Citations

Abstract Background: High risk CLL patients treated with novel targeted therapies continue to experience disease progression (PD), and more than 50% of these PD patients evolve into Richter's syndrome (RS), (Maddocks, Jama Oncol 2015). Standard chemotherapy for large cell lymphoma has limited efficacy (median overall survival <12 months) in RS. Novel immunotherapy using a PD-1 antibody to block immune checkpoint signals to activate the cytotoxic T -cell has significant efficacy in relapsed Hodgkin lymphoma (Ansell, NEJM 2015). We conducted a phase 2 trial to test the safety and clinical efficacy of the anti-PD-1 antibody pembrolizumab in patients with relapsed/refractory CLL and relapsed low grade B non-Hodgkin lymphoma (B-NHL) (MC1485 trial). Methods: MC1485includes two arms: patients with relapsed/refractory CLL (including RS) and patients with relapsed B-NHL. The main end points of this study are safety and overall response rate. The first 6 patients enrolled in either arm were included in a designed safety interim analysis. Here we report the initial interim analysis from the CLL arm. Relapsed/refractory CLL including RS who had ECOG performance 0-2 and normal organ function were included. Patients with active autoimmune disease or interstitial lung disease were excluded. Pembrolizumab 200 mg was administered intravenously every 3 weeks until progression, excessive toxicity, or completion of 2 years of therapy. Soluble plasma PD-L1 levels were measured in these 6 patients using an established ELISA assay (Frigola, Clin Cancer Res, 2011). CD8+ T cell subsets were assessed for their functional status using an established analysis (Liu, Oncoimmunology. 2013) at baseline and after 2 cycles of therapies. Results: As of July 27th, 2015, 16 relapsed/refractory CLL patients including 5 RS patients were enrolled. The median age was 71 years (58-81). The median number of prior therapies was 3 (1-6). All CLL patients had received chemoimmunotherapy (FCR/PCR). 4 out of 5 RS patients had received anthracycline-containing chemotherapy. 5 out of 8 patients who had received prior ibrutinib therapy progressed on ibrutinib. 8 patients had 17p-/TP53 mutation. Herein, we report preliminary results from the interim analysis of CLL arm including 4 RS and 2 CLL as well as the 5th RS who had response evaluation by PET. The median cycles of therapy administered was 4 (3-7). One patient experienced grade 2 cytokine release syndrome with transient febrile neutropenia, grade 3 headache and skin rashes. These symptoms resolved with steroid therapy. One patient experienced grade 3 myalgia and was also treated with steroids. The other patients in this safety cohort tolerated pembrolizumab well. The most common drug-related adverse events were grade 1 dyspnea (33%, 2/6) and grade 1 anemia (33%, 2/6). Based on investigator assessment using the Cheson 2007 International Working Group Criteria, 4 out of 5 RS patients had responded to therapy. One patient had a complete remission after 2 cycles and remains in remission. One patient had almost complete PET response after two cycles and is classified as PR as her bone marrow have not been re-evaluated yet. Two patients had notable responses with nodal and skin lymphoma improvements before they showed potential evidence of progressive diseases. The remaining 1 RS and 2 CLL had stable disease and continued on therapy at the last follow-up. Soluble PD-L1 levels (sPD-L1, n=6) were measured at baseline and after 2 cycles of therapies. 3 RS patients who had responded to therapy had decreased or stable sPD-L1 levels. The 4th RS and two CLL had increased sPD-L1 levels and had not demonstrated clinical response. CD8 T-cell subset analyses performed blindly (n=4) showed increased CD8 T cell function in one of the 4 patients tested. This patient who demonstrated CD8 T cell functional enhancement is the only patient in the 4 tested patients who had notable response to pembrolizumab. Conclusion: Pembrolizumab is tolerated in relapsed CLL and RS patients. Early efficacy observed in heavily pretreated RS patients including patients progressed on both anthracycline-based treatment and ibrutinib indicate PD-1 inhibition is a promising novel approach in patients with RS. Our CD8 T cell subset analysis may be used as a biomarker assay to predict clinical response in the era of novel immunotherapy. This trial and further correlative analysis is ongoing and will be presented at the ASH meeting. Disclosures Ding: Merek: Research Funding. Shanafelt:Cephalon: Research Funding; Pharmactckucs: Research Funding; Janssen: Research Funding; Hospira: Research Funding; Polyphenon E Int'l: Research Funding; Celgene: Research Funding; Glaxo-Smith_Kline: Research Funding; Genentech: Research Funding. Kay:Tolero Pharma: Research Funding; Hospira: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

