ALBERT

Description: BACKGROUND: Chemoimmunotherapy for chronic lymphocytic leukemia (CLL) has been the standard of care for initial treatment. A randomized demonstrated both a progression free survival (PFS) and overall survival (OS) advantage when rituximab was added to fludarabine (F) and cyclophosphamide (C). Alemtuzumab (Campath) (CAM), an anti-CD52 monoclonal antibody, is an effective therapy for patients with both previously untreated and relapsed CLL. Its role in combination with chemotherapy is less certain. METHODS: We conducted a multicenter phase II clinical trial of FC followed by subcutaneous CAM in previously untreated CLL. Patients were eligible if they met standard criteria for initiating therapy, or if they were asymptomatic with the prognostically adverse immunoglobulin heavy chain variable (IGHV) gene unmutated status. Patients received fludarabine (25 mg/m2/day, days 1-3) and cyclophosphamide (250 mg/m2/day, days 1-3) every 28 days for six treatment cycles, followed by a 3-8 week rest period. Disease response was assessed, including minimal residual disease (MRD) status by sensitive flow cytometry in those in complete remission (CR). Patients who achieved less than a CR were eligible to receive standard dose CAM (30 mg thrice weekly for 12 weeks); those who were in CR but MRD positive could receive reduced dose CAM (30 mg weekly for 12 weeks). The primary outcome was duration of response (DOR). Secondary outcomes included the response rates after FC and after the addition of CAM, as well as the safety profile of the regimen. RESULTS: We enrolled 25 patients from November 2004 to June 2007 at 3 centers. The median age of the participants was 62 years (range 42-75). Detailed information was available for 17 patients pre-treatment: high risk Rai stage in 9, IGHV unmutated in 9 including 4 patients who were IGHV unmutated as their indication for treatment. Five patients had trisomy 12, 4 had 13q deletion, 1 each had 17p deletion and 11q deletion, and 6 had no abnormality. One patient was excluded from the analysis due to a diagnosis of mantle cell lymphoma after eligibility review. Four patients had no response evaluation and were considered treatment failures. Seventeen (71%) patients had a CR after 6 cycles of FC, including 11 who were MRD negative, one had a partial response (PR), and two had progressive disease (PD). Four of the 6 patients who were MRD positive received CAM after FC. Two required only a single dose to become MRD negative, and 2 received 12 weekly doses. One of these patients became MRD negative. The median DOR for those achieving CR was 38 months (range 12-105 months). There were no treatment related deaths. Five patients experienced a SAE including one with febrile neutropenia, two with pneumonia, and two with autoimmune hemolytic anemia. There were ten additional treatment emergent adverse events including two that were grade 3 (mucositis and fever) and one CMV reactivation while receiving CAM. Two patients developed treatment related myelodysplasia, one died and the other underwent allogeneic stem cell transplant. There were two deaths due to Richter’s transformation. During long term follow up, there have been five additional deaths. CONCLUSIONS: The CR rate after FC was higher than that reported in prior trials of previously untreated patients and the incidence of MRD negative CR was surprisingly high. The DOR was consistent with prior experience with FC. Too few patients received CAM to draw any conclusions about its role as a consolidative therapy given subcutaneously on a weekly schedule. Both the FC and CAM therapies were well tolerated, with few adverse events associated with their use. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: PI3Kδ signaling is critical for the proliferation, survival and homing/tissue retention of malignant B cells. Idelalisib is a first-in-class, highly selective, oral inhibitor of PI3Kδ recently approved for the treatment of relapsed CLL in combination with R. This report summarizes the long-term follow-up of the Phase 1 combination experience of idelalisib with anti-CD20 antibodies. Methods: This Phase 1 study evaluated idelalisib for relapsed/refractory CLL continuously given at 100 mg BID (4 of the pts receiving R) or 150 mg BID (all other pts) 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 and 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), bulky lymphadenopathy (23, 58%), refractory