ALBERT

Description: Abstract 3074 Children with high-risk NB often receive using multiple treatment modalities including autoHCT. Disease remains the most common cause of treatment failure and the most recent cooperative group studies report survival rates approaching 45%. Prior reports showed comparable outcomes of patients with NB receiving auto- and allo-transplants, despite differences in relapse risk and treatment-related mortality (TRM). To update these data the CIBMTR conducted a retrospective review of 143 transplants reported 1990–2007 at 61centers, the largest group reported to date. For this analysis, patients were categorized into 2 groups for comparison: those without (Group 1; n=97) and those with a prior auto HCT (Group 2; n=46). Of the patients in Group 1, 31% were in first remission, 25% in partial response (PR) or very good PR (VGPR), and 24% with no response or with persistent/progressive disease. Of the patients Group 2, 17% were in first remission, 26% in PR or VGPR, and 28% with no response or with persistent/progressive disease. Median ages at alloHCT were similar for Group 1 (5y, range

Description: True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8+ T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8+ T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.

Description: Key Points Ibrutinib is the first clinically viable irreversible ITK inhibitor. Ibrutinib inhibits the formation of Th2 but not Th1 immunity.

Description: Abstract 775 In chronic lymphocytic leukemia (CLL), mounting evidence points to an aberrant tumor associated Th2 bias that drives leukemic cell immune evasion, promotes formation of a supportive niche microenvironment, and functionally cripples innate and adaptive immunity. The end result is a high incidence of infections which is the primary cause of mortality in CLL. This same Th2 bias is induced by many other types of cancer. Th2 CD4 T-cells are singularly dependent upon IL-2-inducible T-cell kinase (ITK) for activation whereas Th1 CD4 and CD8 T-cells have compensatory resting lymphocyte kinase (RLK) which conducts T-cell receptor activation even in the absence of ITK. Thus, a clinically viable ITK inhibitor would be ideal for targeting immune suppression associated with CLL and potentially other types of cancer. Unfortunately, no such therapeutic is currently available. Ibrutinib, a confirmed inhibitor of the Bruton's tyrosine kinase (BTK) that irreversibly blocks downstream B-cell receptor activation, has demonstrated outstanding clinical activity in phase I/II clinical trials resulting in durable remissions in CLL. Our studies unveiled a previously uncharacterized Th1 cytokine switch in ibrutinib treated CLL patients which could not be attributed to B-lymphocytes. This ibrutinib-induced Th1 T-cell skewing was confirmed using the EμTCL1 mouse model of leukemia. Such alterations in cytokine patterns were reminiscent of mouse studies in which genetic ablation of ITK subverted Th2 immunity, thereby potentiating Th1-based adaptive immunity. The striking homology between BTK and ITK combined with intriguing in silico docking studies and promising in vitro kinase inhibition profiles with ibrutinib led to the hypothesis that this could be the first clinically viable irreversible ITK inhibitor. Cellular probe assays confirmed that the active site of ITK was covalently blocked by ibrutinib at pharmacologically relevant doses. Our comprehensive molecular analyses of T-cell signaling confirmed this in the Jurkat cell line. We further confirmed both molecular and functional outcomes in primary and in vitro polarized Th1 and Th2 CD4 T-cells. We found that mutation of the ITK-Cys442 covalent binding residue for ibrutinib alleviated molecular inhibition. We also demonstrated that Th1 and CD8 T-cell restricted expression of RLK provides a compensatory platform for T-cell activation offering a molecular explanation for the selective outgrowth of cytotoxic Th1 biased immunity. We further confirmed this effect using T-cells directly derived from CLL patients. To demonstrate that ibrutinib-induced ITK inhibition had direct clinical relevance in the setting of CLL we utilized a novel listeriosis/leukemia mouse model. In this model we clearly demonstrated complete recovery of functional immunity and all ibrutinib treated mice survived a potentially lethal Listeria monocytogenes infection. Our results expose novel molecular insights into the mechanism of action of ibrutinib in the context of Th2-biased immunosuppressive leukemia. We also postulate that ibrutinib's irreversible ITK inhibitory effects may prove effective in a number of other autoimmune, inflammatory, and viral diseases, including influenza A and HIV/AIDS. Disclosures: Jaglowski: Pharmacyclics: Research Funding. Chang:Pharmacyclics, Inc.: Employment. Maddocks:Pharmacyclics: Research Funding. Buggy:Pharmacyclics: Employment, Equity Ownership. Byrd:Pharmacyclics: Research Funding.