Abstract Introduction: Ibrutinib has shown remarkable safety and efficacy in CLL. Due to CYP3A4 (3A4) metabolism, the concurrent use of 3A4 inhibitors/inducers with ibrutinib should be avoided. Ibrutinib is also associated with bleeding complications, in part due to effects on collagen-mediated platelet aggregation, thus caution is advised with the simultaneous use of anticoagulant (AC) and antiplatelet agents. It is unknown what proportion of CLL patients starting ibrutinib therapy in routine practice are on these medications. We conducted a retrospective study to evaluate these aspects in a large cohort of CLL pts treated with ibrutinib outside the context of clinical trials. Methods: Following IRB approval, consecutive CLL pts who initiated ibrutinib off-protocol at Mayo Clinic, Rochester, MN from November 2013 through July 2015 were evaluated. A medication review for drug-drug interactions was performed by a pharmacist on all pts. Baseline characteristics, concomitant medications, and toxicity were recorded. Time to toxicity and ibrutinib discontinuation were analyzed by Kaplan Meier and cumulative incidence methods accounting for competing risk of death, respectively. Results: Ninety-six CLL pts started ibrutinib. Median age was 66 years and 64 (67%) were male. Ibrutinib indications included: relapsed/refractory CLL (n=84), treatment-naïve CLL with del17p (n=8), and CLL with Richter's transformation (n=4). Approximately 80% had unmutated IGHV and 45% had del17p or del11q on FISH. Upon initial pharmacy consult prior to ibrutinib, the median number of concomitant medications was 9 (range, 1-31). Sixty (63%) pts were taking concurrent medications increasing their risk of ibrutinib toxicity and 4 (4%) pts were on drugs potentially reducing ibrutinib efficacy. At ibrutinib initiation, 16 (17%) pts were on concomitant 3A4 inhibitors. This included 9 (9%) on moderate 3A4 inhibitors (fluconazole, diltiazem, imatinib, cyclosporine) and 7 (7%) on strong 3A4 inhibitors (voriconazole, posaconazole, clarithromycin, itraconazole). In 4 pts, the 3A4 inhibitor was switched to another agent or discontinued to allow standard 420 mg daily dosing. Ibrutinib was initiated at 140 mg daily in 7 pts on moderate 3A4 inhibitors and at 140 mg every 48 hours in 5 pts on strong 3A4 inhibitors. Four (4%) pts were on strong 3A4 inducers (carbamazepine, rifampin, rifabutin) at the initiation of ibrutinib. The 3A4 inducer was discontinued prior to ibrutinib start in 3 pts, while the initial ibrutinib dose was decreased to 140 mg every 48 hours in the remaining patient (also on 2 strong 3A4 inhibitors). During the course of ibrutinib, an additional 8 (8%) pts were started on 3A4 inhibitors/inducers which necessitated dose modifications. Upon commencing ibrutinib, 9 (9%) pts were on concomitant AC (6 warfarin, 3 enoxaparin). Due to significant bleeding risk, warfarin was switched to enoxaparin in 2 pts, to aspirin (ASA) in 1 and warfarin was discontinued in 1. In 2 pts, an alternative AC could not be used so ibrutinib was begun at 140 mg daily and titrated upward. Twenty-nine (30%) pts were on ASA (3 [3%] also on clopidogrel) at ibrutinib initiation. Nineteen (20%) pts were on selective serotonin release inhibitors (SSRIs), and 9 (9%) were on NSAIDs. Thirteen (13%) pts were on fish oil and 24 (25%) were on herbal medications; all of which were discontinued prior to starting ibrutinib. Ten (10%) pts had clinically significant bleeding on ibrutinib including 4 (4%) requiring hospitalization (1 subdural hematoma). Of these 4 pts, 1 was on enoxaparin, 2 were on a SSRI and 1 a NSAID. Six pts had minor bleeding necessitating a dose reduction of ibrutinib to 140-280 mg daily. After 16 months follow-up, the risk of bleeding was 21% (95% CI: 1-37%, Figure). After a median follow-up of 7.6 months, 73 (76%) pts remain on ibrutinib. There was no difference in rates of discontinuation of ibrutinib between patients who were on 3A4 inhibitors/inducers versus those who were not. Conclusion: In the "real-world" setting, 2 out of 3 CLL patients commencing ibrutinib therapy is on a concomitant medication with a potentially clinically significant drug-drug interaction with ibrutinib. These findings have implications for the practicing hematologist who must maintain a high degree of vigilance when prescribing ibrutinib to CLL pts. We highly recommend a formal medication review by a clinical pharmacist in all patients initiating ibrutinib. Figure 1. Figure 1. Disclosures Ding: Merck: Research Funding. Kay:Hospira: Research Funding; Tolero Pharma: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shanafelt:Glaxo-Smith_Kline: Research Funding; Pharmactckucs: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding; Janssen: Research Funding; Hospira: Research Funding; Polyphenon E Int'l: Research Funding.