disease (15, 38%), multiple prior therapies (median 2, range: 1-9). Almost all pts (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 48% 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 7/15/2014, the median (range) treatment duration was 18 (0-44) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. Primary reasons for study discontinuation (as reported by investigators) included disease progression (14, 35%), adverse events (AEs) (12, 30%), investigator request (3, 8%), withdrawal of consent (n=1), BMT (n=1). There were a total of 8 deaths on study: 2 deaths occurred after disease progression, and 6 pts died because of AEs (all assessed as unrelated/unlikely related to idelalisib by investigators). A total of 4 pts (10%) were continuing idelalisib treatment on the extension study at time of analysis. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (55%/23%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (20%/18%), and pneumonitis (8%/5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Re-exposure to idelalisib after resolution of TA elevation generally was successful; only 1 patient discontinued the study because of (recurrent) TA elevation. Other AEs leading to study discontinuation and reported as possibly/probably related to idelalisib included diarrhea/colitis (4, 10%), pyrexia (n=1), interstitial lung disease (n=1), pneumonia (n=1), rash (n=1), psoriasis (n=1). Secondary malignancies leading to discontinuation (all reported as unrelated) were breast cancer (n=1), recurrent colon cancer (n=1), AML (n=1). There was no obvious overall difference in the toxicity reported for pts receiving idelalisib with rituximab compared to those with ofatumumab. The ORR (N=40) was 83% (33/40), with 2 CRs (5%) reported. Median PFS (N=40) and duration of response (DOR) (n=33) were 24 months. Median (range) time to response was 1.9 (range 1.7-16.9) months. Median overall survival (OS) has not been reached with a KM estimate for OS of 80% at 24 months. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73%, and the median PFS and DOR were 20 and 24 months, respectively. Conclusions: Combinations of idelalisib with anti-CD20 antibodies such as R or O represent non-cytotoxic regimens with acceptable safety profiles and considerable activity resulting in durable tumor control in pts with relapsed/refractory CLL, including those with high risk factors such as del(17p) or TP53 mutations. A Phase 3 trial evaluating the efficacy of idelalisib in combination with ofatumumab is ongoing (NCT01659021). Disclosures Furman: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. de Vos: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. Leonard:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Coutre:Gilead Sciences: Research Funding.

Description: Background: Ibrutinib is a first-in-class, oral covalent inhibitor of Bruton’s tyrosine kinase (BTK) that has shown single-agent efficacy and an acceptable safety profile in patients (pts) with CLL. While BTK is expressed in platelets, bleeding diathesis has not been reported in pts with hereditary BTK deficiency (e.g., X-linked agammaglobulinemia). Pts with CLL often have comorbidities requiring anticoagulants and/or antiplatelet agents, which can increase bleeding risk. We sought to characterize the pattern of use of these agents and describe bleeding adverse events (AEs) observed in 2 trials of single-agent ibrutinib in pts with CLL. Methods: Event-based analysis of data from the ibrutinib phase 2 PCYC-1102 trial and interim analysis of the phase 3 RESONATETM(PCYC-1112 trial) of ibrutinib vs. ofatumumab were analyzed to determine the use of concomitant anticoagulants and/or antiplatelet therapy. Precautionary language on the use of anticoagulant or antiplatelet agents, particularly regarding restrictions on the use of vitamin K antagonists (e.g., warfarin), and recommendations for perioperative holding of ibrutinib, were added late during the 1102 trial. Major bleeding was defined as any grade ≥ 3 bleeding event, or hemorrhage of any grade resulting in one of the following: intraocular bleeding causing loss of vision, need for ≥ 2 units of RBC transfusion, hospitalization, prolonged hospitalization, or any intracranial hemorrhage. Results: In the 2 trials, 327 pts with CLL/SLL were treated; 132 in 1102 trial and 195 in the ibrutinib arm of 1112. Median age was 68 and 67 years, respectively, and median number of prior therapies was 