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  • 1
    Online Resource
    Online Resource
    Durable Responses and Improved Quality Of Life With Midostaurin (PKC412) In Advanced Systemic Mastocytosis (SM): Updated Stage 1 Results Of The Global D2201 Trial
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 106-106
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 106-106
    Abstract: Background Patients (pts) with advanced SM, including aggressive SM (ASM) and mast cell leukemia (MCL), often exhibit debilitating mediator symptoms and impaired quality of life (QoL) due to mast cell degranulation and organ damage. Limited treatment options are available for these poor-prognosis conditions. Midostaurin is an oral inhibitor of multiple tyrosine kinases, including wild-type and D816-mutated KIT. In vitro studies have shown that midostaurin inhibits growth and mediator release in human mast cells and basophils. Previously reported results from stage 1 of the ongoing phase 2 study in pts with advanced SM (D2201/NCT00782067; n = 40) showed a high (60%) overall response rate and good safety profile (Gotlib, et al. ASH 2012). Here, we report QoL results and updated duration of response and overall survival (OS) data for these 40 pts. Methods Midostaurin (100 mg twice daily [BID]) was administered continuously in 28-d cycles until progression or unacceptable toxicity. Responses and eligibility were adjudicated by a study steering committee using modified Valent criteria. Symptoms and QoL were assessed at baseline and after each treatment cycle with the Memorial Symptom Assessment Scale (MSAS; ranging from 0 [no symptoms] to 4 [maximum symptom frequency, severity, and distress]) and the Short-Form Health Survey (SF-12; ranging from 0 [worst] to 100 [best]). The total MSAS score (TMSAS), the global distress index score (GDI), the physical score (PHYS), and the psychological score (PSYCH) were derived from the frequency, severity, and distress values of selected symptoms and summarized for the MSAS questionnaire. The composite physical (PCS) and mental health (MCS) scores were summarized for the SF-12 questionnaire. Scores 〉 50 in the PCS and MCS represent above-average health status. Median values were computed at baseline and for the best value on treatment. In addition, the prevalence of the most frequent symptoms at baseline and at the time of the best TMSAS value was calculated. Results With a median follow-up of 35 mo for all pts (range, 20-46 mo), the median duration of response was 37 mo in the 24 responders (Table). Median OS was 41 mo in the 40 stage 1 pts and not reached in MCL pts. The median best reductions in symptom burden on treatment were 65%, 80%, 68%, and 77% as measured by the TMSAS, GDI, PHYS, and PSYCH assessments, respectively. Compared with baseline, 32% of 37 assessable pts had a 〉 50% improvement in TMSAS lasting more than 6 cycles, 35% in GDI, 27% in PHYS, and 30% in PSYCH, reached at a median time of 142, 114, 59, and 91 days, respectively. The 6 most prevalent symptoms at baseline were lack of energy, drowsiness, diarrhea, bloating, difficulty concentrating, and difficulty sleeping. The prevalence of all 6 was reduced on treatment from −17% for difficulty sleeping to −35% for bloating. The median PCS and MCS scores at baseline were 36 and 45 compared with 45 and 59, respectively, on treatment. Similar trends were observed in responders, indicating substantial physical and mental improvement. QoL was improved and symptom burden reduced in both pts with ASM and MCL. Conclusion In pts with advanced SM, midostaurin demonstrates a high rate of durable responses that are associated with improvement of disease-related symptoms and QoL. These data are the first systematic analyses of symptom burden and QoL changes with any therapy for ASM and MCL. Disclosures: Gotlib: Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, travel support Other. Off Label Use: This abstract describes a clinical trial evaluating the investigational agent midostaurin for use in patients with advanced systemic mastocytosis. George:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Akin:Novartis: Consultancy. Sotlar:Nanostring: Honoraria; Novartis: laboratory services compensation, laboratory services compensation Other. Hermine:AB Science: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Celgene: Research Funding. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals: Speakers Bureau. Mauro:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Morariu:Novartis: Employment. Squier:Novartis: Employment. Villeneuve:Novartis: Employment. Emery-Salbert:Novartis: Employment. Coombs:Novartis: Employment, Equity Ownership. Hartmann:Novartis: member of a Steering Committee Other. Horny:Novartis: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding. Reiter:Novartis: Consultancy, Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.106.106