Abstract BACKGROUND: Consistent with the advanced age at diagnosis (median age ~70 years), most patients with CLL have co-existent health problems. These co-morbidities influence the ability of many CLL patients to tolerate aggressive chemotherapy-based treatment and can also contribute to treatment-related side effects. The recent development of novel signaling inhibitors, particularly the Bruton's tyrosine kinase inhibitor ibrutinib, has been a major treatment advance for patients with CLL. While these agents generally have favorable toxicity profiles relative to standard chemotherapy-based treatments, they are chronic therapies which patients typically stay on for an extended period. Preliminary data suggests ibrutinib may be associated with an increased risk of atrial fibrillation (Afib). In one randomized trial comparing ibrutinib to ofatumumab in patient with relapsed CLL, incident grade 3+ Afib occurred in 3% of ibrutinib treated patients compared to 0% of ofatumumab treated patients (NEJM 371:213). Despite these observations, the baseline frequency of Afib in patients with CLL is not well described - particularly incident atrial fibrillation acquired during the course of the disease. METHODS: We used the Mayo Clinic CLL database to evaluate the prevalence of Afib at the time of CLL diagnosis as well as the incidence of Afib during follow-up. All patients with a new diagnosis of CLL after January 1995 who were seen at Mayo within 12 months of diagnosis were included in the analysis. Afib was identified by chart review and by billing search using ICD9 codes. Data on co-morbid conditions associated with risk of Afib was also abstracted (e.g. hypertension, coronary artery disease [CAD], valvular heart disease, cardiomyopathy, diabetes mellitus, pulmonary disease). RESULTS: A total of 2444 patients with newly diagnosed and previously untreated CLL were seen at Mayo Clinic within 12 months of diagnosis between 1/1995 and 4/2015.Median age at diagnosis was 65 years and 1626 (66.5%) patients were men. A history of Afib was present at the time of CLL diagnosis in 148 (6.1%) patients. Four additional patients had Afib documented in the record but the precise date of onset (e.g. prior to or after CLL diagnosis date) could not be determined. Age, male sex and history of CAD, valvular heart disease, cardiomyopathy, hypertension, and diabetes were associated with a greater likelihood of having a history of Afib at the time of CLL diagnosis (all p&lt;0.01). Among the 2292 patients without a history of Afib at CLL diagnosis, 139 (6.1%) had incident Afib during the course of follow-up for their CLL. The incidence of Afib among patients without a history of Afib at diagnosis was approximately 1%/year (Figure 1A). Considering both Afib present at the time of CLL diagnosis or acquired during the course of the disease, 291 (11.9%) of the 2444 patients in this cohort experienced Afib (median follow-up: 59 months). Among patients without Afib at the time of CLL diagnosis, the following characteristics at the time of CLL diagnosis were associated with an increased risk of incident Afib on multivariate analysis: older age (age 65-74 HR=2.4, p&lt;0.001; age ≥75 HR=3.6, p&lt;0.001), male sex (HR=1.8, p=0.004); valvular heart disease (HR=2.4, p=0.007), and hypertension (HR=1.5; p=0.02). A predictive model for acquired Afib was subsequently constructed based on the independent factors in the Cox regression model. An individual weighted risk score was assigned to each independent factor based on the regression coefficients of the HRs. The Afib risk score (range 0-7) was defined as the sum of the scores of these independent factors. The risk of incident Afib among patients with risk scores of 0-1, 2-3, 4, and 5+ is shown in Figure 1B. Rates for these 4 groups were significantly different (p&lt;0.001), with the 10-year Afib rates (95% C.I.) for those with a score of 0-1, 2-3, 4, and 5+: 4% (2-6%), 9% (6-13%), 17% (11-23%), and 33% (20-43%), respectively. CONCLUSIONS: A history of Afib is present in approximately 1 out of every 16 patients with newly diagnosed CLL. Among patients without Afib at diagnosis, the incidence rate of Afib is ~1%/year. The risk of incident Afib in newly diagnosed CLL patients can be predicted based on age, sex, and co-morbid health conditions present at diagnosis. These data provide context to help interpret data on the frequency of Afib in CLL patients treated with ibrutinib and other novel agents. Disclosures Shanafelt: Janssen: Research Funding; Polyphenon E Int'l: Research Funding; Glaxo-Smith_Kline: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Pharmactckucs: Research Funding. Ding:Merek: Research Funding. Kay:Tolero Pharm: Research Funding; Hospira: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 1. Combinations of effective agents produce at least an additive increase in complete remission rates over that which can be achieved when the agents are used individually. 2. Patients who do not achieve complete remission with initial treatment have a significantly shorter survival. 3. Alternating MTX and 6-MP at 28-day intervals during remission does not prolong the duration of remission over that of combined concurrent 6-MP and MTX. 4. The administration of folic acid antagonists intrathecally at 28-day intervals during antimetabolite maintained remission did not prolong the duration of remission. Meningeal leukemia, however, occurred significantly less frequently in these patients. 5. The duration of combined 6-MP and MTX maintained remission is not greater than that of 6-MP maintained remission. 6. The toxicity of 6-MP and MTX in combination in patients in remission is additive. The above conclusions were drawn from this comparative study of combinations of chemotherapeutic agents in children with acute lymphocytic leukemia.

