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Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naive older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naive older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930.

Systemic sclerosis (SSc) is a multisystem disease of presumed autoimmune pathogenesis for which no proven effective treatment exists. High-dose immunosuppressive therapy (HDIT) has been proposed as an investigational treatment for severe autoimmune diseases. Nineteen patients with poor-prognosis SSc underwent HDIT. The median age was 40 years (range, 23-61 years), the median modified Rodnan skin score (a measure of dermal sclerosis) was 31, and the median DLCO was 57%. Conditioning therapy involved 800 cGy total body irradiation (TBI) (± lung shielding to approximately 200 cGy), 120 mg/kg cyclophosphamide, and 90 mg/kg equine antithymocyte globulin. CD34-selected granulocyte–colony-stimulating factor–mobilized autologous blood stem cells provided hematopoietic rescue. With median follow-up at 14.7 months, the Kaplan-Meier estimated 2-year survival rate was 79%. Three patients died of treatment complications and one of disease progression. Two of the first 8 patients had fatal regimen-related pulmonary injury, a complication not found among 11 subsequent patients who received lung shielding for TBI. Overall, internal organ functions were stable to slightly worse after HDIT, and 4 patients had progressive or nonresponsive disease. As measured by modified Rodnan skin scores and modified health assessment questionnaire disability index (mHAQ-DI) scores, significant disease responses occurred in 12 of 12 patients evaluated at 1 year after HDIT. In conclusion, though important treatment-related toxicities occurred after HDIT for SSc, modifications of initial approaches appear to reduce treatment risks. Responses in skin and mHAQ-DI scores exceed those reported with other therapies, suggesting that HDIT is a promising new therapy for SSc that should be evaluated in prospective randomized studies.

Introduction PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B cells. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that has shown considerable monotherapy activity in patients with heavily pretreated CLL. Methods This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 150 mg BID in combination with a total of 8 infusions of rituximab (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumab (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisib, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results 40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16 40%) were enrolled. 19 pts received idelalisib in combination with R, 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (24, 60%), refractory disease (14, 35%), multiple prior therapies (median 2, range: 1-;9). Almost all patients (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisib + O had received prior O. 63% of the pts receiving idelalisib + R, and 43% of the pts receiving idelalisib + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludarabine: 28, 70%]). Data available from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV. As of May 2013, the median (range) treatment duration was 18 (0-33) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. A total of 14 pts (35%) were continuing idelalisib treatment on the extension study. The most common reasons for discontinuation either from the primary or extension study were disease progression (10, 25%) and adverse events (AEs) (9, 23%). There were 6 deaths reported on study; 3 pts experienced PD before death. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea (53%/10%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (18%/15%), colitis (10%/10%) and pneumonitis (10%/7.5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Of those, only 1 pt discontinued the study because of (recurrent) TA elevation. The ORR (N=40) was 83% (33/40), with 3 CRs (8%), and a median (range) time to response of 1.9 (1.7-21.8) months. Median progression-free survival (PFS) for all patients (N=40) and duration of response (n=33) were 20 and 19 months, respectively. Median overall survival (OS) has not been reached. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73% (8/11) and the median PFS and DOR were 19 months. Conclusions Combinations of idelalisib with therapeutic anti-CD20 antibodies such as rituximab or ofatumumab represent non-cytotoxic regimens with acceptable safety profiles and high activity resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase 3 trials evaluating the efficacy of idelalisib in combination with R or O are ongoing (NCT01539512, NCT01659021). Disclosures: Furman: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. De Vos:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Fowler:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.

Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS > 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.

