of therapy have been administered with a median of 1.5 cycles (range 1 to 10). No dose limiting toxicity was documented and the maximal tolerated dose was therefore not reached. At the 75 mg × 10 days dose, one patient died unexpectedly and subsequently 6 additional patients were treated with no additional severe toxicities observed. Common non-hematological toxicities were fatigue, loss of appetite, constipation, skin rash, fevers and weight loss. Of 6 patients that had not received prior therapy, 5 were evaluable for response and 3 (60%) achieved a complete response at doses of 25 and 50 mg of LEN. No response was observed in previously treated patients but 9 (47%) had stable disease. In conclusion, the combination of 5-azacitidine with high dose LEN up to 75 mg orally × 10 days is safe in patients with AML/MDS. The study continues now in a phase II extension of N=40 patients with LEN at a dose of 50 mg daily × 10 days. Disclosures: No relevant conflicts of interest to declare.

Abstract: With the advent of tyrosine kinase inhibitors (TKIs), significant improvement has been made in the survival outcome of chronic myeloid leukemia (CML) patients. However, blastic phase (BP) CML remains a therapeutic challenge. Extramedullary disease (EMD) is a diagnostic criterion for BP, and patients with this presentation represent a unique subgroup of BP CML. The characteristics of EMD in BP CML patients have not been well described, especially in the era of TKIs. Methods We have analyzed CML patients with extramedullary BP either at the time of diagnosis or progressing from CP/AP from 2000 to 2011 and treated with different TKIs such as imatinib, nilotinib, dasatinib, bosutinib, and ponatinib at a single institution. All demographic, clinicopathologic variables and medication data including TKIs were collected at the time of the diagnosis of BP. Primary outcomes, overall survival (OS) were defined as time from diagnosis of BP to death. Results Among a total of 284 BP CML patients, median age was 52.6 (range: 15-81) years. Males were 65.0%. 72.2% were in myeloid BP versus 27.7% in lymphoid BP. Median follow up was 1.5 (range: 0.01-12) years. Median time from diagnosis of CML to BP was 2.3 (range: 0.01-28) years. 128 (45%) patients have died. Cytogenetic analysis at diagnosis demonstrated that 34% had only Philadelphia chromosome (Ph) present while 66% had other chromosomal abnormalities besides Ph. Trisomy 8 was the most common additional chromosomal abnormality (18%). 280 (99%) were treated with TKIs. Among them, 176 (623%) were treated with TKI monotherapy, and the rest with a combination of TKI and conventional chemotherapy. Among the patients treated with TKI, 134 (48%) used imatinib; 85 (30%), dasatinib; 48 (17%), nilotinib; 7 (3%), bosutinib; and 6 (2%), ponatinib. EMD was diagnosed in 78 patients (28%) of all BP CML patients. Patients with EMD had a median age of 52.8 (range: 19-80) while BP patients without EMD had a median age of 52.2 (range: 15-81). There were no statistically significant differences in age, gender, ethnicity, or time from diagnosis of CML to BP between EMD and non-EMD patients. Among patients with EMD 76% were myeloid, and 23% lymphoid compared with 70% myeloid and 30% lymphoid in patients without EMD (p=0.3). Patient with EMD had more Ph-only disease compared with patients without EMD (41% vs. 28%, p=0.03). Among 28 patients with deletion 7 chromosomal abnormality, only 1 patient had EMD (EMD vs. non-EMD chi-square p=0.002). There was no association between the presence of EMD and other chromosomal abnormalities such as double Ph, isochromsome 17, trisomy 8, deletion Y and variant Ph. Among patients with EMD, 39 (50%) had EMD in CNS; 22 (28%) in soft tissue, skin, or lymph nodes; 9 (12%) in bones; 8 (10%) in lung or pleura; and 4 (5%) in GI tract and liver. Among patient with BP CML, there were no statistically significant differences between the EMD and non-EMD groups in both complete hematologic response (CHR) rate and complete cytogenetic response (CCyR) rate at 3 months after the initiation of therapy (CHR: EMD 18% vs. non-EMD 22%, p=0.4; CCyR: EMD 8% vs. non-EMD 15%, p=0.1). However, the presence of EMD was associated with worse survival outcome (Hazard Ratio [HR]=1.62, Confidence Interval [CI] = 1.13-2.32, p=0.008). Median overall survival in patients with EMD was 0.8 versus 2.5 years in patients without EMD (log-rank test p=0.008, Figure 1). EMD in CNS was not associated with survival (HR=0.87, CI=0.50-1.51, p=0.6). In multivariate analysis controlling for age, gender, ethnicity, white cell counts, cytogenetics (presence of additional chromosomal abnormality), and pathology (myeloid versus lymphoid), EMD was still linked with adverse survival (adjusted HR=1.53, CI=1.04-2.26, p=0.03). Conclusion BP CML patients presenting with EMD are likely to have less additional chromosomal abnormality and have inferior overall survival compared with those without EMD. EMD may represent more aggressive pathophysiology in BP CML and may require more intensive treatment. Disclosures: No relevant conflicts of interest to declare.