Abstract Background: Patients with polycythemia vera (PV) can have a pronounced symptom burden that negatively impacts their quality of life (QoL). Traditional treatment options such as phlebotomy, hydroxyurea, and interferon provide clinical benefit but frequently do not alleviate symptoms. The ongoing REVEAL study is being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the US. This preliminary analysis describes the burden of PV based on patient-reported outcomes (PROs), including health-related QoL and work productivity. Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study. Eligible patients are ≥18 years of age with a PV diagnosis and currently under active management by a physician in the US. PROs are being collected at study enrollment and every 3 months thereafter. Each of the 10 items on the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) are graded from 0 (absent) to 10 (worst imaginable), with individual symptom scores ≥7 considered severe; total symptom score (TSS) ranges from 0-100. Raw scores for items on the 30-item European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) are standardized by linear transformation to 0-100. Higher scores on the EORTC QLQ-C30 indicate better functioning for global health status/QoL and functional subscales and worse severity for symptom subscales. Outcomes with the 6-item Work Productivity and Activity Impairment Specific Health Problem questionnaire (WPAI-SHP) are presented as a proportion from 0% (minimal/no impairment) to 100% (maximal impairment/productivity loss). Analyses of these preliminary data were descriptive. Results: At the time of data cutoff (June 9, 2015), REVEAL had enrolled 865 patients (total planned enrollment, n=2000), the majority were male (55.5%) and white (89.5%), with a median age of 67 (range, 22-95) years. 782 patients had completed the PRO questionnaires at the enrollment visit. A majority of patients reported ≥1 PV-related symptom. Mean (SD) MPN-SAF symptom scores were highest for fatigue (3.5 [2.7]), early satiety (2.7 [2.8]), inactivity (2.7 [2.9]), itching (2.6 [3.1]), and concentration problems (2.1 [2.6]). The mean (SD) MPN-SAF TSS (sum of 10 symptom scores) was 19.6 (16.1). The most frequently reported severe symptoms were fatigue, itching, inactivity, early satiety, night sweats, concentration problems, and bone pain (Table 1). Mean (SD) global health status/QoL reported on the EORTC QLQ-C30 was 72.8 (23.4); functional subscales were as follows: cognitive functioning, 80.3 (24.5); emotional functioning, 80.7 (24.0); physical functioning, 83.1 (20.6); role functioning, 84.3 (26.1); and social functioning, 85.0 (25.0). The most severe mean (SD) symptom subscale scores were fatigue (30.7 [28.5]), insomnia (29.5 [34.5]), pain (20.9 [29.3]), and dyspnea (17.3 [28.6]). Among patients who were employed at baseline (n=273), mean (SD) PV-related WPAI-SHP scores were as follows: absenteeism (ie, work time missed), 2.9% (10.6%); presenteeism (ie, impairment at work/reduced on-the-job effectiveness), 10.7% (20.4%); work productivity loss (ie, absenteeism plus presenteeism), 12.0% (22.2%); and activity impairment, 21.0% (28.0%). Conclusion: Preliminary descriptive data from patients currently enrolled in REVEAL suggest that patients with PV have notable impairment in QoL because of their disease; patient-reported scores on the MPN-SAF and EORTC QLQ-C30 were similar to those reported previously for patient populations with MPNs. Similarly, PV is associated with marked work productivity loss among patients who are currently employed. Subsequent analyses from REVEAL will evaluate changes over time in PROs and investigate correlations with disease progression and treatment. REVEAL can provide novel insights into questions related to the contemporary real-world QoL burden and its impact on PV-related symptoms and work productivity. Disclosures Mesa: Pfizer: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Promedior: Research Funding. Boccia:Incyte Corporation: Honoraria. Moliterno:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Naim:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: The Food and Drug Administration (FDA) approved ibrutinib in February 2014 based on results from a pivotal phase 2 clinical trial that enrolled 85 patients with relapsed/refractory CLL. A subsequent phase 3 trial confirmed the superior progression-free survival (PFS) and overall survival (OS) of ibrutinib compared to ofatumumab in 391 CLL patients. However, there is no information on the efficacy and safety of ibrutinib in CLL patients treated outside the context of clinical trials. Additionally, it is unclear if the reasons for discontinuation of ibrutinib differ in routine clinical practice from those described in patients treated on clinical trials. We conducted a retrospective study to evaluate these aspects in a large cohort of CLL patients treated with ibrutinib off-protocol. Methods: After IRB approval, CLL patients seen at Mayo Clinic, Rochester, MN, and treated with commercial ibrutinib from November 2013 through July 2015 were evaluated. The baseline characteristics, time to therapy discontinuation, reasons for discontinuation and survival following discontinuation were abstracted. Results: One hundred thirty-five patients with CLL were treated during the study interval; 124 received ibrutinib for relapsed/refractory CLL and 11 received ibrutinib for treatment-naïve CLL with TP53 disruption (either del17p on FISH or TP53 mutation). Patients with relapsed/refractory CLL (n=124) Patients were high-risk, with a median of 3 prior therapies (range, 1-15), 81% had unmutated IGHV, and 38% had either del11q or del17p on FISH testing. After a median follow-up of 6.4 months, 101 remain on ibrutinib therapy. The estimated proportion of patients continuing ibrutinib at 6 months was 84% (95% CI: 77-92%) and at 12 months was 70% (95% CI: 59-83%). Of the 23 who discontinued ibrutinib therapy, 8 discontinued for progressive disease (2 progressive CLL; 6 Richter's transformation). The remaining 15 discontinued therapy for reasons other than progression, including: infection (n=3), bleeding (n=3), diarrhea (n=1), atrial fibrillation (n=1), rash (n=1), immune thrombocytopenia (n=1), renal dysfunction (n=1), severe edema (n=1), MDS (n=1) and physician preference (n=2). Table 1 shows the reasons for discontinuation of ibrutinib in patients treated