Background PI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a selective, oral inhibitor of PI3Kδ that has been previously shown to be safe and tolerable and has demonstrated considerable activity as monotherapy or in combination with other agents in patients with relapsed/refractory (R/R) CLL. We provide an update on the safety and efficacy of a phase 1 study of idelalisib (IDELA) 150mg po BID administered continuously on a 28-day cycle in combination with two chemo-immunotherapy regimens: bendamustine/rituximab (IDELA+BR) and chlorambucil/rituximab (IDELA+ChR). Methods Twenty-nine adult subjects (15/14 IDELA+BR; IDELA+ChR) with R/R CLL requiring treatment were enrolled between April and Aug 2011 for the IDELA+BR cohort and Mar and Jul 2012 for the IDELA+ChR cohort. Median age 64 yrs (Min, Max: 41, 82), gender M/F (%) 65/35, WHO PS (%) 0/1/2 59/38/3, current Binet stage (%) A/B/C 21/28/41, and 62% of subjects had bulky adenopathy (presence of ≥1 node with diameter ≥5 cm). Median number of prior therapies was 3 (Min, Max: 1, 9). Thirty-five percent of subjects had refractory disease (not responding to a standard regimen or progressing within 6 month of the last course of a standard regimen) and 55% of subjects were refractory to rituximab. The treatment schedule was as follows: IDELA+BR (IDELA 150 mg BID po d1-28 until progression or withdrawal, rituximab 375 mg/m2 IV on d1 of cycles 1-6, bendamustine 70 or 90 mg/m2 intravenously on d1 and d2 of cycles 1-6). For the IDELA+RCh cohort (IDELA 150 mg BID po on d1-28 until progression or withdrawal, chlorambucil 10 mg/m2 po once a d1-7 of cycles 1-12, rituximab 375 mg/m2 IV d1 of cycles 1-6). Response was assessed by the investigators based on scheduled CT evaluations and clinical criteria following IWCLL 2008. Results The data cut-off date for this analysis was May 2013. Objective response rates for the 2 cohorts were 89.7% (95% CI (%): 72.6-97.8). Median time to response in both cohorts was 1.9 months. For IDELA+BR, the ORR was 86.7% (95% CI (%): 59.5-98.3) (CR 6.7%, PR 80%), neither median DOR nor median PFS have been reached and median exposure was 18.4 months (Min, Max: 1.2, 24.7). For IDELA+ChR, the ORR was 92.9% (95% CI (%): 66.1-99.8) (CR 14.3%, PR 78.6%), neither median DOR nor median PFS has been reached, and median exposure was 7.7 months (Min, Max: 1.9, 11.1). Commonly reported treatment-emergent AEs (≥20% of all subjects) and lab abnormalities of interest for IDELA+BR were (total(%)/≥grade 3 (%)): pyrexia (46.7/0) diarrhea (26.7/13.3), fatigue (20/0), neutropenia (86.7/60), thrombocytopenia (26.7/6.7), transaminase elevations (26.7/0), anemia (33.3/13.3). For IDELA+ChR, common TEAEs were: pyrexia (57.1/7.1), diarrhea (64.3/7.1), fatigue (42.9/21.4), neutropenia (64.3/42.9), thrombocytopenia (42.9/21.4), transaminase elevations (50.0/21.4), and anemia (42.9/14.3). Conclusion The combination of IDELA+BR or IDELA+ChR is tolerable and demonstrates strong activity with an ORR of 89.7%. Median PFS and DOR have not been reached in the IDELA+BR or the IDELA+ ChR cohorts. The ability to induce responses in this particularly difficult-to-treat patient population with refractory disease, the non-overlapping toxicity with these agents, and the ease of administration makes this an option in this patient population. These results support further studies with these chemo-immunotherapy regimens in patients with CLL. Disclosures: Barrientos: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Wagner-Johnston:Gilead Sciences: Research Funding. De Vos:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Adewoye:Gilead Sciences: Employment. Furman:Gilead Sciences: Research Funding.