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    Serum Alkaline Phosphatase Level On Day 4 Of G-CSF Administration Could Be a Simple Yet Practical Surrogate Marker For CD34 Mobilization and Collection
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4519-4519
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4519-4519
    Abstract: Granulocyte colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) have become the primary source of stem cells in the majority of allogeneic stem cell transplantations, mainly because of ease of collection and rapid hematopoietic reconstitution. G-CSF for 4 days is the preferred stem cell mobilization method for normal donors. Peripheral blood CD34+ cell count on day 4 of G-CSF is used as a guide to initiate apheresis and PBSC collection. The actual cutoff for PBSC collection varies by institutional preferences. At our center, we collect PBSCs when the CD34+ cell count is greater than 15/ml. Since the turnaround time for CD34 count is about 3 hours; there is a delay in the start of apheresis which extends the PBSC collection to a second day. A reliable and faster method which estimates CD34+ cell count will enable us to avoid delays in collection to the next day. We report the data from our center on the utility of serum alkaline phosphatase (ALK.ph) level as a surrogate marker for the adequacy of peripheral blood CD 34+ cell count suitable for stem cell collection. Methods A retrospective chart review on normal PBSC donors for allogeneic stem cell transplant between January 1, 2009 and March 31, 2013, was performed after obtaining IRB approval. Data was collected at baseline to include sex, age, BMI, WBC, ALK.ph and day 4 ALK.ph, WBC and CD34 count. Results 51 PBSC donors were evaluated, 2 patients were excluded for baseline ALK.ph 〉 200 which was due to undetermined causes. None of these donors had a history of hematologic malignancies or underwent previous apheresis procedures. Of the 49 evaluable patients (23 were males); the median age was 53 years (range 11-72), and the median body mass index (BMI) was 29.1 (range 14-78). Median baseline ALK.ph was 72 (range 42-150), the median day 4 ALk.ph was 164 (54-279). The median CD34 count on first day of collection was 47 (5-218) and there were no mobilization failures. A positive correlation was observed between CD34 count and increase in ALK ph levels 0.4171 (p=0.002). For every one unit/ liter increase in alkaline phosphatase there is 0.48 times (95% CI 0.17-0.78) increase in CD34 count. On univariate regression analysis, the factors that were correlated with CD34+ cell counts were day 4 alkaline phosphatase (p=0.015), day 4 WBC count (p 〈 0.001) and change in alkaline phosphatase as compared to baseline (p=0.002). However, on multivariate robust regression analysis, factors that were correlated with CD34 counts were gender (p=0.04), day 4 WBC count (p 〈 0.001) and baseline alkaline phosphatase (p=0.027). Conclusion Our analysis suggests a potential utility of the change in serum alkaline phosphatase level at day 4 after GCSF in predicting peripheral blood CD34+ cell count. Further studies are underway to utilize this information as part of an algorithm to improve efficiency and prevent delays in normal donors undergoing PBSC mobilization and harvesting. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4519.4519
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 3
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    Online Resource
    A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3136-3136
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3136-3136
    Abstract: Background: Aberrant activation of B-cell receptor (BCR) signaling is considered to be a major oncogenic mechanism that leads to the development and progression of multiple B-cell malignancies. ARQ 531 is a reversible ATP competitive inhibitor of BTK that inhibits ibrutinib-resistant BTK-C481S mutant CLL cells and has demonstrated antitumor activity in CLL, Richter's transformation, and DLBCL mouse models. Objectives: The primary objectives of the clinical study are to assess the safety and tolerability, and to determine the recommended Phase 2 dose and schedule of ARQ 531. The secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of anti-tumor activity of ARQ 531. Methods: This is a first in human, Phase 1 dose escalation study in patients with relapsed or refractory CLL/SLL, Waldenstrom's macroglobulinemia, or B-cell NHL who received at least 2 prior lines of systemic therapy. Prior therapy must have included a BTK inhibitor, if FDA approved for their disease. Dose escalation was performed according to a 3+3 study design. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v.4.03. Tumor responses were evaluated per disease specific guidelines. Results: A total of 16 patients enrolled (median age 65.5 years, male 93.8%, 2 DLBCL, 2 follicular lymphoma, 12 CLL/SLL, 5 median prior systemic regimens) and were treated at dose levels of 5, 10, 15, 20 and 30mg QD. No dose limiting toxicities have been reported with ARQ 531. Drug related TEAEs included diarrhea, nausea, vomiting, fatigue, pneumonia, amylase increased, lipase increased, neutrophil count decreased, platelet count decreased, decreased appetite, hypernatraemia, arthralgia, groin pain, dizziness, facial paralysis, headache, tremor and restlessness in one patient (6.3%) each. Drug related grade 3 or worse TEAEs included lipase increased and platelet count decreased in one patient (6.3%) each. No drug related serious TEAEs were reported. Among the 12 patients who have received at least 1 dose of study drug and have at least 1 post-treatment tumor measurement data, 5 achieved stable disease (SD) (1 follicular lymphoma, 1 DLBCL, 3 CLL) and 7 had progressive disease (6 CLL, 1 follicular lymphoma). Three of 5 SD patients (1 follicular lymphoma, 1 DLBCL, 1 CLL) had 35%, 34% and 29% tumor reduction and 2 of them are ongoing on study treatment at 53 and 18 weeks. The CLL patient with 29% tumor reduction had BTK C481S mutation. Preliminary PK data showed ARQ 531 exposure was close to dose proportional and the estimated plasma half-life generally ranged from 20-24 hours. Consistent with increases in exposure, pBTK knockdown was observed. In Cohort 4 (20mg QD), all three patients showed 100% pBTK knockdown at a mean plasma Cmax exposure of 300nM (~4h post dose). Levels of CCL3 protein, a plasma biomarker for BCR pathway activation, was significantly suppressed in CLL patients. Conclusions: ARQ 531 has demonstrated a manageable safety profile to date. Diminished pBTK signaling and CCL3 protein levels have been observed in CLL patients. Additionally, preliminary anti-tumor activity has been observed at doses of ARQ 531 that were not predicted to completely inhibit BTK. Updated safety, PK, biomarker and anti-tumor activity data will be presented at the meeting. Disclosures Flinn: Gilead: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Verastem: Consultancy, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Curis: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Janssen: Research Funding; ArQule: Research Funding; Calithera: Research Funding; Genentech: Research Funding; Forma: Research Funding; Agios: Research Funding; Constellation: Research Funding; Trillium: Research Funding; Verastem: Research Funding; Portola: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Forty Seven: Research Funding; BeiGene: Research Funding. Savage:ArQule, Inc.: Employment. Eathiraj:ArQule, Inc.: Employment. Tith:ArQule, Inc.: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-116338
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    Online Resource
    Incidence, Type, and Management of Venous and Arterial Thrombosis during Ibrutinib Treatment
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3148-3148
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3148-3148
    Abstract: BACKGROUND: Ibrutinib is an irreversible inhibitor of BTK in the B-cell receptor signaling cascade and is widely used to treat chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits the tyrosine kinase Tec in platelets, which may be one of the mechanisms of its bleeding toxicity. This makes concomitant use of anticoagulation (AC) or antiplatelet agents challenging, which is a common delimma as many patients taking ibrutinib are elderly and have increased risks of venous and arterial thromboses. The incidence of thrombosis in patients taking ibrutinib is unknown, and we hypothesized that the risk of thrombosis may be reduced during ibrutinib treatment. Therefore, we conducted a single-institution retrospective cohort study to determine the incidence and type of both arterial and venous thromboses during ibrutinib treatment and their management. METHODS: We reviewed medical records of all patients treated with ibrutinib for a hematological malignancy at the Ohio State University between 6/1/2010 and 3/31/2016. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All thrombotic events occurring at any time during treatment with ibrutinib and within three days of its discontinuation were recorded. Time to thrombosis was calculated from the date of starting ibrutinib to the date of thrombosis or censored at the last assessment date, treating discontinuation of ibrutinib or death prior to thrombosis as competing risks. The cumulative incidence of thrombosis was estimated and the Fine and Gray regression models accounting for competing riskes were used to examine the association between patient characteristics and risk of thrombosis. RESULTS: The cohort included 565 patients. Median age was 65 (range 23- 〉 89) years and 70.3% (397/565) were men. The majority of patients had CLL (73.6%, 416/565). Other diagnoses included mantle cell lymphoma (9.9%, 56/565), indolent B-cell malignancies (8.1%, 46/565), and aggressive lymphomas (8.3%, 47/565). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/565) of patients were treatment naïve. Prior to ibrutinib, 144 of 565 patients (25.5%) had a history of thrombosis. Sixty-four (11.3%, 64/565) patients had only venous thromboses, 66 (11.7% 66/565) had only arterial thromboses, and 14 patients had both. Concurrently with ibrutinib, 193 (34.2%) patients received antiplatelet agents, 16 (2.8%) patients received AC, and 31 (5.5%) patients received both. Total ibrutinib exposure for the cohort was 1,429 person-years with a median exposure of 2.39 (range 0-7.36) years per patient. A second antineoplastic agent was given with ibrutinib in 30.8% (174/565) of cases, including an immunomodulatory drug in 24 (4.2%, 24/565) patients. During ibrutinib treatment, 22 of 565 (3.9%) patients experienced 24 acute thrombotic events, mostly arterial (Table 1). The incidence of thrombosis was 1.7 (95% CI 1.1-2.5) per 100 person-years of ibrutinib exposure. Of the venous thromboses, 87.5% (7/8) were deep vein thromboses and developed at a median of 7.5 (range 0.5-75.3) months after starting ibrutinib. Of the arterial thromboses, the majority were acute cerebrovascular accidents (37.5%, 6/16) and developed at a median of 27.4 (range 0.4 - 56.6) months after starting ibrutinib. Thrombosis treatment is summarized in Table 1. After thrombosis, ibrutinib was discontinued or held in the majority of cases (75%, 18/24). One patient developed a recurrent thrombosis while on ibrutinib and AC. There were six bleeding events, 3 major (based on ISTH criteria) and 3 minor: all were taking ibrutinib and most were on AC (2 patients on antiplatelet, 1 on AC, 2 on both, 1 on neither). On univariable analysis, the only factors associated with significant (p 〈 0.05) and substantial (HR 〉 2) increased risk of venous thrombosis were prior venous (HR 4.73, CI: 1.06-21.11) and arterial (HR 15.66, CI: 3.07-79.87) thromboses. Antiplatelet use was not significantly associated with either thrombus type. CONCLUSIONS: The cumulative incidence of thrombosis during ibrutinib treatment was low (1.7 per 100 person-years), with the majority being arterial. Prior thrombosis was associated with increased venous thrombosis risk. There are more bleeding than thrombotic complications after patients develop thromboses on ibrutinib, and optimal treatment strategies for this population requires further investigation. Disclosures Kander: AstraZeneca: Consultancy. Wang:Daiichi Sankyo: Consultancy, Other: Travel.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-110556
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
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  • 5
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    Online Resource
    BI 836826, a Novel Fc-Engineered Antibody in Combination with Phosphoinositide-3-Kinase Inhibitor for Treatment of High Risk Chronic Lymphocytic Leukemia and Lymphoma
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 2767-2767
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2767-2767
    Abstract: Background Targeting new antigens in chronic lymphocytic leukemia (CLL) and lymphoma may increase flexibility in the clinic and help circumvent resistance. The tetraspanin CD37 domain mediates transduction of survival and apoptotic signals (Lapalombella et al.,Cancer Cell, 2014), and has been clinically validated by recent trials of otlertuzumab (TRU-016) in CLL and Non-Hodgkin Lymphoma . Ligation of CD37 by this reagent simultaneously induced pro-apoptotic signaling and inhibited pro-survival signaling of phosphoinositide 3-kinase δ (PI3Kδ), which introduces a unique opportunity to use combination strategies employing activation of CD37 and inhibition of PI3Kδ. A new agent BI 836826 is an Fc-engineered anti-CD37 IgG1 that displays improved effector activities as well as crosslinker-independent direct cytotoxicity. We have evaluated the efficacy of BI 836826 combined with the PI3Kδ-selective inhibitor idelalisib in diffuse large B-cell lymphoma (DLBCL) cell lines and primary human CLL B-cells in the University and then by industry to validate the synergistic finding initially reported. Methods Cell viability assays usedCellTiterGlo to measure inhibition of antibody, isotype control, idelalisib or a combination of antibody and compound over 72h in culture. The cell viability of vehicle is measured at the time of dosing (T0) and after seventy-two hours (T72). A GI reading of 0% represents no growth inhibition, GI 100% represents complete growth inhibition, and a GI 200% represents complete death of all cells in the culture well. Annexin V-FITC and propidium iodide measure by flow cytometry was used to assess enhanced killing of primary CLL cells, with incubation of BI 836826 (0.1 µg/mL) and/or idelalisib (1 µM) at 37°C for 24 hours. Trastuzumab included as a non-specific IgG1 control. Data was reported as percentage of viable cells (Annexin V negative, PI negative) normalized to untreated control. Results DLBCL cell lines were variably sensitive to single agent BI 836826. In most of the cell lines tested, the cell viability was