on clinical trials (Maddocks, JAMA Oncology, 2015) compared to the current cohort of patients. The estimated cumulative incidence of discontinuation of ibrutinib therapy due to CLL progression/Richter's transformation at 6 and 12 months was 9% (95% CI: 4-17%) and 12% (95% CI: 5-23%), respectively. The estimated cumulative incidence of ibrutinib discontinuation due to reasons other than progression at 6 and 12 months was 10% (95% CI: 5-17%) and 22% (12-34%), respectively (Figure). The median survival after discontinuation of ibrutinib for patients who had CLL progression was 3.5 months, not reached in patients who developed Richter's transformation and not reached in those patients who discontinued ibrutinib due to reasons other than progression. Patients with treatment-naïve CLL (n=11) All patients had evidence of TP53 disruption (9 had del17p, 3 had TP53 mutation, and 1 had both). After a median follow-up of 2.8 months, no patient has had progression of CLL, and 2 patients have discontinued ibrutinib therapy for reasons other than CLL progression (atrial fibrillation, n=2). The estimated proportion of patients continuing ibrutinib at 6-months was 71% (95% CI: 45-100%). All 11 are still alive, and no patient has undergone allogeneic stem cell transplantation. Conclusion: This is the first study that describes the outcomes of a large cohort of CLL patients treated with ibrutinib outside the context of clinical trials. Patients treated in routine practice appear more likely to discontinue ibrutinib for reasons other than progression of disease, compared to those participating in clinical trials. Our results confirm the poor survival of CLL patients who progress on ibrutinib. Table 1. Comparative analysis of reasons for discontinuation of ibrutinib in patients with relapsed/refractory CLL: Characteristic Current Study (%) Maddocks (JAMA Oncology 2015) (%) No. of patients 124 308 Median follow-up (months) 6.4 20 Reasons for Discontinuation Progression of disease CLL 2 (2) 13 (4) Richter's transformation 6 (5) 15 (5) Non-progression of disease Infection 3 (2) 28 (9) Other 12 (10) 17 (5) Figure 1. Figure 1. Disclosures Ding: Merek: Research Funding. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Tolero Pharm: Research Funding. Shanafelt:Cephalon: Research Funding; Celgene: Research Funding; Glaxo-Smith_Kline: Research Funding; Polyphenon E Int'l: Research Funding; Hospira: Research Funding; Janssen: Research Funding; Pharmactckucs: Research Funding; Genentech: Research Funding.

Abstract Background: Midostaurin (M) is a multi-targeted small molecule FLT3 inhibitor which has single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant FLT3 AML. The objective of this global rand phase III trial was to determine if the addition of M to ind and consol therapy followed by one year of maint would improve overall survival (OS) compared to standard chemotherapy in younger adults with activating FLT3 muts. Methods: Between May 2008 and October 2011, 3279 previously untreated AML pts age 18-60 (exclusive of acute promyelocytic leukemia) in 225 sites/17 countries were screened for FLT3 muts at one of 7 academic labs (subject to extensive assay cross-validation). Hydroxyurea was allowed for up to 5 d prior to beginning ind therapy while awaiting results of mut testing. Pts were rand for the duration of therapy to M or P stratified by FLT3 mut subtype (TKD v ITD high allelic mut fraction (>0.7) vs low mut fraction (0.05-0.7). Ind therapy consisted of D 60 mg/m2 IV d1-3 and C 200 mg/m2 d1-7 CIV plus M or P (50 mg po bid, d 8-22). Re-treatment with a second blinded course was allowed if residual AML was noted on a d 21 marrow exam. Pts achieving complete remission (CR) received 4 cycles of C 3g/m2 over 3h q 12h on days 1, 3, and 5 plus M or P (50 mg po bid, d 8-22) followed by a year of maint therapy with M or P (50 mg po bid). Transplantation (SCT) was allowed. With a sample size of 717 pts, the trial was powered to detect an improvement from 16.3 (P) to 20.9 (M) months in median OS (HR = 0.78) using a one-sided alpha of 0.025 and power of 84%. The final analysis was to occur after 509 deaths, but given the slow rate of events (359 deaths by April 2015), the trial was amended to change the timing of the OS analysis, and promote event free survival (EFS, defined as the earliest of death, relapse, or no CR within 61 d of the start of ind) as a key secondary endpoint. The critical value for this primary analysis is set at 0.02286 (1-sided) accounting for the alpha spent at the interim analysis (0.5%). Support: U10CA180821, U10CA180882, CA31946, Novartis Results: 717 pts (341 FLT3 ITD-Low, 214 FLT3 ITD-High; 162 FLT3 TKD) were rand to either M (n=360) or P (n=357). There were no significant differences between the arms in age (median, 48y), race, FLT3 subtype, or baseline CBC except for gender (M, 48.2% male; P, 40.6% male; p=.04). All pts are off active treatment, with a median follow-up of 57 months for surviving pts. No statistically significant differences were observed in the overall rate of grade 3 or higher hematologic or non-hematologic adverse events (AEs) between M and P (regardless of attribution). A total of 37 grade 5 AEs were reported (M, 5.3%; P, 5.0%; p=1.0). No differences in treatment-related grade 5 AEs were observed (M, 3.1%; P, 2.5%; p=0.82). CR rate is 59% (M) and 54% (P) (p=0.18). The HRs comparing M to P for OS is 0.77 (one-sided p = 0.007; Figure 1), and for EFS is 0.80 (one-sided p = 0.004; Figure 2). 402/717 (57%) pts received an allogeneic SCT (M, 58%; P, 54%) at any time; 177/717 (25%) in CR1 (M, 27%; P, 22%). Median time to allogeneic SCT was similar on each arm (M, 5.0 months; P, 4.6; p=0.23). Secondary analyses for OS and EFS censoring at the time of SCT provided similar results (Table). The benefit of M was consistent across all FLT3 subgroups for both EFS and OS (Figure 3). Conclusions: The C10603 trial demonstrated that a prospective trial in a pre-therapy genetically defined subgroup of AML pts was feasible and that the addition of the multi-kinase inhibitor M to standard chemotherapy and for one year of maint therapy significantly improved EFS and OS (in both uncensored and censored for transplant analyses) in pts whose blasts had a TKD or ITD (low or high FLT3 mut burden). These findings may lead to improved outcomes through the use of M as a component of therapy in younger adults with mutant FLT3 AML. Table.ArmMedian, mos (95% CI)p-value 15-year Event rate% (95% CI)HR2(95% CI)OSM74.7 (31.5, * )0.00750.8 (45.4-55.9)0.77 (0.63, 0.95)P26.0 (18.5, 46.5)43.1 (37.6-48.4)OS, SCT censoredM* (*,*)0.04762.6 (54.6-69.7)0.77 (0.56,1.05)P* (36.9, *)54.9 (46.2-62.8)EFSM8.0 (5.3, 10.6)0.004426.7 (22.2-31.5)0.80 (0.67, 0.95)P3.0 (1.9, 5.8)19.1 (15.1-23.6)EFS, SCT censoredM8.2 (5.5, 10.7)0.02524.2 (18.9-29.8)0.84 (0.70, 1.0020)P3.0 (1.9, 5.8)21.8 (16.8-27.3)1Stratified on FLT3 subtype; one-sided, log-rank p-value.2Cox model stratified on FLT3 subtype.