Introduction Alkylating agent-rituximab combinations are a current standard of care for patients with iNHL. Most iNHL will eventually become refractory to current therapies. Particularly, once iNHL becomes “double-refractory” to rituximab + alkylating agents, there are few data available on beneficial therapeutic options and development of novel therapies is essential for this patient population. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated considerable activity in recurrent iNHL in a phase 1 trial (Kahl, ICML 2011). We thus evaluated idelalisib in a phase 2 trial for patients with double-refractory iNHL, an area of unmet medical need. We present mature response data and extended follow-up of this study. Methods Eligible iNHL patients (pts) included those with measurable disease who were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to, or progression of lymphoma within 6 months of completion of therapy, documented by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007). The new data cutoff date for this analysis was June 2013, 8 months after the last patient enrolled. Results Enrolled pts (N=125) had a median age of 64 years [range 33-87] and were 64% male. Indolent NHL subtypes included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], most common regimens included bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and 14 pts (11%) had a prior autologous transplant. 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. Median time since completion of last regimen was 3.9 months. At baseline, pts had elevated LDH (30%), bulky disease >7 cm (26%), anemia ≥grade 1 (51%), neutropenia ≥ grade 1 (24%), and thrombocytopenia ≥grade 1 (34%). With a median follow up 9.4 months, the overall response rate (ORR) was 57% (95% CI = 47.6, 65.6) with 71 responders, comprising 7 CRs (6%), 63 PRs (50%), and 1 minor response (MR) in a WM pt. There were 42 pts with stable disease (SD) (33%). 90% of pts experienced some decrease in tumor burden (Figure 1). Median time to response was 1.9 months (range 1.6-8.3), median time to CR was 3.7 months (range 1.9-12). ORR for iNHL subtypes was: FL (54%), SLL (61%), LPL/WM (80%), and MZL (47%). ORR for bendamustine refractory pts was 59%. ORR for pts with The most common adverse events were (total%/≥ grade 3%) diarrhea (43/13), fatigue (30/2), nausea (30/2), cough (29/0), pyrexia (28/2), dyspnea (18/3), rash (13/2), and pneumonia (11/7). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 16 pts (13%). Drug was held for these pts, and 11/14 pts (79%) were re-treated without recurrence of ALT/AST elevation. Grade ≥3 neutropenia occurred in 27%, thrombocytopenia in 6%, and anemia in 2%. 20% of pts have discontinued therapy due to adverse events. Conclusions Idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in this double-refractory iNHL population with an ORR of 57%. The ORR was consistent across all subgroups, regardless of disease histology, number of prior regimens, refractoriness to bendamustine, or tumor bulk. With continued administration of idelalisib, responses were durable beyond one year, substantially exceeding the median DOR for the last prior therapy. Mature response data demonstrate that idelalisib can provide clinical benefit to patients with the unmet medical need of double-refractory iNHL. Disclosures: Gopal: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Kahl:Gilead Sciences: Advisory Board Other, Research Funding. De Vos:Gilead Sciences: Advisory Board Other, Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment. Li:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment. Godfrey:Gilead Sciences: Employment. Salles:Gilead Sciences: Research Funding.

Background Myelofibrosis (MF) is characterized by activation of the JAK-STAT pathway, with the JAK2 V617F mutation found in 50-60% of patients. Although JAK inhibitors, such as FDA-approved ruxolitinib, have been effective in reducing splenomegaly and mitigating symptoms, patients uniformly exhibit “disease persistence” which is equated with a lack of hematologic or molecular remissions, or with loss of clinical improvement over time. Prior studies using cell lines or primary patient samples have shown that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is dysregulated in MPNs and is a potential therapeutic target (Kamishimoto et al, Cell Signal 2011; Huang et al, ASH 2009 Abstract 1896; Vannucchi et al, ASH 2011 Abstract 3835; Khan et al, Leukemia 2013). In CLL and other B-cell malignancies, the PI3K pathway is constitutively upregulated and is dependent on PI3Kδ. Idelalisib is a δ-isoform-specific PI3K inhibitor that is efficacious in