3 in both trials. Overall, 65 pts (20%) received concomitant anticoagulation across the 2 trials, 70 (21%) received ASA, and 7 (2%) received clopidogrel (Table). The most common bleeding AEs were grade 1 petechiae and contusion. In the 1102 trial, grade 1 bleeding AEs occurred in 52%, grade 2 in 5%, and grade 3 in 3%. In the ibrutinib arm of 1112, grade 1 bleeding AEs occurred in 41%, grade 2 in 4%, and grade 3 in 1%. Overall, major bleeding occurred in 8 of 327 pts (2.4%): 5% in 1102 (6 of 132) and 1% in the ibrutinib arm of 1112 (2 of 195). For comparison, in the ofatumumab arm of 1112, major bleeding occurred in 1.6% of pts (3 of 191). Among the 8 ibrutinib-treated pts with major bleeding, 5 were reported to have concomitant use of either an anticoagulant alone (LMWH, n=1), an antiplatelet agent alone (ASA, n=1; NSAID, n=1), or both an anticoagulant and an antiplatelet agent (ASA and warfarin, n=1; NSAID, heparin and LMWH, n=1). The case of major bleeding on warfarin occurred on the 1102 trial before a protocol amendment restricted its use. Bleeding AEs led to discontinuation of ibrutinib in 4 pts (1.2%) from the 2 studies (3 on 1102 and 1 on 1112), all due to major bleeding. Conclusions: In summary, the concomitant use of anticoagulant or antiplatelet agent was common in 2 clinical trials of single-agent ibrutinib in 327 pts with CLL/SLL. Bleeding AEs in these trials were primarily grade 1 and associated with low rates of treatment discontinuation. Major bleeding events were uncommon and most cases occurred in pts taking one or more concomitant anticoagulant and/or antiplatelet agents. Importantly, there was no difference in the incidence of major bleeding between the 2 arms of the randomized 1112 trial while many of these pts were receiving concomitant anticoagulants or antiplatelet agents. Adherence to appropriate drug-withholding guidelines perioperatively and precautions surrounding the use of antiplatelet agents and anticoagulants, as applied in the 1112 trial, resulted in few major bleeding complications. Table. Concomitant anticoagulants or antiplatelet agents used in single-agent trials n (%) 1102 (n=132) 1112 ibrutinib arm(n=195) Total (N=327) Any anticoagulant 23 (17) 42 (22) 65 (20) Vitamin K antagonist* Heparin LMWH Dabigatran Rivaroxaban Apixaban Alteplase 6 (5) 3 (2) 14 (11) 0 0 0 1 (1) 4 (2) 5 (3) 34 (17) 3 (2) 1 (1) 1 (1) 0 10 (3) 8 (2) 48 (15) 3 (1) 1 (

Description: Abstract 4742 Introduction While the distance patients travel to a treatment center (DTC) adversely impacts survival of patients with trauma, cardiac, or neurological disorders, as well as certain solid tumors, less is known of its influence in acute myeloid leukemia (AML). Care for patients with AML involves frequent emergent and urgent management, often complicating primary therapy provided in distant tertiary referral centers. We therefore hypothesized that increased DTC has a negative impact on outcome. We tested this hypothesis by assessing the effect of DTC on survival of patients with AML receiving care at a single institution. Patients and Methods Within the Stanford Leukemia Database, we identified 884 consecutive adult patients between 1993 and 2009 meeting the following criteria: age 〉=18, newly diagnosed AML (excluding APL), clinical management at Stanford University Medical Center (SUMC), and verified residence location available for DTC determination. Of these, 571 were deemed fit by the admitting physician to receive myelosuppressive induction chemotherapy. DTC was calculated by straight-line journey distance between home address at the time of diagnosis and treatment center. Results The median age for the entire cohort is 55 years and 322 patients (36%) are older than 60 years of age. Median survival for the entire cohort was 14.0 months. DTC was not univariately associated with outcome as a continuous variable. When testing for a critical DTC threshold impacting outcomes across the entire cohort, we found a significant correlation between longer DTC and adverse outcomes, shorter DTC was associated with lower OS. Patients living within 20 miles of SUMC had a worse median overall survival (10.4 months versus 15.0 months, HR 1.23, corrected p-value 0.02). However, when adjusted for administration of induction chemotherapy (p