Abstract: Background: The combination of low intensity therapy with inotuzumab ozogamicin improved survival compared to intensive chemotherapy and to single agent inotuzumab ozogamicin in first salvage (Jabbour et al. Cancer. 2018 (in press)). The incidence of veno-occlusive disease (VOD) is minimized with weekly divided dosage and reduced dose of inotuzumab ozogamicin per cycle. Blinatumomab single agent improves survival in relapsed / refractory ALL compared to that of standard chemotherapy. The sequential addition of blinatumomab to mini-hyper-CVD + inotuzumab ozogamicin might further improve survival and minimize the risk of veno-occlusive disease (VOD) by allowing a reduction of inotuzumab dose and spacing allogeneic stem cell transplant (ASCT) from the last dose of inotuzumab. Methods: Patients with relapsed / refractory Philadelphia chromosome negative ALL were eligible. The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracycline. Even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. Inotuzumab ozogamicin was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 67 pts were treated, an amendment was made to incorporate 4 cycles of blinatumomab after 4 cycles of mini-hyper-CVD + inotuzumab ozogamicin. Inotuzumab ozogamicin was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 at subsequent cycles; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with ASCT was based on the discretion of the treating physician after discussion with the patient. Results: From 2/2013 to 5/2018, 84 patients were enrolled and treated including 17 patients with mini-hyper-CVD + inotuzumab + blinatumomab. The median follow-up is 31 months (range, 0.1-64.1). Patient characteristics and outcome are summarized in Table 1. The median age was 35 years (range, 9-87), and 23% of patients had received prior ASCT. The overall response rate was 80% (CR, 58%, CRp/CRi, 21%). These rates were 92% in S1 (primary refractory, 100%; CR1 duration 〈 12 months, 82%; CR1 duration 〉 12 months, 100%) and 56% in S2, and 60% in S3 or higher. Among 64 evaluable patients for minimal residual disease (MRD) assessment, 51 patients (80%) achieved negative MRD by 6-color flow cytometry with higher rates of negative MRD at 85% in salvage 1. Thirty four patients (40%) received ASCT. Three-year CR duration and overall survival (OS) rates were 49% and 33%, respectively (Figure 1). The median OS was 25 months, 6 months, and 7 months in salvage 1, salvage 2, and salvage 3 or more, respectively (p=0.001). Historical comparison showed median OS of 14 months and 6 months in hyper-CVD + inotuzumab ozogamicin +/- blinatumomab and inotuzumab ozogamicin single agent, respectively (p=0.001) (Figure 2). Among the 79 evaluable patients, VOD was observed in 9 (11%). The incidence of VOD was reduced from 9/61 (15%) with single dose of inotuzumab ozogamicin to 0/18 (0%) with weekly divided dose schedule. Of the 17 patients treated with mini-hyper-CVD + inotuzumab ozogamicin + blinatumomab, 3 patients underwent ASCT (2, haploidentical transplant; 1, cord blood transplant). Conclusion: The combination of inotuzumab ozogamicin plus/minus blinatumomab with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with relapsed/refractory ALL. The risk of VOD can be minimized with fractionated inotuzumab ozogamicin dosing. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding. Short:Takeda Oncology: Consultancy. Jain:Verastem: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Research Funding; Pharmacyclics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Servier: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Kadia:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Research Funding.