patients with CLL and indolent NHL. Herein, the specific aims of our study were: 1) to determine whether the PI3Kδ isoform is expressed in progenitor cells from MF patients, and 2) to evaluate the inhibitory effects of idelalisib on basal and thrombopoietin (TPO)-stimulated AKT/S6RP phosphorylation (p-AKT/p-S6RP) in cell lines and in primary samples from MF patients who were either on chronic ruxolitinib (RUX) therapy or were not exposed to ruxolitinib (RUX-naïve or off-therapy at the time of sample collection). Methods To evaluate isoform expression, CD34+ cells from the peripheral blood of MF patients were sorted by FACSAria and cell lysates were analyzed by Simple Western using Peggy (ProteinSimple) with recombinant protein as a positive control. For cell line studies, BaF3/MPL W515L and UT-7/TPO cells were stimulated with recombinant human TPO and incubated with idelalisib. Whole cell lysates were analyzed by Western blot to quantify the % of p-AKT and p-S6RP levels compared to idelalisib-untreated cells. For MF patient samples, PBMCs were isolated from the whole blood of MF patients who were either RUX-naïve or on chronic RUX therapy and treated for 2 hours with idelalisib. Antibodies specific to p-AKT Ser473 and pS6RP Ser235/236 were used to quantify the proportion of p-AKT and pS6RP in basal and TPO-stimulated CD34+/CD3-/CD14-/CD19-/CD66- gated cells. Results The PI3Kδ isoform was found to be the predominant isoform expressed in 3 of 3 RUX-naïve and 4 of 4 chronic RUX patients tested; PI3Kβ was expressed at lower levels and no PI3Kα or γ was detected (Figure 1). In BaF3/MPL cells, p-AKT levels decreased by 51%, 64% and 67%, with 0.1, 1.0, 2.0 µM idelalisib, respectively, when compared to idelalisib-untreated cells; p-S6RP levels decreased by 24%, 27%, and 41%, respectively. Similarly, for UT-7/TPO cells, p-AKT decreased by 11%, 44%, and 55%, and p-S6 decreased by 13%, 28% and 48%, respectively. In CD34+ cells from RUX-naïve patients (n=3), p-AKT and p-S6RP levels decreased with increasing concentrations of idelalisib (0.02, 0.2, 2 µM). All patients on chronic RUX treatment demonstrated decreased p-AKT (n=3) and p-S6RP (n=4 basal, n=3 TPO-induced; patient 4 was only tested for basal) levels with increasing concentrations of idelalisib in both basal (Figure 2A) and TPO-stimulated (Figure 2B) assays. All 4 chronic RUX and 2 of 3 RUX-naïve patients tested carried the JAK2 V617F mutation. Conclusions The PI3Kδ isoform was identified as the predominant isoform expressed in CD34+ cells from MF patients. In both cell lines and patient samples, idelalisib inhibits the PI3K/AKT pathway, with a dose-dependent decrease of p-AKT and p-S6RP. Inhibition was observed for both RUX-naïve and chronic RUX-treated patients. Studies are underway to evaluate the effects of idelalisib on progenitor colony formation and induction of cell cycle arrest and apoptosis. * Meadows and Nguyen are first co-authors Disclosures: Meadows: Gilead: Employment, Equity Ownership. Queva:Gilead: Employment, Equity Ownership. Lannutti:Gilead, Acetra, Effector: Consultancy, Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Kashishian:Gilead: Employment, Equity Ownership. Jun:Gilead: Employment, Equity Ownership. Coutre:Gilead: Research Funding. Dansey:Gilead: Employment, Equity Ownership. Gotlib:Gilead: Consultancy, Research Funding.

Background PI3K-delta (δ) is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (IDELA) is a potent and selective orally administered inhibitor of PI3Kδ with demonstrated activity in patients with R/R CLL as a single agent (Brown, ASCO 2013), in combinations with cytotoxic chemotherapy or with anti-CD20 mAbs, and in triplet combinations with chemotherapy and anti-CD20 mAbs (Barrientos ASCO 2013; Coutre EHA 2013; Barrientos EHA 2013). This report summarizes the Phase 1 combination experience of IDELA with cytotoxic chemotherapies. Methods Subjects were sequentially enrolled into one of 3 regimens of IDELA in combination with either (1) Bendamustine (B), 90 mg/m2 IV days 1,2 every 28 days x 6 cycles (N=15, enrolled Apr 2010-Nov 2011); (2) Fludarabine (F), 40 mg/m2 orally days 1-5, every 28 days x 6 cycles (N=12, enrolled Apr 2011-Aug 2011), or (3) Chlorambucil (Ch), 10 mg/m2 orally days 1-7, every 28 days x minimum of 3 and maximum of 12 cycles (N=18, enrolled Mar 2012-Aug 2012). IDELA was dosed at 150 mg po BID continuously. Response assessment was investigator determined, using scheduled CT scans and clinical criteria and applying IWCLL 2008 guidelines. Results 45 subjects were enrolled. The median age was 65 years; 73% Rai III/IV; median 3 prior regimens, (range 1-9); 58% refractory to last therapy. Prior therapy included rituximab (93%), F (82%), an alkylating agent (80%), and B (38%). 