inhibited by 40%-50% with BI 836826 in the concentration range of 1-1000 ng/mL (Figure 1A). A synergistic effect was noted in several DLBCL cell lines when BI 836826 was combined with idelalisib. When the maximal effect of BI 836826 was greater than isotype control (GI% 〉 12, dotted line) and the effect of idelalisib showed a GI50 〈 1uM, 3/5 cell lines showed synergy in combination (red dot, Figure 1B). A shift in the EC50of idelalisib can be seen with the addition of increasing amounts of BI 836826 (Figure 1C). In primary CLL B-cell cultures, 1 µM idelalisib displayed weak single agent activity following 24-hour incubation. The cytotoxicity of BI 836826 at 0.1 µg/mL was more variable, although treatment of samples from most CLL patients resulted in 20-50% B-cell death. The combination of these 2 agents resulted in enhanced cytotoxic activity (Figure 2A), and this effect was not attenuated by the presence of del(17)(p13.1), as there was no significant difference in cytotoxicity against these cells compared to those with lower risk cytogenetics (Figure 2B,C). Additionally, the combination was beneficial in CLL B-cells isolated from patients who were refractory to ibrutinib (Figure 2D). Conclusions This collaborative industry and academic endeavor with cross validation of initial mechanistic studies of synergy between CD37 and idelalisib demonstrates that addition of idelalisib to BI 836826 augments cytotoxicity against DLBCL cell lines and primary human CLL B-cells in an additive-to-synergistic manner. In addition, it maintains efficacy against CLL B-cells with del(17)(p13.1) and those from ibrutinib-refractory patients. Further exploration of this therapeutic strategy in clinical trials is strongly warranted. Disclosures Jones: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Grosmaire:Gilead: Employment. Jones:Gilead: Employment. DiPaolo:Gilead: Employment. Tannheimer:Gilead Sciences: Employment. Heider:4Boehringer Ingelheim RCV: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.2767.2767
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 6
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    Ibrutinib: targeting the hidden CLL
    American Society of Hematology ; 2014
    In:  Blood Vol. 123, No. 21 ( 2014-05-22), p. 3215-3216
    Details
    In: Blood, American Society of Hematology, Vol. 123, No. 21 ( 2014-05-22), p. 3215-3216
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2014-04-565333
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 7
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    Final Results and Follow-up of a Phase I Study of the Fc Engineered CD19 Antibody XmAb®5574 (aka MOR00208) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1993-1993
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1993-1993
    Abstract: CD19 is an attractive target in lymphoid malignancies as it is highly expressed in nearly all CLL and non-Hodgkin’s lymphomas. While development of CD19 directed antibodies (abs) had previously been limited by antigen internalization, improved ab modification technology has restored this potential target. XmAb5574 (MOR00208) is a novel humanized IgG1 CD19 monoclonal ab with an engineered Fc region to enhance Fc gamma receptor binding affinity. We have previously presented safety and efficacy data from a first in human trial of this ab in relapsed or refractory (R/R) CLL, and now update these results along with results of a maintenance therapy cohort, follow-up efficacy data on all patients (pts), and correlative studies. This study was a multi-institutional phase I trial of XmAb5574 in pts with R/R CLL. An accelerated titration design was used, with dose levels of 0.3, 1, 3, 6, 9, and 12 mg/kg with an expansion to a total of 16 pts at the maximal tolerated dose (MTD). Patients received 9 intravenous infusions of XmAb5574: days 1, 4, 8, 15, and 22 of cycle 1, and days 1, 8, 15, and 22 of cycle 2. Once 5 patients were treated in the maximal dose cohort, additional patients who had at least stable disease after 2 cycles had the option to receive Xmab5574 every 28 days for an additional 4 infusions. Toxicity was assessed using the National Cancer Institute’s Common Criteria for Adverse Events v4.0 for non-hematologic toxicity, and IWCLL 2008 guidelines for hematologic toxicity. Disease response assessment by physical exam was performed on C1D28, C2D28, and 4, 8, and 12 weeks after the end of Cycle 2. CT assessment was performed C2D28. 27 pts were enrolled, with a median age of 66 years (range 40-84). The pts were generally high risk: 14 had high-risk disease by Rai stage, 8 had del(11q22.3) and 10 had del(17p13.1) by FISH, and 24 had IgVH unmutated disease. The median number of prior therapies was 4 (range 1-13). Toxicity with this agent was modest with no MTD identified. 