Abstract: Introduction: Germline predispositions to hematologic malignancies were historically thought to be rare; however growing awareness has raised clinical challenges regarding how to identify, test, and manage these patients. Germline mutations in the gene DDX41 predispose to moderately increased lifetime risks of MDS and AML with a later age of onset. Optimal clinical care of these patients relies on identifying germline mutations and innovative strategies are needed to improve clinical detection. Methods: 1,262 individuals with myeloid malignancies underwent next-generation sequencing (NGS)-based molecular sequencing of DDX41. Individuals identified to have ≥1 DDX41 alterations present at 〉 40% variant allele frequency (VAF) in the bone marrow were flagged for potential referral to genetic counseling (GC). All individuals referred for GC underwent standard genetic counseling evaluation and were offered DDX41 germline analysis on cultured skin fibroblasts. Results: Of 1,262 individuals, 32 (2.5%) were identified to have ≥1 somatic DDX41 mutation(s). Fourteen (44%) were referred for GC and germline confirmation testing. Eleven patients were male (78.5%) and 13/14 (93%) were Caucasian. Average age at diagnosis of myeloid neoplasm was 65 years (range 53-77 years). Fifty-seven percent (8/14) individuals were diagnosed with AML, 6/14 presented with MDS, including therapy-related MDS. 12/14 patients had diploid cytogenetics at presentation. A second somatic DDX41 mutation (biallelic) was identified in 10/14 (71%). There were no other significantly recurrent concomitant somatic mutations. Thirteen patients underwent germline evaluation and 12/13 (92%) were confirmed to have a germline DDX41 mutation. Six individuals underwent hematopoietic stem cell transplantation (SCT); five from a matched related donor, and in four cases, the related donor was negative for the familial DDX41 mutation. Six patients (43%) reported antecedent cytopenias: five with leukopenia and one with anemia. Five patients had a prior history of malignancy: three with prostate cancer, one with Non-Hodgkin's lymphoma and melanoma, and one with MGUS. 13/14 (93%) patients reported a family history of cancer, six (43%) of which included hematologic malignancies and/or cytopenias. From the 12 DDX41 germline-positive patients, 11 unaffected relatives underwent genetic testing. Four (36%) tested positive for the familial DDX41 mutation and seven (64%) tested negative. Conclusions: The detection of somatic DDX41 mutations at near-heterozygous frequencies on NGS panel testing is highly suggestive of a germline mutation and germline testing is strongly recommended. Our data validates existing reports in DDX41 germline patients including primarily high grade myeloid neoplasms, diploid cytogenetics, and later age at diagnosis. Interestingly nearly half of our patients had antecedent cytopenias, most often leukopenia. NGS screening for DDX41 mutations through multi-disciplinary collaboration is a useful and feasible tool to screen unselected myeloid neoplasm patients for high likelihood of germline DDX41 mutations enabling timely and appropriate care of these patients. Disclosures Daver: Novartis: Consultancy; Incyte: Research Funding; Pfizer: Consultancy; ImmunoGen: Consultancy; Pfizer: Research Funding; Sunesis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Sunesis: Research Funding; Kiromic: Research Funding; Karyopharm: Research Funding; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Incyte: Consultancy; Otsuka: Consultancy; Karyopharm: Consultancy. Oran:AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; ASTEX: Research Funding. Kadia:Abbvie: Consultancy; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Celgene: Research Funding; BMS: Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. DiNardo:Karyopharm: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Abbvie: Honoraria; Medimmune: Honoraria; Agios: Consultancy.

Abstract: The hyper-CVAD regimen is an effective frontline program for de novo adult ALL. Expression of CD20 was identified as an adverse prognostic factor, associated with a higher incidence of relapse, lower 3-year complete remission duration (CRD) and lower 3-year overall survival (OS) rate. The addition of rituximab to the hyper-CVAD program in patients with CD20-positive ALL (≥20% expression by multicolor flow cytometry - FCI) improved outcome with 3-year CRD and OS rates by 68% and 65%, respectively. Ofatumumab (HuMax-CD20) targets a membrane proximal small-loop epitope on the CD20 molecule and was found to be more potent than rituximab in promoting complement-dependent cytotoxicity in vitro. Ofatumumab’s safety and efficacy has been proven in chronic lymphocytic leukemia. Therefore a combination of the hyper-CVAD regimen and ofatumumab may be associated with better response rates, higher 3-year complete remission duration (CRD) and overall survival rates. Methods In this phase II trial, pts with newly diagnosed ALL and pts who received one prior course of chemotherapy received 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); ofatumumab was given on courses 1 and 3, and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8); ofatumumab was given on courses 2 and 4. This treatment will be followed by POMP (6-mercaptopurine, MTX, VCR, prednisone) maintenance therapy for approximately 30 months, interrupted by intensifications months 6, 7 and 18, 19 with MTX/Pegylated asparaginase and hyper-CVAD-ofatumumab. Central nervous system prophylaxis with MTX and ara-C was administered. When indicated local radiotherapy was administered in patients with bulky mediastinal disease Results To date 17 pts with de novo ALL and 2 pts in complete remission (CR) previously treated (1 with prior cycle of hyper-CVAD and 1 post fludarabine-cytarabine based regimen) have received a median of 5 cycles (1-8) of therapy; 3 pts did not receive the full 8 planned courses of induction-consolidation. 8 pts are receiving maintenance in CR. Median age is 50 years (39–71). Median WBC at diagnosis was 5.5 x 109/L (1 -189 x 109/L). CD20 expression above 20% was found in 11 pts (58%), between 10 and 20% in 1 (5%) and below 10% in 7 (37%). 2 pts (11%) had concomitant CNS disease at diagnosis. Among the 15 pts with evaluable baseline cytogenetic analysis, 10 (67%) were abnormal. All but one pt (94%) achieved a CR after cycle 1; 1 pt died of septic shock and multiple organ failure at day 21 of cycle 1. All eighteen (100%) pts achieved minimal residual disease (MRD) negativity as assessed by FCI; of whom 12 (67%) achieved MRD negativity after induction. Median time to neutrophil and platelet recovery for cycle 1 was 19 and 23 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥ 3 toxicity included increase of LFT’s in 7 pts (37%), increase of bilirubin in 5(26%), thrombotic events in 1 (5%) and neuropathy in 1 (5%). Febrile neutropenia episodes during induction and consolidation cycles were reported at rates of 76% and 65%, respectively. With a median follow up of 8 months (1-23), 18 pts are alive and in CR; 1 pt has undergone an allogeneic stem cell transplant after cycle 3 by reason of a highly complex karyotype at diagnosis. The 1-year CRD and overall survival rates were 100% and 95% respectively. Conclusion The combination of hyper-CVAD with ofatumumab is safe and highly effective in pts with CD20-positive ALL. Disclosures: Jabbour: GSK: Research Funding. Off Label Use: Ofatumumab in ALL. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria.