44% of B cohort subjects had prior B, and 75% of F cohort had prior F. Adverse prognostic factors: 42% del(17p)/TP53 mutated; 84% IGHV unmutated; 26% NOTCH1 mutated. As of May 1, 2013, the median idelalisib exposure for the B, F and Ch cohorts was 10.6 mo (range 1-32.5), 13.1 mo (2-22.4), and 11.1 mo (0.9-12.9), respectively. 18 (40%) subjects remain on treatment. Of the 27 discontinuations (D/C), 8 were for AEs, including diarrhea in 4 (9%); febrile neutropenia led to D/C in only 1. The most common (≥10% overall) Grade ≥3 AEs were febrile neutropenia (22%) and diarrhea (16%). Treatment-emergent Grade≥3 lab abnormalities in B/F/Ch/total (%) were neutropenia in 67/58/73/67, thrombocytopenia in 22/17/33/24, anemia in 28/17/20/22 and ALT/AST increased in 22/25/0/16. 42 subjects were evaluable for response. The ORR was 78% for the entire group of 45. Best responses (PR%/CR%) were 78/0 with B, 92/0 with F, and 60/7 with Ch; all non-responding subjects had stable disease. Among 42 subjects with genetic data, the ORR in the 19 with either del(17p) and/or TP53 mutation was 70% vs. 83% among 23 subjects with neither. The median time to response was 1.9 mos for each regimen. Median duration of response (mos) / median PFS (mos) was 26.6/19.9 for B, NR/NR for F, NR/NR for Ch, and 26.6/28.5 for the entire group (NR: not reached). Conclusions IDELA can be combined with the cytotoxic single agents B, F and Ch with acceptable safety. In this heavily pretreated group of patients, many with refractory disease and adverse genetic markers, the ORR of 78% and estimated DOR and PFS of 28.5 months are indicative of significant clinical activity. Disclosures: De Vos: Gilead Sciences: Research Funding. Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies. Furman:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Dansey:Gilead Sciences: Employment. Kim:Gilead Sciences: Employment. Holes:Gilead Sciences: Employment. Dubowy:Gilead Sciences: Employment. Coutre:Gilead Sciences: Research Funding.

Background Idelalisib (IDELA) is a potent, competitive PI3Kδ inhibitor currently in Phase 3 clinical development. In numerous Phase 1/2 studies, IDELA alone or in combination with other therapies demonstrated clinical efficacy in patients with various hematologic malignancies (e.g., indolent non-Hodgkin lymphoma [iNHL] and chronic lymphocytic leukemia [CLL]) and overall safety of IDELA has been characterized in these patients. The relationship between IDELA plasma exposures and its inactive circulating metabolite, GS-563117, and clinical efficacy and safety findings were evaluated. Methods IDELA and GS-563117 plasma exposure were generated using population pharmacokinetic (PK) models for IDELA and GS-563117 based on data from several phase 1/2 clinical studies. Efficacy and safety data from 2 clinical studies, a Phase 1 dose ranging study (101-02; 50 mg to 350 mg BID, 150 mg and 300 mg QD) and a Phase 2 study (101-09), were included in the PK/PD analyses. Efficacy endpoints including best overall response rate (BOR), duration of response (DOR), progression free survival (PFS), sum of products of the greatest perpendicular diameters (SPD) of index lesions, and lymph node response rate (LNR) were evaluated against IDELA plasma exposure (AUCtau and Ctau). Safety endpoints evaluated included neutropenia, diarrhea, skin rash, infection, and aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation (vs. plasma exposure of IDELA and GS-563117, specifically AUCtau and Cmax). Results Over a wide dose/exposure range in Study 101-02, median SPD response increased with IDELA exposure (Ctau) quartiles, before reaching a plateau at the third quartile (Q3: range ∼280-405 ng/mL), which encompasses the mean IDELA Ctau at 150 mg BID dose (381 [56%] ng/mL). IDELA exposures were less than dose proportional and modestly higher at doses >150 mg BID (eg. Ctau ∼48% higher at 350 mg vs. 150 mg BID). No relationships were observed between the incidence rate (yes/no) of Grade 3 or 4 AST or ALT elevation or the severity (Grade 1 to Grade 4) of elevation over the range of IDELA plasma exposure. Taken together, these data supported the selection of 150 mg BID for further development. No relevant association was observed between IDELA exposure (Ctau: median (Q1, Q3) = 294 (203, 437) ng/mL) vs. any of the efficacy endpoints evaluated in Study 101-09, indicating the absence of exposure-efficacy relationships at 150 mg BID (Table 1). In Study 101-09, no association was observed between IDELA or GS-563117 plasma exposures vs. incidence of neutropenia, diarrhea, rash, infection, or Grade 3 or 4 AST or ALT elevation. Conclusions There were no exposure-response relationships observed for efficacy or safety endpoints at IDELA 150 mg BID, which was selected based on comprehensive exposure-response analyses over a wide dose/exposure range. These data support the use of IDELA 150 mg BID as a monotherapy for treating patients with hematologic malignancies. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Fang:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment, Equity Ownership. Newcomb:Gilead Sciences: Employment, Equity Ownership. Dansey:Gilead: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