Description: Key Points Previously untreated patients with severe hemophilia A caused by F8 null mutations show a more severe phenotype than previously untreated patients with non-null mutations. The phenotypic differences are modest, and as such not likely to affect decisions regarding when and how to start prophylaxis.

Description: Cluster of differentiation (CD)8+ T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8+ T cells for patient treatments is controversial and understudied. We investigated human CD8+ T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or “exhaustion,” maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy.

Description: Abstract 4384 AML is a group of neoplastic disorders resulting from clonal expansion of immature hematopoietic cells in the bone marrow, blood and other tissues. AML represents approximately 90% of all acute leukemias in adults. The median age at diagnosis is 65 years. Geographic variations in the incidence and subtype of AML have been reported in different parts of the world. The classification of AML has evolved from the standard morphological FAB classification to the most recent 2008 World Health Organization (WHO) classification that consider the morphological, immunological, cytogenetic, genetic, and clinical features. In this study we report and for the first time from Qatar the clinico-pathological features and the outcome of adult patients diagnosed as AML between January 2006 and January 2010 at Al-Amal Oncology/Hematology Center. Diagnosis was based on combined morphologic, immunophenotypic & cytogenetic studies. Seventy three patients were found to have AML accounting for 73% of all adult acute leukemias diagnosed in our center. Age was between 17 and 100 years with a median age of 40 years. Fifty five patients were males and 18 were females with a male to female ratio of 3:1. Most of the patients were non-Qatari (83.5%). The most common FAB subtype was AML –M2 (27.3%). The second most prevalent is AML-M3 (23.2%). Within this group (17.7%) were of the classical hyper granular type, while (82.3%) showed different morphological variants. Cytogenetic analysis was attempted in 64 cases. Intermediate was the most common cytogenetic risk group (64%). The most common clinical presentations were Bleeding tendency (55 patients), symptomatic anemia (52 patients) and fever (29 patients). Fifty patients were treated in our center in Qatar. Pre-treatment death occurred in 14 patients (8 patients presented with septic shock and 6 with intracranial haemorrhage). Three patients were initially palliative, 33 patients received treatment in forms of 2 inductions with Doxorubicin + Cytosine Arabinoside (DA 3+7) and 3 consolidations with Cytosine Arabinoside, pre-treatment required in 13 patients, 2 of them required leukopharesis and 11 underwent cyto-reduction by hydroxy-carbamide. Complete remission was achieved in 28 patients (85%), and 5 patients were resistant disease. Patients were followed from 60 to 1620 days with average of 429 days and Median of 330 days. As of June 2010, 24 (73%) patients are still alive, and 9 (27%) patients died. Infection was the main cause of death. In conclusion AML in Qatar have a lower median age, and an increase incidence of AML-M3 (Acute Promyelocytic) subtype that exhibit significant morphological heterogenecity (variant APL). Doxorubicin is still in use for induction in our center due to unavailability of other anthracyclines. Despite this, cardiac toxicity was not seen in our cases so far, and our complete remission and disease free survival are comparable to international data. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2691 Background: Pre-treatment cytogenetics are utilized for risk-stratification in many hematologic malignancies but not in MCL, where improved risk-stratification is needed due to the heterogeneity of outcomes. A review at our institution found a significant association of CK with median time to relapse (1005 days for CK vs. not reached in those without CK (NCK), p=0.008) in pts undergoing autologous transplantation in first remission (Cohen, BMT Tandem Mtgs 2012). To evaluate the impact of CK at diagnosis on PFS and overall survival (OS) regardless of initial therapy or eligibility for transplant, we reviewed all pts with newly diagnosed MCL at the Ohio State University (OSU) from 2000–2011. Methods: We included all pts with confirmed MCL and available bone marrow (BM, n = 68) or peripheral blood (n = 12) pretreatment cytogenetics. Unstimulated cytogenetic analysis, standardly performed at OSU from 2000–2008, was performed in 48 pts, and stimulated analysis utilizing CpG oligonucleotides was performed in 32 pts beginning in Jan 2008. CK was defined as ≥3 unrelated chromosomal abnormalities, including t(11;14). Associations between CK and clinical variables were performed using Fisher's Exact and Wilcoxon rank sum tests. PFS and OS curves were constructed from date of pathologic diagnosis until date of relapse or death by the Kaplan-Meier method and evaluated using the log-rank test. A multivariable proportional hazards model for PFS was constructed using a limited backwards selection procedure. Results: In 80 untreated pts, median age was 63 (range 37–81), 70% were male, 28% had bulky disease ≥5cm, and 95% had stage IV disease. Sixty-five of 77 evaluable pts (84%) had BM involvement. Median time from diagnosis to pretreatment cytogenetic analysis was 21 days (range:−20 to 1094). CK was detected in 32 pts (40%, 95% CI: 0.29 to 0.52), and CK rate was higher in stimulated versus unstimulated analyses (56% vs 29%, p=0.02). CK was associated with several adverse markers, including a higher MCL international prognostic index (MIPI; median 6.3 vs 5.9, p=0.003) and simplified MIPI scores (median 6 vs 4, p=0.0006), increased percent involvement of BM cellularity (68% vs 10%, p=0.005), splenomegaly (73% vs 38%, p=0.005), and B-symptoms (57% vs 26%, p=0.01). CK was not associated with age (p=0.98) or bulky disease ≥5cm (p=0.80). Thirty-six pts (45%) underwent transplant in first remission, 35 autologous and 1 allogeneic. Intensive induction included R-HyperCVAD (n=10), methotrexate with augmented R-CHOP (n=31), and R-CHOP (n=17); less intensive induction included R-Bendamustine (n=4) and other non-anthracycline containing therapies. There were no large differences between CK and NCK patients with respect to receipt of intensive induction (76% vs 75%) or transplant in first remission (44% vs. 46%). With a median follow-up of 24 months for PFS and 32 months for OS, the estimated PFS at 2 years for CK and NCK pts was 47% and 71%, respectively (p=0.04; Figure 1A), and the estimated OS was 57% and 84% (p=0.02). For pts with unstimulated evaluation, the association of CK with shortened PFS and OS remained significant (PFS, p=0.02 and OS, p=0.01), with no association of method of analysis with PFS (p=0.35). In a multivariable analysis, high-risk (≥6.2) vs. low-risk (