Abstract: Abstract 4239 Nelarabine is a prodrug of arabinosylguanine (ara-G), a cytotoxic nucleoside analogue that targets T-cells. In vitro investigations and clinical trials in pediatric and adult patients (pt) demonstrated activity in T-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (T-LBL) resulting in FDA approval for the treatment of refractory or relapsed T-ALL/T-LBL. The schedule of drug infusion was daily × 5 or on days 1, 3, 5 with an infusion-duration of two hours. While this bolus infusion was clinically effective, the dose-limiting toxicity was neurotoxicity: which can manifest as somnolence, seizures, paralysis, or most commonly chronic peripheral neuropathy. Based on experience with similar nucleoside analogues such as cytarabine, we hypothesized that neurotoxicity with nelarabine could be dosing schedule-related and a continuous infusion (C.I.), rather than bolus, may mitigate this toxicity. A phase I trial was designed to determine the safety, pharmacokinetics (PK), and maximum tolerated dose (MTD) of nelarabine given as a C.I. for 5 days. We report the preliminary results of clinical efficacy and PK and pharmacodynamics (PD) from a dose-escalation study of C.I. nelarabine. Four dose levels are planned, starting at 200mg/m2/d for 5 days (d) on a 28 d cycle, escalating according to the classic 3+3 design (200, 300, 400, and 500 mg/m2/d). The starting dose (200 mg/m2/d × 5 d) is 22% of the recommended bolus-infusion dose (1500 mg/m2/d on days 1, 3, 5 of a 21 d cycle). Six pts (1 female) have been enrolled thus far with a median age of 29 (range 24–70 yrs). Five pts (83%) had a diagnosis of relapsed T-ALL, and 1 had relapsed T-prolymphocytic leukemia (PLL). The median number of prior therapies is 1 (1–3). All 6 patients were treated at the first dose level (including 3 in an expansion cohort) and all patients received at least one course of therapy. Five patients are evaluable for toxicity and response after completion of cycle 1. Overall, the infusion was well tolerated with no infusion reactions. All patients experienced myelosuppression. Most non-hematologic toxicities were grade 1 or 2 in severity: 1 occurrence of grade 1 respiratory distress, and 1 grade 1 neuropathy. One patient was admitted for neutropenic fever, sepsis, and grade 3 renal dysfunction related to sepsis. One patient developed grade 3 peripheral neuropathy, which was defined as a dose limiting toxicity. At this starting dose level, 2 patients with T-ALL had stable disease, 1 had a partial response, and 1 had a complete response for an overall response rate of 40% (2/5). The patient with T-PLL had progressive disease. The 2 patients with T-ALL who achieved a response were both able to go onto allogeneic stem cell transplant. Plasma pharmacokinetics of nelarabine and steady-state ara-G are being analyzed. Cellular pharmacokinetics data (n = 5) suggest that the triphosphate of ara-G (ara-GTP) increased for 2–3 days without reaching a steady-state level. Ara-GTP accumulation in leukemia cells continued throughout the 6-day infusion in 3 patients. The Cmax concentration of ara-GTP was 109 uM (range 58 – 205 μ M). In conclusion, preliminary evaluation of continuous-infusion nelarabine suggests that the safety profile is acceptable for the selected patient population. Clinical activity has been observed at a low dose with C.I., and additional pts are needed to be evaluated to establish utility of this schedule. Continued dose escalation is planned. Disclosures: Kadia: Glaxo Smith Kline: Research Funding. Off Label Use: Nelarabine given as a continuous infusion for any lymphoid malignancy is an off label, investigational use. Borthakur:Glaxo Smith Kline: Research Funding.