5 pts experienced grade 3 or 4 treatment-related toxicity, which included neutropenia (3 pts), thrombocytopenia (2 pts), increased aspartate aminotransferase (AST; 1 pt), febrile neutropenia (1 pt), and tumor lysis syndrome (1 pt). Grade 1 and 2 toxicities assessed as possibly related to XmAb5574 that occurred in more than 10% of pts included infusion reactions, increased AST, increased alanine aminotransferase, neutropenia, thrombocytopenia, fever, chills, and peripheral neuropathy. Infusion reactions occurred in 67% of patients, however, all were grade 1 or 2, and no reactions were seen following the first infusion. On the basis of physical exam and laboratory studies, 18 patients (66.7%) achieved a partial response (PR), and the remaining 9 patients (33.3%) achieved stable disease (SD). Adding CT criteria, 8 patients (29.6%) achieved a PR with an additional 16 patients (59.3%) achieving SD. Two patients had progressive disease by CT criteria. No patient dosed below 3 mg/kg had an objective response. Of the 16 pts treated at the maximum dose, 12 patients (75%) had a PR by physical exam criteria and 6 patients (37.5%) had a PR by CT criteria, with 2 of these pts achieving a PR during the maintenance phase. Median progression free survival (PFS) for all patients was 199 days (95% CI: 168-299 days). For patients on all dose levels who received 9 doses or less, PFS was 189 days, and for the 8 patients on the extended treatment cohort, PFS was 420 days (95% CI: 168 days-not reached). Flow cytometry was performed for absolute T and NK cell counts as well as activation. During the first 12 weeks, there was no significant change in T or NK cell counts; however, from cycle 1 day 1 pre to end of infusion there was a significant decrease in both T and NK cell number. There was no significant change in T or NK cell activation at any point. PK was best modeled by a two-compartment model. Half-life was 14 days, with clearance 5mL/day/kg that was not dose-dependent. A steady-state was reached at or before infusion 9. In conclusion, this Phase I trial demonstrates safety and preliminary efficacy of a novel Fc engineered CD19 monoclonal antibody XmAb5574 (MOR00208) and justifies movement into the Phase II setting. The modest toxicity combined with preliminary efficacy as a single agent will likely allow for successful combination therapies, and current studies in CLL are investigating XmAb5574 in combination with other active agents. Disclosures Foster: Xencor, Inc: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1993.1993
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Update On The Safety and Efficacy Of The Pan Class I PI3K Inhibitor SAR245408 (XL147) In Chronic Lymphocytic Leukemia and Non-Hodgkin’s Lymphoma Patients
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4170-4170
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4170-4170
    Abstract: Constitutive activation of phosphatidylinositol 3-kinase (PI3K)/ mammalian target of rapamycin (mTOR) pathway by various mechanisms has been implicated in the pathogenesis of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). There is mounting evidence suggesting that along with PI3Kγ, PI3Kα may be involved in CLL/NHL. SAR245408 is a potent and selective inhibitor of all α, γ and δ class I PI3K isoforms. It has been shown to inhibit PI3K signaling and impact tumor growth in preclinical tumor models. The impact of SAR245408 on safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor effect was evaluated in patients with relapsed/refractory CLL and NHL from the Sanofi sponsored phase 1 single-agent study (NCT00486135) [Brown et al. ASH Annual Meeting Abstracts 2011. 118 (21): 2683]. Methods SAR245408 was administered orally, once daily, with continuous dosing in monthly cycles. A total of 25 patients were enrolled at the maximum tolerated dose identified in solid tumor patients as part of the expansion cohort in relapsed/refractory lymphoproliferative malignancies. Plasma cytokines and chemokines were evaluated using the Myriad RBM Human Discovery MAP250+ panel ( 〉 250 analytes) and ELISA assays. Results Among the 25 patients (pts), 40% (n=10) had refractory CLL and 60% (n=15) had various relapsed/refractory lymphomas (R/RL), including follicular lymphoma (FL) (n=5), diffuse large B-cell lymphoma (DLBCL) (n=4), Waldenstrom's macroglobulinemia (WM) (n=3), Hodgkin lymphoma (n=2) and B-cell prolymphocytic leukemia (n=1). The median age was 65 years (range 28–83), and 56% were female. Eighty percent of pts had stage III-IV disease and 48% had bulky disease. Five pts were categorized as having refractory disease and the median number of prior regimens was 1 (range 1-7) for CLL pts and 3 (range 0-9) for R/RL pts. For all 25 patients, the median starting absolute lymphocyte count was 1.15 x 103/μL (range 0.3–37.2), the median starting hemoglobin was 11.4 g/dL (range 9.1–15) and the median platelet count was 162 x 103/μL (range 60–431). The median number of cycles administered in CLL pts was 10 (range 5-24) and 5 (range 1-26) in R/RL pts. Six CLL pts experienced an increase in absolute lymphocyte counts within 2-4 weeks of