Description: Background: Ibrutinib is a first-in-class inhibitor of Bruton's tyrosine kinase (BTK) approved for the treatment of relapsed and high-risk CLL/SLL. Autoimmune cytopenias (AIC), including autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), are common in CLL/SLL and can be precipitated by treatment with standard chemotherapy agents, most notably fludarabine. The effects of ibrutinib on AIC have not previously been reported. This retrospective cohort study was undertaken to characterize the incidence of AIC arising during ibrutinib treatment for CLL/SLL. Methods: The study population included pts with relapsed/refractory CLL/SLL and related disorders enrolled on 3 sequential clinical trials: PCYC-1102 (phase 1b/2 single agent ibrutinib), PCYC-1109 (phase 1b/2 study of ibrutinib and ofatumumab), and OSU 11133 (phase 2 single-agent ibrutinib). Pts with a history of AIC arising at any time since the diagnosis of CLL/SLL were identified. Pts were classified as having active AIC at treatment start if an episode of AIHA or ITP had occurred in the 3 months prior to starting ibrutinib and they remained on AIC treatment. Treatment emergent AIC was defined as incident diagnosis after beginning ibrutinib treatment. Relapsed pts were those with a history of AIC who were diagnosed with a recurrence while receiving ibrutinib. Results: The study population was comprised of 271 patients: median age was 65 and they had received median 3 prior treatments (range 0-13). Of these patients 195 (72.0%) were IGVH unmutated, 152 (56.1%) had a complex karyotype, and 104 (38.4%) had a deletion17p. Fludarabine had been given to 195 (72.0%), 228 (84.1%) had received an alkylating agent, and 257 (94.8%) had prior anti-CD20 monoclonal antibody therapy. The incidence of AIC arising at any time in the CLL/SLL disease course was 24.0% (n=65). There were no demographic differences between this group and the study population as a whole. AIHA occurred in 46 (70.8%) of AIC pts and 25 (38.5%) had ITP, the majority (92.3%, n=60) arising before beginning treatment with ibrutinib. Of those, 21 (32.3%) had experienced an episode in the 3 months prior to starting ibrutinib and 11 (16.9%) had an active autoimmune cytopenia at treatment start. Of patients receiving AIC treatments while on ibrutinib 11 of 22 (50%) were able to discontinue them. Four pts were diagnosed with treatment-emergent AIC while taking ibrutinib: 1) pt developed AIHA 5 months into ibrutinib treatment and successfully continued ibrutinib after treatment with prednisone; 2) pt with controlled AIHA at starting ibrutinib developed ITP 8 months into treatment when prednisone was tapered but remained on ibrutinib and subsequently tapered immune suppression; 3) pt was diagnosed with AIHA possibly antedating study entry, was successfully treated with IVIG, and remained on ibrutinib; 4) pt with inactive AIHA at starting ibrutinib developed autoimmune neutropenia associated with emergence of a T-cell LGL clone which was successfully controlled with cyclosporine. Only 2 pts had relapse of antecedent AIC during ibrutinib treatment: 1 pt with active/controlled AIHA at treatment start relapsed 4 weeks into treatment requiring discontinuation of ibrutinib for protocol-excluded high dose steroids; 1 pt with prior ITP diagnosis developed recurrent ITP and rash two years into ibrutinib treatment after starting sulfasalazine. Ibrutinib was discontinued, but ITP was uncontrolled with steroids. Conclusions: Despite a study population with an incidence of AIC (24.0%) higher than historical controls, relapse of AIC was uncommon (0.7%). Treatment-emergent AIC was rare (1.5%) and remained uncontrolled only in cases where ibrutinib treatment was not restarted. Ibrutinib does not appear to trigger AIC and can facilitate tapering of chronic AIC treatments. These data support prospective study of ibrutinib for treatment of CLL/SLL-related AIC. Development of AIC in ibrutinib treated patients. TableTiming of AICTotal (n=271)AIC at any time since CLL/SLL diagnosis65 (24.0%)History of AIC prior to ibrutinib60 (22.1%)Never active on treatment Active at treatment start On AIC treatment at ibrutinib start Stopped AIC treatment on ibrutinib50 (18.5%) 11 (4.1%) 18 (6.6%) 11 (4.1%)Developed AIC on ibrutinib6 (2.2%)New Relapsed4 (1.5%) 2 (0.7%)Developed AIC after stopping ibrutinib1 (0.4%) Disclosures Blum: Janssen, Pharmacyclics : Research Funding. Jaglowski:Pharmacyclics: Research Funding. Maddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Byrd:Pharmacyclics: Research Funding; Genentech: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding.