Description: Abstract 3288 Introduction: The elderly constitute the majority of patients (pts) with AML. Effective and tolerable therapeutic alternatives are necessary for these pts, in whom outcomes with standard induction therapy are poor. Azacitidine (AZA), a DNA methyltransferase inhibitor, decreases methylation of tumor suppressor gene (TSG) promoters, which correlates with clinical responses. Lenalidomide (LEN), an immunomodulatory and anti-angiogenic agent, has anti-leukemic activity when used as a single agent. We hypothesized that combining these two agents would decrease promoter methylation and upregulate TSG expression. We present the Phase I results of a Phase I/II clinical trial that sequentially combines AZA with LEN in elderly, previously untreated AML pts. Methods: Eligible pts were ≥ 60 years, had a World Health Organization-confirmed diagnosis of non-M3 AML, a performance status (PS) ≤ 2, adequate organ function, no prior leukemia therapy and were not candidates for standard induction. All pts had a white blood cell count ≤ 10,000/mm3 at the time of study entry; the use of hydroxyurea to attain this was permitted. Pts were enrolled into 4 cohorts using a 3+3 dose escalation design. In cohort 1, pts received 75 mg/m2 AZA SC/IV on d 1–7, followed by 21 days of observation for a 28-day cycle. At the completion of this “cycle 0,” pts were escalated to cycle 1, in which they received the same dose and schedule of AZA followed by LEN 5 mg PO daily on d 8–28, and then observation on d 29–42. Cohorts 2, 3 and 4 received the same dose and schedule of AZA with LEN doses of 10, 25 and 50 mg respectively, at the same schedule described for cycle 1. Intra-cohort dose escalation after cycle 0 was not permitted. Baseline bone marrow biopsies were compared to biopsies obtained after cycles 0, 1, 3, 6 and 12, and response assessments were based on International Working Group criteria. Adverse events (AEs) were graded according to the NCI CTCAE v 3.0. Pts were eligible for a maximum of 12 cycles, provided they tolerated therapy and achieved a response (defined as a complete response [CR], a CR with incomplete recovery of blood counts [CRi] or a partial response [PR]). Result: Eighteen pts were enrolled between April 2009 and July 2010. The median age was 72 years (64-86), 67% were male and 94% were Caucasian. The median PS was 1 (0-2) and the median hematopoietic cell transplant comorbidity index score was 0.5 (0-4). Six of 18 (33%) required hydroxyurea prior to enrollment. Seven of 18 (39%) had de novo AML and 11/18 (61%) had secondary AML (1 therapy-related, 1 evolved from primary myelofibrosis and 9 with myelodysplasia-related changes). The median bone marrow blast percentage was 63.5% (21-91%). Three of 18 (17%) pts had adverse cytogenetics, while 15/18 (83%) pts exhibited intermediate grade cytogenetics (11/15 with normal karyotype). Grade 3 serious AEs with a suspected relationship to treatment included neutropenic fever (NF) (n=5), fatigue (n=3), renal insufficiency (n=2), hyponatremia (n=1) and bleeding (n=1). In Cohort 4, 1/6 pts experienced grade 4 NF; however, 5/6 did not experience DLT, and therefore, the MTD was not reached. Pts have completed a median of 2 treatment cycles (0-6), with a median follow up of 94 days (21-275). Presently, of the 17 evaluable pts, 9/17 (53%) are alive. The overall response rate (ORR; defined as CR+CRi+PR) is 8/17 (47%) and the CR+CRi rate is 4/17 (24%). Thirty-day mortality was 12% (2/17); both deaths occurred in the first cohort in pts who had not received the drug combination, and were related to disease progression. Of the 5 pts enrolled in cohort 1, none responded, and all ultimately died of disease progression. However, among those in cohorts 2–4, 9 of 12 (75%) evaluable pts are alive with an ORR of 67% (CR+CRi= 4/12 [33%]), a median of 104 days after initiation of treatment (42-275). No responder has relapsed to date. Of the 3 post-cohort 1 deaths, 1 was from disease progression and 2 were from infectious complications. Conclusion: The sequential combination of AZA and LEN was well tolerated in elderly, untreated AML pts. The MTD was not reached at the highest dosing cohort, and the Phase II dose and schedule is AZA 75 mg/m2 d 1–7 and LEN 50 mg d 8–28, on a 6-week cycle schedule. The preliminary ORR of 47% is encouraging, as is the 67% ORR in pts who received ≥10 mg of LEN. Six month follow up will be presented. This trial was registered at ClinicalTrials.gov as NCT00890929. Disclosures: Off Label Use: Azacitidine and lenalidomide for AML. Liedtke:Celgene: Lecture Fee, Research Funding.