treatment, as has been seen with other PI3K inhibitors. According to modified International Workshop on Chronic Lymphocytic Leukemia (IWCLL) response criteria, 4 CLL pts had partial response (PR), 1 had nodal PR with increased lymphocytosis, and 5 had stable disease (SD); the progression free survival (PFS) in the responding pts was 22, 21.2, 15.6 and 15.4 months while in the SD pts was 12.5, 9.2, 7.4, 5.6, 4.6 and 3.6 months. According to the modified International Working Group response criteria, 3 PRs were reported in R/RL pts [1 WM, 1 DLBCL (transformed) and one FL with PFS of 23.7, 18.4 and PFS 4.8 months respectively]. One hundred percent of CLL and 80% of R/RL pts reported grade 3 or higher AEs, with the most common (≥ 10% of patients) including neutropenia, diarrhea, anemia and hypotension. SAR245408 induced a reduction in levels of chemokines involved in lymphocyte trafficking in CLL subjects (n=8), including CXCL13, CCL3, CCL22 and CCL19 (64, 58, 52 and 54% reduction, respectively, p 〈 0.05) similar to what was reported with PI3K δ specific inhibitors. In addition, a reduction of tumor necrosis factor receptor 2 (TNFR2) and interleukin-2 receptor alpha (IL-2Rα) levels was observed (63% reduction each, p 〈 0.01). Conclusions The recommended phase 2 dose of SAR245408 in solid tumor patients was confirmed as safe and tolerable in patients with CLL and R/RL. Single agent SAR245408 demonstrates clinical activity in patients with relapsed or refractory CLL and promising pharmacodynamic effects on chemokine levels involved in lymphocyte trafficking. Disclosures: Brown: Emergent: Consultancy; Onyx: Consultancy; Sanofi Aventis: Consultancy; Vertex: Consultancy; Novartis: Consultancy; Genzyme: Research Funding; Avila: Consultancy; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy. Off Label Use: The abstract shows scientific information on SAR245408 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication. Egile:Sanofi: Employment. Ruiz-Soto:Sanofi: Employment. Awan:Lymphoma Research Foundation: Research Funding; Spectrum Pharmaceuticals Inc.: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4170.4170
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 9
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    Presence of a Translocation Is Associated with Short Time to Treatment from Diagnosis in IGHV Mutated Chronic Lymphocytic Leukemia (CLL) Patients
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 4372-4372
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4372-4372
    Abstract: Chronic Lymphocytic Leukemia (CLL) has a varied clinical course; some patients experience a long survival and others succumb to disease in a short time. Clinical factors correlated with either time to first treatment (TFT) and/or overall survival include Rai stage, IGHV somatic hypermutation status, fluorescence in situ hybridization (FISH) abnormalities, especially del(17p), karyotypic complexity and the presence of a cytogenetic translocation. Previous studies have included patients both at diagnosis and at various times throughout their diseases, and many included limited numbers of patients, precluding extensive analyses of relationships between the prognostic factors and their relative impact on clinical outcome. We sought to identify which factors determined within a short time of diagnosis (i.e., 1 year) were prognostic for TFT in untreated CLL patients. We identified 329 untreated CLL patients who had stimulated karyotypic and FISH analyses within 1 year of diagnosis seen at The Ohio State University (OSU). Patient characteristics and outcome were obtained from patient records. The studies were approved by the OSU IRB and were conducted according to the Declaration of Helsinki. A complex karyotype was defined as ≥ 3 unrelated aberrations by karyotype. Patient characteristics are given in Table 1. Translocations occurred in 87 (26.4%) patients: 38 balanced and 49 unbalanced translocations. Initial statistical analyses showed no large difference in TFT between balanced and unbalanced translations, so they were combined for final analyses. 144 patients (49 with and 95 without a translocation) had unmutated IGHV, and 144 patients (22 with and 122 without a translocation) had mutated IGHV. IGHV data were not available for 41 patients. TFT was calculated from date of diagnosis to date of first treatment. Untreated patients were censored at last known untreated date. Kaplan-Meier curves estimated TFT probability, and proportional hazard models were used to examine the association between potential risk factors and TFT. Using backward selection, variables with statistical significance when adjusting for all other covariates were included in the final model. To evaluate potential effect modifications, pairwise interactions among all the variables in the final model were examined and retained if statistically significant. Stata 14 (College Station TX) was used, and all tests were two-sided with statistical