*= not attained Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Stone: Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Amgen: Consultancy; Agios: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Celator: Consultancy; Juno: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy. Off Label Use: midostaurin- FLT 3 inhibitor. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Medeiros:Celgene: Honoraria, Research Funding; Agios Pharmaceuticals: Honoraria. Schlenk:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Research Funding; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Research Funding. Larson:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy, Research Funding; Pfizer: Consultancy.

Abstract Background: Follicular lymphoma (FL) is the most common indolent NHL with a heterogenous natural history of disease and a median survival of 8 to 12 y, albeit ranging between 1 to 20 y. Casulo et al. (2015) identified a high-risk FL cohort of patients with progression of disease (POD) at ≤24 months following initiation of immunochemotherapy with R-CHOP. Idelalisib (Zydelig) is a first-in-class, highly selective, oral inhibitor of PI3Kd which is indicated for relapsed FL or SLL following receipt of at least two lines of systemic chemotherapy. Retrospective subgroup analysis of the idelalisib registrational trial NCT01282424 (101-09) of a cohort with early POD following immunochemotherapy was performed to assess possible activity of idelalisib in this population. Methods: A subset of 46 patients enrolled in study 101-09 were identified as having been diagnosed with FL and having received first-line immunochemotherapy, of which 37 experienced early POD, defined as starting second-line treatment within 24 months of initial first-line treatment. For the latter group, descriptive statistics of demographic and baseline characteristics and inter-treatment intervals in months as well as Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) following initiation of immunochemotherapy and idelalisib were calculated. Population: Demographic characteristics of these 37 patients included median (range) age at initiation of idelalisib of 64 (33-84) y and 18 (48.6%) females. Histologic grade at diagnosis included 33 (89.2%) with grades 1 or 2 as well as 4 (10.8%) with grade 3A, while 21 (56.8%) patients had a FLIPI score ≥3. The mean (s.d.) number of prior therapies was 3.4±1.4, with a range of 2 to 8, while first-line therapies included 21 (56.8%) patients who received R-CHOP-based regimens, 7 (18.9%) who received BR, and 5 (13.5%) who received R-CVP. Mean (s.d.) inter-treatment intervals included 12.5±6.1 months between first- and second-line for all patients, 9.7±9.3 months between second- and third-line for all patients, 11.9±12.0 months between third- and fourth-line for 24 (64.9%) patients, and 11.8±7.6 months between fourth- and fifth-line for 15 (40.5%) patients. Median (range) time from first-line therapy to idelalisib initiation was 30.3 (8.9-94.7) months; no patient received idelalisib as second-line therapy. Results: Best responses included 5 (13.5%) patients with CR, 16 (43.2%) with PR, 2 (5.4%) with SD, and 1 (2.7%) with PD; median duration of response for those with CR or PR was 11.8 months (95% CI: 3.8 months, not evaluable). There were 7 (18.9%) deaths and 21 (56.8%) PFS events in this group. Estimated probabilities of survival (s.e.) and progression-free status at 2 y following initiation of idelalisib were 79%±7% and 29%±10%, respectively. Median PFS was 11.1 months (95% CI: 5.5, 19.3 months). Estimated probability of survival (s.e.) at 5 years following initiation of first-line treatment was 79%±8%. Median overall survival from both initiation of first-line immunochemotherapy as well as with idelalisib was not reached during the course of this study. Conclusions: Idelalisib may have significant clinical activity in high-risk and doubly-refractive FL following early relapse status post first-line immunochemotherapy. Given the small size of the studied subset population which may not be representative, further characterization in additional patients is warranted to ensure the generalizability of this finding, including consideration of further investigational protocols featuring targeted therapies employed both as single agents and in combination. Figure 1. Overall Survival From Initiation of First-line Treatment Figure 1. Overall Survival From Initiation of First-line Treatment Figure 2. Overall Survival From Initiation of Idelalisib Figure 2. Overall Survival From Initiation of Idelalisib Figure 3. Progression-Free Survival From Initiation of Idelalisib Figure 3. Progression-Free Survival From Initiation of Idelalisib Disclosures Gopal: Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Kahl:Roche/Genentech: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy; Cell Therapeutics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Pharmacyclics: Consultancy; Juno: Consultancy. Flowers:Infinity Pharmaceuticals: Research Funding; Genentech: Research Funding; Spectrum: Research Funding; Millennium/Takeda: Research Funding; Seattle Genetics: Consultancy; Spectrum: Research Funding; Pharmacyclics: Research Funding; AbbVie: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Research Funding; Onyx Pharmaceuticals: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; OptumRx: Consultancy; Gilead Sciences: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding; Acerta: Research Funding; Infinity Pharmaceuticals: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding. Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Ye:Gilead: Employment. Koh:Gilead: Employment. Abella:Gilead: Employment. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Abbvie: Consultancy; Gilead: Consultancy. Salles:Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau.