Description: Abstract 2832 Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate a variety of cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B cell proliferation and survival. CAL-101 is an isoform-selective inhibitor of PI3Kδ (EC50 of 8 nM in a cell-based assay with 〉200-fold selectivity relative to other PI3K isoforms). A Phase 1 study of single-agent CAL-101 demonstrated clinical activity in patients with indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma, and chronic lymphocytic leukemia (CLL); a favorable safety profile suggested that CAL-101 might successfully be combined with other agents active against lymphoid malignancies. Methods and Patients: This Phase 1 study was undertaken to evaluate the safety and activity of CAL-101 in combination with rituximab and/or bendamustine in patients with relapsed or refractory B-cell indolent NHL and CLL. All patients received CAL-101 100 mg orally twice per day (BID) in 28-day cycles for up to 12 cycles. Patients also received either rituximab 375 mg/m2 administered weekly for 8 weeks, starting on Day 1 of Cycle 1, or bendamustine 90 mg/m2 administered on Days 1 and 2 of each cycle for 6 cycles. Tumor response was evaluated according to standard criteria. Results: At data cutoff, 12 patients were enrolled in the study, including 6 with NHL and 6 with CLL. Patients included: males/females n=8 (67%)/4 (33%) with median age [range] of 65 [55-80] years, and relapsed/refractory disease n=8 (67%)/4 (33%). The median [range] number of prior therapies was 3 [1-11]. The number (%) of patients with specific prior therapies included: rituximab n=12 (100%), alkylating agent n= 10 (83%), purine analog n=9 (75%), and anthracycline/anthracenedione n=6 (50%). All patients received CAL-101 100 mg BID; 6 patients received rituximab and 6 received bendamustine. One patient with NHL had a dose reduction of bendamustine due to hiccups and 1 patient with NHL had a dose reduction of CAL-101 due to increased ALT/AST; all other patients received the full-dose regimen with acceptable tolerability. Preliminary clinical response assessments were available for 6 patients who had completed 2 cycles of combination treatment; the results are shown in the table. Enrollment is ongoing and dose escalation of CAL-101 is planned. Updated data will be presented at the meeting. Conclusions: Early results from this Phase 1 study of CAL-101, an oral PI3Kδ isoform-selective inhibitor, in combination with rituximab or bendamustine show acceptable safety and promising clinical activity in patients with relapsed or refractory indolent B-cell NHL and CLL. Disclosures: Flinn: calistoga: Research Funding. Off Label Use: CAL-101 for NHL. Leonard:Calistoga: Consultancy, Research Funding. Holes:Calistoga: Employment. Peterman:Calistoga: Employment. Yu:Calistoga: Employment.