Introduction: Myelosuppressive chemotherapy (CT) is associated with many neutropenic complications (eg, hospitalizations and CT dose reductions and delays), which often occur in the first cycle and may compromise clinical outcomes. In a recent nationwide survey, Lyman found 40% of 4522 patients (pts) treated with CHOP-like regimens for diffuse, aggressive NHL in community practice experienced CT dose reductions, and 24% of pts experienced CT dose delays. Additionally, the incidence of neutropenia increases for patients with risk factors for neutropenia; Morrison determined 41% of diffuse large B-cell NHL pts ≥ 60 years receiving anthracycline-based chemotherapy experienced febrile neutropenia events, with 20% of pts experiencing events in cycle 1. The ability of pegfilgrastim to reduce complications of CT-induced neutropenia has now been established in clinical trials for pts receiving moderately myelosuppressive CT, (Vogel 2005) in addition to highly myelosuppressive CT (Holmes 2002). This study evaluates the effectiveness of pegfilgrastim to support pts with NHL receiving CT in community practice. Methods: This open-label, single-arm study enrolled 2249 pts at 319 sites (including 331 pts with NHL) who were ≥ 18 yrs with malignancies other than leukemia or MDS, including pts with major comorbid illnesses not generally eligible for clinical trials. Pts receiving weekly CT or concurrent radiotherapy were not eligible. Pts received pegfilgrastim 6 mg ~24 hours post-CT in each cycle. Endpoints included neutropenic complications and physician-reported CT dose reductions and delays. Point estimates and 95% confidence limits (CL) are provided for this planned, interim analysis. Results: First cycle and second cycle data are available for 111 pts with NHL. The median (range) age was 65 years (24, 87), 50% were men, 67% had advanced-stage (III-IV) disease, and 31% had major comorbidities (e.g., myocardial infarction, peripheral vascular disease). Most pts (76 of 111) received CHOP±R (cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab). Few pts experienced neutropenic complications (table). Serious adverse events were consistent with those expected in NHL pts receiving CT. Conclusions: The NHL pts in our study are older (≥50% pf pts were 65 years or older) and represent ‘real-world’ pts as the only major entry criterion is confirmed diagnosis of malignancy. Despite this, many pts received CHOP±R with virtually no neutropenia-related alterations in CT dose and schedule early in the course of therapy indicating the effectiveness of pegfilgrastim in this setting. Final data for all NHL pts (n=331) to be presented. | | All Patients (n=111) | Subset of Patients Receiving CHOP±R (n=76) | |:--------------------------------------------------------:| -------------------- | ------------------------------------------ | | | % (95% CL) | % (95% CL) | | Febrile neutropenia in cycle 1 | 5 (2, 10) | 7 (2, 15) | | Neutropenia-related IV antibiotic use in cycle 1 | 5 (2, 11) | 8 (3, 16) | | Neutropenia-related hospitalizations in cycle 1 | 5 (2, 10) | 7 (2, 15) | | CT dose reductions in cycle 1 and 2 (physician-reported) | | | | All causes | 6 (3, 13) | 4 (1, 11) | | Neutropenia-related | 1 (

Introduction: Although non-Hodgkin’s lymphoma (NHL) is frequently diagnosed in older patients, few randomized clinical trials are conducted in this setting. Furthermore, older patients who are included in clinical studies are a highly selected group and are not likely to be representative of patients treated in the community. Increased age is an established risk factor for chemotherapy-induced neutropenia, and older patients often receive suboptimal doses of chemotherapy as a result, especially in community practice (Lyman et al, J Clin Oncol2004;22:1–10). In a large (n=528) study of older patients with diffuse large B-cell lymphoma receiving CHOP or R-CHOP with no cycle-1 growth factor, 41% of patients had febrile neutropenia over