significance set at p 〈 0.05. Median follow-up for censored patients was 30 months (range 0.03-102 months). Median TFT for the entire cohort was 47 months (95% confidence interval (CI) 40-63 months). In a univariable model, the following factors were significant: presence of a translocation (hazard risk (HR) 2.69, CI 1.91-3.78, p 〈 0.001), Rai stage III/IV (HR 3.73, CI 2.32-5.99, p 〈 0.001), complexity (HR 2.92, CI 1.98-4.31, p 〈 0.001), unmutated IGHV (HR 3.54, CI 2.42-5.17, p 〈 0.0001), del17p (HR 2.10, CI 1.31-3.37, p=0.002), del11q (HR 2.91,CI 1.92-4.40, p 〈 0.001). In the multivariable model, there was significant effect modification of IGVH status on the relationship between translocation and TFT (p 〈 0.001). In IGHV mutated patients, those with a translocation had over 5 times the risk of starting treatment relative to those without a translocation (HR 5.30, CI 2.76-10.17); however, in IGHV unmutated patients, a translocation did not significantly increase the risk of starting treatment (HR 1.32, CI 0.86-2.03). Independent of IGHV and translocation, Rai Stage (HR 2.07, CI 1.24-3.45, p=0.01) and del11q (HR 1.68, CI 1.09-2.60, p=0.02) were the only variables that remained statistically significant. Notably, once these variables were accounted for in the model, complexity did not provide additional significant prognostic information (p=0.12), perhaps due to its strong association with a translocation (p 〈 0.001). In summary, the presence of a translocation in IGHV mutated patients appeared to negate the improved prognosis associated with mutated IGHV, but the presence of a translocation did not have an effect on TFT in high-risk IGHV unmutated patients (Figure 1). Table 1 Table 1. Figure 1 Time to Treatment for patients with vs without a translocation and with mutated vs unmutaed IGVH Figure 1. Time to Treatment for patients with vs without a translocation and with mutated vs unmutaed IGVH Disclosures Jones: Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Woyach:Morphosys: Research Funding; Acerta: Research Funding; Karyopharm: Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.4372.4372
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Targeting the Tumor Evasion Interaction of NKG2A and Its Ligand HLA-E Increases Natural-Killer Cell Activity in Chronic Lymphocytic Leukemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1289-1289
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1289-1289
    Abstract: Chronic Lymphocytic Leukemia (CLL) represents the most frequent adult leukemia, and remains incurable with current standard therapies. Natural Killer (NK) cell count is predictive of CLL disease progression and their dysfunction in mediating cytokine release and direct or antibody dependent cellular cytotoxicity (ADCC) against CLL B-cells is well documented. Detailed mechanistic insight into the etiology of NK-cell dysfunction in CLL patients is currently lacking. CLL B-cells overexpress HLA-E, the natural ligand for heterodimer CD94/NKG2A receptor complex that is expressed on the surface of NK cells, and this interaction suppresses NK cell activation. While NKG2A/CD94/HLA-E interaction is known to assist NK cells in recognizing "self", tumor cells utilize this mechanism to evade effector cell killing. Utilizing a novel anti-NKG2A monoclonal blocking antibody (mab) we explored the in vitro preclinical activity of targeting the NKG2A receptor, and the NKG2A/HLA-E interaction as a mechanism of tumor evasion in patients with CLL. We hypothesized that limiting the interaction of HLA-E/NKG2A will reverse NK cell anergy and result in increased direct cytotoxicity of CLL cells. Our results confirm the over expression of HLA-E on CLL B-cells and demonstrate NKG2A expression on CD16+ NK cells from CLL patients. Next, we examined the effect of anti-NKG2A mab on NK cell direct cytotoxicity. Treatment of NK cells, from both healthy donor and CLL patients, with anti-NKG2A mab increased direct cytotoxicity over isotype control on targets at various effector to target ratios of 25:1 (54% vs. 46%, p 〈 0.05, n= 12), 12:1 (43% vs. 35%, p 〈 0.05, n=14), and 6:1 (31% vs. 23%, p 〈 0.05, n= 12, for anti-NKG2A mediated cytotoxicity vs isotype mediated cytotoxicity respectively). These results were also validated with HLA-E over and underexpressing target cells. Fc-gamma receptor blocking experiments were also performed to confirm the specificity of the interaction. Further studies are being performed to confirm the specific activity of the antibody including its ability to modulate NK cell activation, enhance ADCC, and the impact of anti-NKG2A therapy for reversing ibrutinib mediated NK-cell dysfunction. This work has laid the foundation for the clinical utility of this reagent in patients with relapsed CLL in combination with ibrutinib. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1289.1289
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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