Description: Background Asparaginase is an important component of induction and consolidation chemotherapy for acute lymphoblastic leukemia (ALL). Effective asparagine depletion in adult patients with ALL results in a longer duration of overall survival and disease free survival. Variation in asparaginase activity is in part due to the formation of anti-asparaginase antibodies that inactivate asparaginase and result in inadequate asparagine depletion. In addition, the presence of anti-asparaginase antibodies influences dexamethasone pharmacokinetics by increasing dexamethasone clearance, which has been shown to correlate with a higher risk of relapse. Hypoalbuminemia is a recognized side effect of asparaginase, and has been studied as a measure of asparaginase inhibition of liver protein synthesis. The purpose of this retrospective study was to evaluate the effect of asparaginase activity during induction, using serum albumin as a surrogate marker, on overall outcomes. We hypothesized that patients with lower albumin levels, and thus increased asparaginase activity, would have improved survival. Methods A retrospective electronic chart review was performed on 108 adult patients with newly diagnosed ALL who underwent induction chemotherapy treatment with Cancer and Leukemia Group B (CALGB) 9511 protocol at Stanford Hospital and Clinics between 2004 and 2012. PEG-asparaginase (2000 units per m2, capped at 3750 units) administration on day 5 of induction was confirmed on the electronic medical administration record. Patients also received therapy per protocol including prednisone (60mg per m2 per day) from days 1 through 21, with the exception of patients 〉60 years old who received prednisone from days 1 through 7. The primary outcomes measured were median overall survival and disease free survival. Patients were divided based on percent change in albumin level at day 14 of induction, using 20% decrease from pre-treatment baseline as a cut-off. The log rank test was used to calculate differences in survival and the Cox proportional hazards model was used to calculate hazard ratios. Baseline characteristics between the two groups were compared using chi-square or t-test analysis. Results A total of 104 patients with newly diagnosed ALL were included in the final analysis (1 patient did not receive PEG-asparaginase and 3 were lost early to follow-up). Of these, 52% were male. The median age was 49 years, and 20% of patients were 60 or older. The majority had B cell ALL (88%). Cytogenetics were normal in 28% of patients; t(9;22) was observed in 28% and t(4;11) in 4%. The induction mortality was 9% and 88% achieved complete remission (CR). In the entire patient population, the median overall survival was 27.4 months, and the median disease free survival was 25.0 months. For the patients who achieved at least a 20% decrease in albumin at day 14 of induction (57 patients), there was a statistically significant difference in median overall survival compared to those who had less than a 20% decrease in albumin, with an overall survival duration of 47.4 months and 15.8 months, respectively (HR = 2.23, P = 0.007). The median duration of disease free survival in those who achieved at least a 20% decrease in albumin at day 14 was 39 months compared to 13 months in those with less than a 20% decrease (HR = 1.93, P = 0.039). There was no statistically significant difference in the rate of CR between the two groups (P = 0.503). There was also no statistically significant difference in the baseline characteristics (age, WBC at diagnosis, presence of Philadelphia chromosome, and proportion of patients who eventually underwent BMT) between the two groups. Conclusion This study found a correlation between a decrease in albumin levels during induction, which was used as a surrogate measure of asparaginase activity, and duration of overall survival and disease free survival. This suggests that lower albumin levels associated with higher asparaginase activity and adequate asparagine depletion are important predictors of outcomes. Further studies assessing the effect of optimal individualized dosing of asparaginase based on albumin levels and/or asparagine depletion might be helpful to improve outcomes of adult patients with ALL. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Ibrutinib (Imbruvica®), a first-in-class Bruton’s tyrosine kinase inhibitor is a once-daily single-agent approved by the US FDA for patients with chronic lymphocytic leukemia (CLL) who have received ≥1 prior therapy, and for CLL with a 17p deletion. The phase III trial evaluating the efficacy and safety of ibrutinib in patients with relapsed/refractory CLL or small lymphocytic leukemia has previously been reported (Byrd et al. N Engl J Med, 2014). Allogeneic hematopoietic stem cell transplantation (HSCT) is also used to treat CLL, particularly in those who are at high risk. Patients with CLL who relapse after allogeneic HSCT are extremely difficult to treat with chemotherapy due to impaired hematopoietic reserve and/or infections. Furthermore, both B and T cells are known to play a role in the immunopathophysiology of graft-versus-host disease (GVHD), and in preclinical studies, ibrutinib, which inhibits both ITK and BTK, reversed established chronic GVHD. To evaluate whether ibrutinib is safe and effective in treating patients with CLL with a history of prior allogeneic HSCT, we evaluated the subset of patients enrolled in ibrutinib clinical trials who had undergone prior HSCT. Methods: Data were collected for patients with relapsed/refractory CLL who had undergone allogeneic HSCT and had been treated with ibrutinib, either as a single agent or in combination with ofatumumab, in 1 of 4 clinical trials (PCYC-1102, PCYC-1109, PCYC-1112, and PCYC-1117). Two of the studies (PCYC-1112 and PCYC-1117) allowed only patients who were 〉6 months post-HSCT and without GVHD to enroll. Efficacy evaluations included assessment of overall response rate (ORR) by iwCLL criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety evaluations included reporting of adverse events (AEs), including serious AEs (SAEs). Results: A total of 16 patients from 4 ibrutinib clinical trials had undergone prior allogeneic HSCT. Median patient age was 54.5 years (range, 43-68); 12.5% were ≥ 65 years of age, 11 were male, and all 16 patients had an ECOG performance status of 0 or 1. Chromosomal abnormalities del17p and del11q were reported in 10 and 3 patients, respectively. More than 4 prior therapies were reported for 12 patients. Of the 16 patients, 13 had received an intervening salvage therapy between allogeneic HSCT and the start of ibrutinib treatment. The median time since the most recent transplant was 27 months (range, 8-115). Baseline neutropenia, anemia, and thrombocytopenia were reported in 31%, 25%, and 38%, respectively. Median time on ibrutinib was 18.1 months (range, 0.4-38.8) including 12 patients who were treated with ibrutinib for 〉12 months. At the time of data cut-off, 11 patients were continuing treatment. Reasons for discontinuation included disease progression (n=2), AEs (n=2), and withdrawal of consent (n=1). No dose reductions were reported. Investigator-assessed responses included 2 complete responses, 9 partial responses, and 3 partial responses with lymphocytosis, resulting in a best ORR of 87.5%. Median DOR, median PFS, and median OS were not reached at a median follow-up of 23 months. The 24-month PFS and OS rates were each 77% and 75%, respectively. Treatment-emergent grade ≥3 SAEs were observed in 11 patients and included infections (n=6), with the remaining events occurring in 1 patient each, including febrile neutropenia, atrial flutter, colitis, perirenal hematoma, subdural hematoma, postprocedural hemorrhage, hypercalcemia, bone lesion, syncope, hematuria, urinary retention, and dyspnea. The only AE leading to discontinuation of ibrutinib was pneumonia in 2 patients; both were fatal events (at 0.9 and 2.3 months). Two additional deaths occurred on study due to disease progression at 24 and 28 months. Conclusion: Ibrutinib was well tolerated in patients who had undergone prior allogeneic HSCT, with a safety profile similar to that observed in the overall population of patients with relapsed/refractory CLL. The best ORR of 87.5% in this subgroup was also consistent with the 90% reported for the broader relapsed/refractory population in the PCYC-1102 study of single-agent ibrutinib. These data support use of ibrutinib in CLL patients with previous allogeneic HSCT and exploration of ibrutinib treatment for chronic GVHD (ongoing clinical trial: clinicaltrials.gov NCT 02195869). Disclosures Coutre: Janssen, Pharmacyclics: Honoraria, Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Byrd:Pharmacyclics: Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Miklos:Pharmacyclics: Research Funding. Zhou:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Styles:Pharmacyclics: Employment. Jaglowski:Pharmacyclics: Research Funding.

Description: 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.

Description: Key Points The results met predefined goals in poor-risk older patients with non-M3 AML. The results in good-risk patients are comparable to those with chemotherapy-based regimens, with a better safety profile.