Description: Introduction Incidental pulmonary embolism (IPE) is defined as a pulmonary embolism diagnosed on a CT-scan performed for reasons other than a clinical suspicion of PE. Generally identified on staging scans, IPE has been estimated to occur in 3.1% of all cancer patients and is a growing challenge for clinicians and patients. Nevertheless, knowledge about the treatment and prognosis of cancer-associated IPE is scarce. In order to determine the outcome more accurately, and to identify clinical characteristics related to the prognosis, we pooled individual patient data from eleven observational studies and ongoing registries. Methods A systematic literature search aiming to identify studies reporting on patients diagnosed with cancer-associated IPE was performed. Authors of selected studies were invited to participate. Incidence rates of objectively diagnosed symptomatic recurrent venous thromboembolism (VTE), major bleeding and mortality during 6-month follow-up were pooled. Individual patient data was collected to perform subgroup analyses, for which all patients were considered as one cohort. Hazard ratios (HR) were adjusted for age, sex and cancer stage. Results Individual patient data of 926 cancer patients with IPE from 11 observational studies and ongoing registries were included (Table 1). The overall pooled 6-month risk of symptomatic recurrent VTE was 5.8% (95%CI 3.7-8.3), of major bleeding 4.7% (95%CI 3.0-6.8) and of mortality 37% (95%CI 28-47). The VTE recurrence risk was comparable in patients treated with VKA and LMWH with incidence rates of 6.4% (95%CI 2.2-12) and 6.2% (95%CI 3.5-9.6), HR 0.89 (95%CI 0.27-2.9). In contrast, this incidence rate was 12% (95%CI 4.7-23) in patients who were left untreated, HR 2.9 (95%CI 0.65-13; Figure 1). The risk of major bleeding was significantly higher in patients treated with VKA compared to those treated with LMWH, 13% (95%CI 6.4-20) versus 3.9% (95%CI 2.3-5.9), HR of 3.2 (95%CI 1.4-7.4) (Figure 2). The 6-month mortality was 37% (95%CI 29-44) in patients treated with LMWH, 28% (95%CI 18-40) in those treated with VKA and 47% (95%CI 28-66) amongst untreated patients. The all-cause mortality at 6 months was significantly higher for patients with a central thrombus (either central or lobar) compared to those with a more peripheral IPE (either segmental or subsegmental); 42% (95%CI 33-52) versus 30% (95%CI 25-36, HR 1.8 (95%CI 1.4-2.3). Conclusions The most important finding of this study is the 12% 6-month risk of symptomatic recurrent VTE in patients with cancer-associated IPE who did not receive anticoagulant treatment, which is more than double the risk of patients who were anticoagulated. These numbers recall the effect size of anticoagulants used in symptomatic PE and support the judicious initiation of anticoagulant treatment in cancer-associated IPE. The association between more centrally-located thrombi and mortality following IPE is a new finding that parallels outcomes for symptomatic PE, and one which may further support similar management. Regarding the choice of anticoagulant, VKA were associated with a significantly higher risk of major bleeding than LMWH, with a comparable risk of recurrent VTE. The findings of this observational study should be preferably confirmed in a randomized trial. Figure 1: Figure 1:. The 6-month risk of recurrent venous thromboembolism related to anticoagulant treatment. Figure 2: The 6-month risk of major bleeding related to anticoagulant treatment. Figure 2:. The 6-month risk of major bleeding related to anticoagulant treatment. Abstract 590. Table 1: Baseline characteristics Treatment All patients n=926 (100%) LMWH n=732 (79%) VKA n=100 (11%) No treatment n=53 (6%) Other treatment n=41 (4%) Mean age (SD) 65 (12) 64 (12) 68 (12) 65 (14) 68 (13) Male sex, n (%) 491 (53) 378 (52) 60 (60) 31 (58) 22 (54) Cancer stage, n (%) Metastatic 501 (54) 400 (55) 56 (56) 33 (62) 12 (29) Non-metastatic 192 (21) 143 (20) 34 (34) 12 (23) 3 (7.3) Unspecified 233 (25) 189 (26) 10 (10) 8 (15) 26 (63) Cancer type, n (%) Lung 176 (19) 135 (18) 16 (16) 18 (34) 7 (17) Colorectal 185 (20) 150 (20) 20 (20) 9 (17) 6 (15) Other gastrointestinal 187 (20) 147 (20) 15 (15) 13 (25) 12 (29) Breast 65 (7.0) 52 (7.1) 10 (10) 1 (1.9) 2 (4.9) Gynaecological 64 (6.9) 56 (7.7) 5 (5.0) 0 (0) 3 (7.3) Other 206 (22) 155 (21) 31 (31) 10 (19) 10 (24) Haematological 43 (4.6) 37 (5.1) 3 (3.0) 2 (3.8) 1 (2.4) Largest artery involved, n (%) Central 292 (32) 230 (31) 30 (30) 11 (21) 21 (51) Peripheral 495 (53) 395 (54) 62 (62) 29 (55) 9 (22) Unspecified 139 (15) 107 (15) 8 (8.0) 13 (25) 11 (27) Disclosures No relevant conflicts of interest to declare.