all cycles and 20% in cycle 1 (Morrison et al, ASH 2004 poster). The benefit of pegfilgrastim in supporting moderately to highly myelosuppressive chemotherapy regimens has previously been shown. Methods: As part of a large (n=852), prospective, randomized, open-label study, we assessed the effectiveness of first-cycle pegfilgrastim among patients ≥ 65 years old receiving chemotherapy for NHL in community practice. Patients were randomized to 1 of 2 treatment arms - pegfilgrastim in first and subsequent cycles (Arm A) or no pegfilgrastim in cycle 1 with subsequent use at the physician’s discretion (Arm B). Results: The primary analysis set included 146 patients with NHL, 73 per treatment arm. Median age was 73 years, range 65 to 87, with nearly 75% of patients aged 70 and older. R-CHOP was the most common chemotherapy, administered to 82% of patients. The overall incidence of febrile neutropenia was significantly lower for patients in Arm A (15%; [95% confidence limit (CL): 8, 25]) compared with patients in Arm B (37% [95% CL 26, 49]; p=0.0043). The first cycle incidence of febrile neutropenia was also lower in Arm A (7% [95% CL: 2, 15]) than in Arm B (25% [95% CL: 15, 36]), as was the overall incidence of hospitalization due to neutropenia-related events (17% [95% CL: 10, 28] vs 37% [95% CL: 26, 49]). Pegfilgrastim was administered frequently in Arm B, with 61% of patients initiating treatment in cycle 2, and 91% of patients (29/32) receiving pegfilgrastim by cycle 6. The main reasons for pegfilgrastim use in Arm B were grade 3/4 neutropenia, followed by febrile neutropenia. Dose reductions occurred in 16% of Arm A patients (95% CL: 9, 27) and in 8% of Arm B patients (95% CL: 3, 17) and dose delays occurred in 29% (95% CL: 19, 41) and 23% (95% CL: 14, 35) respectively; however, 19% of patients in Arm B discontinued from the study after cycle 1 compared with only 5% in Arm A, confounding the incidence of both parameters. Adverse event profiles were similar between the 2 treatment arms and were consistent with the population under study. Conclusions: The results of this study support the feasibility of conducting community-based trials in older patients, demonstrate that older patients can safely receive myelosuppressive chemotherapy, and show the effectiveness of first-cycle use of pegfilgrastim among older patients with NHL treated in the community setting.

When faced with a severely thrombocytopenic cancer patient with acute or chronic thrombus, oncologists often avoid antithrombotic treatment until the platelet count is above 50 x 109/L. Few attempts have been made to examine the feasibility of safely administering low-molecular-weight-heparins (LMWHs) in the presence of concurrent thrombocytopenia. We retrospectively investigated the safety of low-dose LMWH in hematopoeitic stem cell transplantation (HSCT) patients, a population at risk of bleeding. Our initial experience with the safe use of the LMWH enoxaparin in an HSCT patient published in 2002 (Annals of Pharmacotherapy 2002; 36:1478) was extended to 26 patients. Between August 2001 and August 2004, 26 HSCTs patient received at least one dose of enoxaparin during thrombocytopenia. Patients’baseline characteristics are shown below. Table 1. Baseline characteristics of the study patients (n=26) Two patients received enoxaparin twice during 2 successive thrombocytopenic periods, thereby accounting for 28 safety evaluations. Subcutaneous enoxaparin 40 mg once daily was given in 85% (22/26) of the cohort. Minor bleeding occurred in 4 patients (15%) whereas major episodes developed in 2 patients (8%). These two patients experienced retroperitoneal bleeding during the transition full/low- dose anticoagulation. Dose/platelet count at the time of bleeding were: 2.35 mg/kg/d and 81 x 109/L, and 1.15 mg/kg/d and 52 x 109/L in the first and second patient respectively. The latter patient had an elevated serum creatinine at 2 mg/dl. The mean number of platelets days 55 Kg. The safety of low-dose LMWHs below 20 x 109/L remains to be established. Importantly, the transition from/to low-dose enoxaparin should be done at a higher platelet count threshold than 55 x 109/L, all the more in the presence of compromised renal function. Table 1. Baseline characteristics of the study patients (n=26) | Age (median; range) | 53 years (24–67) | |:----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | --------------------------------------------------------------------------------------------------- | | Two patients received enoxaparin during 2 successive thrombocytopenic periods ¹, 2 patients had upper and lower extremity DVT, 2 patients