Abstract Background: Patients with polycythemia vera (PV) have an increased symptom burden (eg, fatigue, pruritus, and splenomegaly-related symptoms) and an increased risk of mortality compared with the general population, often resulting from thrombotic events, disease transformation to myelofibrosis, or secondary malignancies. There are limited data regarding PV burden and treatment patterns in a contemporary, real-world US setting. REVEAL is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the US. The objective of this assessment is to describe the clinical characteristics at enrollment among patients currently enrolled in REVEAL (enrollment from July 22, 2014 to June 9, 2015). Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study. Eligible patients are ≥18 years of age with a PV diagnosis and currently under active management by a physician in the US. Data regarding disease and clinical characteristics, patient-reported outcomes, and health resource utilization are being collected at usual-care visits over a planned 36-month observation period. Analyses of these preliminary data were descriptive. Results: At data cutoff, 865 patients were enrolled (total planned enrollment, n=2000) from 174 sites (academic, n=27; community, n=147). Median (range) age at enrollment was 67 (22-95) years, 55.5% were male, 89.5% were white, and 45.4% had a history of smoking. Most patients (99.4%) had health insurance, including Medicare (56.0%), PPO (24.3%), or HMO (11.6%). Fifty-two percent were retired, 29.6% were employed, and 4.5% were unable to work or disabled. A total of 40.2% of patients completed a college/graduate degree, 19.9% had some college, and 32.5% completed high school or the equivalent. Documented major World Health Organization diagnostic criteria included JAK2V617F mutation in 50.9% of patients, elevated hemoglobin in 52.3%, and red cell mass in 5.5%. A bone marrow biopsy was conducted in 24.0% of patients, approximately half of whom (52.4% of the 24.0%) had trilineage myeloproliferation. Erythropoietin levels were abnormal in 19.7% of patients. Approximately half (46.6%) of patients had physician-reported PV-related symptoms at diagnosis, most frequently fatigue (25.2%) and pruritus (14.0%). At enrollment, median disease duration was 52.6 months; 42.3% of patients were diagnosed ≥5 years before enrollment. The most common comorbidities were hypertension (51.3%), obesity (14.2%), dyspnea (13.4%), myalgia (11.2%), and diabetes mellitus (11.1%). Mean hematocrit was 44.9%, hemoglobin was 14.5 g/dL, white blood cell count was 11.4×109/L, platelet count was 363.7×109/L, and absolute neutrophil count was 363.7×109/L. Twenty-one percent of patients had a history of thrombotic events, with 13.1% and 8.6% of patients experiencing ≥1 venous or arterial thromboembolic event, respectively. Of the 261 reported thrombotic events, 43.7% occurred after diagnosis of PV. The most common PV symptoms recorded at enrollment (using the Myeloproliferative Neoplasm Symptom Assessment Form) were fatigue (37.1%), pruritus (24.0%), headache (18.6%), insomnia (17.0%), dizziness (13.2%), bone pain (10.5%), and blurred vision (7.9%); 19.7% of 518 evaluable patients had palpable splenomegaly. Fewer than half of patients were receiving aspirin at enrollment (47.7%). The most common PV treatments ± aspirin were phlebotomy (PBT; 63.5%), hydroxyurea (HU; 42.2%), watchful waiting (5.3%), and ruxolitinib (3.1%); 23.0% of patients received PBT + HU. Conclusion: The REVEAL study is unique in that it captures data from both academic and community centers, and therefore includes a broader segment of the PV population typically not described in the literature. REVEAL can provide novel insights into questions related to the contemporary demographics of PV, practice patterns regarding diagnosis and therapy, and the real-world burden of PV and its impact on patients' quality of life and work productivity. Preliminary descriptive data from this early subset of patients suggest that a high proportion of patients report having PV-related symptoms at diagnosis, fewer patients are treated with aspirin than expected, and that thromboembolic event rates remain high after diagnosis. Disclosures Stein: Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moliterno:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Boccia:Incyte Corporation: Honoraria. Naim:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Peng:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Mesa:Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding.