had lower extremity DVT and pulmonary embolism² | | Gender (M/F) | 17/9 | | Weight (median; range) | 83.4 Kg (53–176) | | Type of HSCT¹ | Autologous (20), Allogeneic (2), non-myeloablative (3), cyclophosphamide priming (3) | | Thrombotic event² | upper extremity DVT (11), lower extremity DVT (9), pulmonary embolism (5), miscellaneous events (5) | | Number of patients on full-dose enoxaparin prior to thrombocytopenia (%) | 14 (54%) | | Indications for HSCT | multiple myeloma (10), lymphoma (9), leukemia (2), breast cancer (2), miscellaneous indications (3) | | Age (median; range) | 53 years (24–67) | |:----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | --------------------------------------------------------------------------------------------------- | | Two patients received enoxaparin during 2 successive thrombocytopenic periods ¹, 2 patients had upper and lower extremity DVT, 2 patients had lower extremity DVT and pulmonary embolism² | | Gender (M/F) | 17/9 | | Weight (median; range) | 83.4 Kg (53–176) | | Type of HSCT¹ | Autologous (20), Allogeneic (2), non-myeloablative (3), cyclophosphamide priming (3) | | Thrombotic event² | upper extremity DVT (11), lower extremity DVT (9), pulmonary embolism (5), miscellaneous events (5) | | Number of patients on full-dose enoxaparin prior to thrombocytopenia (%) | 14 (54%) | | Indications for HSCT | multiple myeloma (10), lymphoma (9), leukemia (2), breast cancer (2), miscellaneous indications (3)

Introduction: The pivotal trials of pegfilgrastim and filgrastim demonstrated their value as primary protection if initiated 24 hours after chemotherapy (CT) administration from CT cycle 1. Current clinical use patterns for pegfilgrastim and filgrastim may differ and may include primary protection in cycle (C) 1 or secondary protection in later cycles. Additionally, the initiation day within a CT cycle could be early (primary protection), late (reactive use), or for treatment of established neutropenia or febrile neutropenia (FN). A retrospective chart review is underway to determine current use patterns and applications of once-per-cycle pegfilgrastim (approved in 2002) and daily filgrastim. Methods: Patient (pt) medical records are being retrospectively collected from 100 randomly selected US private oncology practices. Eligible pts are ≥18 years of age, diagnosed with non-Hodgkin’s lymphoma (NHL), Hodgkin’s disease (HD), lung (LC), ovarian (OC), colorectal (CRC) or breast (BC) cancers, and have received ≥1 CT cycle. This planned interim analysis evaluates pegfilgrastim and filgrastim utilization in cancer pts receiving CT in 2003. Results: Medical records of 624 pts from 34 sites receiving pegfilgrastim or filgrastim have been abstracted to date. Pegfilgrastim was initiated in 351(56%) pts and filgrastim was initiated in 273 (44%) pts. Of the 624 pts, 120 (19%) received both pegfilgrastim and filgrastim (no pt used both products in the same cycle). Of these, 94 (78%) received pegfilgrastim after initially receiving filgrastim while 26 (22%) received filgrastim after initially receiving pegfilgrastim. The distribution of tumor types for the 325 pts receiving only pegfilgrastim was BC 43%; LC 24%; NHL 20%; HD 5%; OC 5%; CRC 3%. The planned CT cycle length (days) for pts receiving pegfilgrastim was: Q21 (56%), Q14 (11%), Q28 (11%), Q7 (2%). In C1, 58% of pts received pegfilgrastim; in C2, 86% received pegfilgrastim. In C1, pegfilgrastim was administered ≤3 days after CT in 76% (142/187) of pts and in 83% (200/240) of pts in C2. C1 use of pegfilgrastim was 68% for lymphoma and 54% for solid tumor pts. The distribution of tumor types for the 179 pts receiving only filgrastim was BC 46%; LC 24%; CRC 12%; NHL 9%; HD 6%; OC 4%. The planned CT cycle length (days) for pts receiving filgrastim was: Q21 (35%), Q28 (17%), Q14 (15%), Q7 (12%). In C1, 62% of pts received filgrastim; in C2, 83% received filgrastim. In C1, filgrastim was administered ≤3 days after CT in 31% (34/111) of pts increasing to 48% (52/108) of pts in C2. Filgrastim was initiated ≥10 days after CT in C1 in 48% (53/111) of pts and in 26% of pts (28/108) in C2. C1 use of filgrastim was 58% for lymphoma and 63% for solid tumor pts. Conclusions: From this interim analysis, most pts initiated pegfilgrastim in C1 and early within a cycle, suggesting primary protection. Most pts initiated filgrastim also in C1, however the day of initiation is much later, suggesting reactive use or treatment of established neutropenia or FN. Future analyses will evaluate factors associated with use (or non-use) of pegfilgrastim and filgrastim including baseline and treatment characteristics.