Abstract Background: PRCA is characterized by severe normochromic normocytic anemia, reticulocytopenia, and markedly reduced bone marrow erythroid precursors with intact leukocytic and megakaryocytic lineages. There is limited information about the prevalence and outcomes of PRCA in CLL, with the vast majority of information derived from case reports and small series comprising <10 patients. Here, we describe the clinical features, therapy, and outcomes of CLL patients with PRCA seen at our institution. Methods: The Mayo Clinic CLL Database includes all patients with a diagnosis of CLL evaluated at Mayo Clinic Rochester, MN between January 1995 and December 2014. We identified patients diagnosed with PRCA per the following diagnostic criteria: those who presented with normocytic anemia, had decreased erythroid precursors on bone marrow examination, and reticulocytopenia that could not be explained by any other cause besides PRCA. The baseline demographics, clinical characteristics, therapy, and outcomes were abstracted from the electronic medical records. We generated descriptive statistics and calculated overall survival (OS) from diagnosis date (PRCA, autoimmune cytopenia [AID], or CLL) to last known alive or death date. OS was plotted using Kaplan Meier curves and compared between groups using log-rank statistic. The Mayo Clinic IRB approved this study. Results: Of the 3945 CLL patients seen during the study interval, we identified 30 patients who met the diagnostic criteria of PRCA as described in the Methods section. The baseline characteristics, etiology and therapy for PRCA are shown in Table 1. The median time to PRCA from CLL diagnosis was 4.5 years (range-0.1-14 years). Of the 13 patients with IGHV results available, 12 (92%) were IGHV unmutated. Twenty-one (70%) were male and their median age at PRCA diagnosis was 67 years (range 40-81 years). Parvovirus testing was positive in 6 of 24 (25%) patients who were tested; 3 of these patients were treated with IVIG, 2 were treated with prednisone and IVIg, and 1 was treated with prednisone and rituximab. Eight patients (27%) had both PRCA and autoimmune hemolytic anemia (AIHA), and 1 patient (3%) had concomitant PRCA and immune thrombocytopenia (ITP). Of the 27 patients for whom we have treatment data, 10 required only one treatment regimen and 17 required 2-6 treatment regimens, with two patients requiring splenectomy for concomitant AIHA. The median survival of CLL patients after a diagnosis of PRCA was 4.6 years (Figure 1). There was no difference in survival between PRCA cases with and without parvovirus (p=0.92). Compared to newly diagnosed CLL Rai stage III/IV patients, there was no difference in OS (p=0.53). There was no statistically significant difference in survival from an AID cytopenia diagnosis when comparing PRCA, ITP, AIHA, and Evans syndrome (Figure 1; median 5 years for PRCA and 6 years for other groups; p=0.17). Conclusion: PRCA is a rare complication in CLL, occurring in <1% CLL patients seen at our institution over the past 20 years. Parvovirus was the etiologic factor in ~25% of patients and did not influence outcomes. There appears to be no significant difference in outcomes of PRCA patients compared to patients with other AID in CLL. Table 1. Patient Characteristics Characteristic N [range] or (%) Number of patients 30 Males 21 (70) IGHV status* · Unmutated · Mutated 12 (92) 1 (8) FISH results at CLL diagnosis* · 17p- · 11q- · Trisomy 12 · 13q- · Negative 0 (0) 1 (10) 3 (30) 3 (30) 3 (30) At PRCA Diagnosis Median age 67 [40 - 81] Median hemoglobin (gm/dL)* [normal range 12-15.5 gm/dL] 8.2 [3.5 - 10.8] Median absolute reticulocyte count (x 109/L)* [normal range: 38 - 113 x 109/L] 3.5 [0.0 - 25.3] Patients treated for CLL prior to PRCA diagnosis 25 (83) Etiology of PRCA Parvovirus (n = 24) 6 (25) Therapy-related: · Fludarabine · Alemtuzumab/rituximab · Pentostatin/cyclophosphamide/rituximab 3 (10) 1 (3) 1 (3) Autoimmune (neither therapy nor parvovirus related) 19 (63) Initial Therapy of Non-Parvovirus Related PRCA Steroids alone 2 (8) Steroids and Rituximab 3 (13) Steroids in combination with: · IVIG, Chlorambucil · Cyclosporine · Rituximab, IVIg · IVIg, splenectomy 1 (4) 2 (8) 1 (4) 1 (4) Monoclonal Ab alone · Alemtuzumab · Rituximab 1 (4) 4 (17) Cyclosporine 1 (4) Cyclophosphamide 2 (8) RCP (Rituxan, Cyclophosphamide, and prednisone) 2 (8) IVIg 1 (4) Not available 3 (13) *Not available for all patients Figure 1. Figure 1. Disclosures Ding: Merck: Research Funding. Kay:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Shanafelt:Cephalon: Research Funding; Hospira: Research Funding; Glaxo-Smith-Kline: Research Funding; Genentech: Research Funding; Jannsen: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding.