- Email: [email protected]
PI3K in Primary CNS Lymphoma (PCNSL)
Abstracts AIDS related NHLs represent a challenge for the practicing oncologist. Prognostic factors have been shown to be useful to risk stratify the disease. Here we examine potential prognostic indicators that may improve the performance of current prognostic systems in AIDS related NHLs. Patients: with HIV associated aggressive B-cell NHL were identified between 2001- 2014 at Moffitt Cancer Center. Patients with and primary central nervous system lymphoma were excluded. Survival curves analyzed using the Kaplan Meier method and statistical significance was assessed using the log-rank test. A total of 85 patients were included. The male:female ratio was 6.7. Median age was 44.3 years (range 25 e 65). The median time from HIV to NHL diagnosis was 29 months (0 e 284). Seventyeight percent presented with stage III/IV disease. The most common histologies were Diffuse Large B Cell Lymphoma (DLBCL) and Burkitt’s lymphoma with 49 and 34%, respectively. Bulky disease was present in 27.3%, elevated LDH in 61.5%, and CD4 count < 100/mL at diagnosis in 29.5% patients. The mean Hb, SA and CD4 count were 3.6 g/dL, 11.8 g/dL and 205.9 k/uL, respectively. A serum albumin (SA) < 3.7 g/dL and Hb < 10 g/dl were present in 33% and 23.2% of patients, respectively. Forty-six percent had had cART at time of diagnosis. The cohort’s median OS was 5.9 years. KM curves showed poor median OS with SA < 3.7 g/dl (OS¼3.9 y, p¼0.021), Hb < 10 g/dl (0.7 y, p¼ 0.001) and OI (OS¼ 1.0 y, p¼0.018), There was a trend with worse OS with NCCN-IPI score > 3 (OS¼1.1 y, p¼ 0.165). MV analysis showed that SA < 3.7 retained statistical significance (HR: 2.45, CI: 1.03-5.84, p¼0.042). New prognostic scoring systems have improved the risk stratification of AIDS-related lymphomas (Barta el al, Haematologica 2014). SA < 3.7 is associated with worse OS in this study (Figure 1). SA could improve the stratification of AIDS related lymphomas in the cART era. A validation of the role of SA should be performed in larger cohorts.
aim of our study to determine efficacy and safety assessment of the modified chemotherapy protocol NHL-BFM-90 (m NHL-BFM90) in the treatment of the PIAL with AF. Patients: 29 previously untreated pts with PIAL underwent mNHL-BFM-90 treatment between 2002 e 2012 years: 20 (69%) - DLBCL, 9 (31%) BL; mean age 35 years (range 15-65); M/F¼20/9; stage >I 26 pts (89,6%); all pts had one or more AF. Isolated colon involvement were revealed in 8 (27, 5%), small intestine in 4 (13, 7%) and combined small and large bowel in 18 (58, 6%) pts. LDH level was elevated in 21 (72%), Bulky disease (>10 cm) in 16 (55%) cases. 17 (58, 6%) patients received surgical treatment before chemotherapy. NHL-BFM-90 program modified in the following way: doxorubicin (50mg/m2) added on the third day of course A. All pts underwent from 4 to 6 courses. Results: Complete remission achieved in 26 (89%) pts: BL - 9 from 9 (100%) pts, all alive in remission; DLBCL - 17 from 20 (85%) pts. Three of DLBCL pts without remission: two of them died due to progression and treatment complications and one alive in remission for 8 years after salvage therapy. With a median follow-up of 84 months, (range 1154) progression-free and overall survival of 29 pts constituted 89% and 93%, respectively. Hematologic toxicity of grade 3 and 4 observed in 80% of pts. Severe complications became the reason for subsequent switch to CHOP therapy after two courses in 3 pts. Conclusions: The mNHL-BFM-90 demonstrated acceptable toxicity and high efficacy in patients with PIAL with AF.
NHL-127 Targeting mTOR/PI3K in Primary CNS Lymphoma (PCNSL) Agnieszka Korfel ,1 Elisabeth Schorb,2 Uwe Schlegel,3 Dimitrijevic ,4 Saana D’Allonzo,4 Sa sa Dimitrijevic 5 Martin Dreyling, Ullrich Herrlinger,6 Philipp Kiewe1 1
University Hospital Charité Berlin, Berlin, Germany; 2University
Hospital Freiburg, Freiburg, Germany; 3University Hospital Bochum,
NHL-126 Long-Term Follow-Up of Primary Intestinal Aggressive Lymphomas Treated with mNHL-BFM-90 Evgeniy Zvonkov, Nelli Gabeeva, Anna Sidorova, Anna Morozova, Olga Gavrilina, Hunan Julhakyan , Darya Koroleva, Alla Kovrigina, Tatyana Obukhova, Elena Parovichnikova, Valeriy Savchenko National Research Center for Hematology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
Context: The primary intestinal aggressive lymphomas (PIAL) account about 70% of all intestinal lymphomas. Among them, diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is the most frequent. R-CHOP chemotherapy can induce favorable results for localized-stage. However, the presence of adverse factors (AF) and advanced stages decrease the efficacy of this therapy: 5-year progression-free survival (PFS) and overall survival (OS) are about 50%. Due to the rarity PIAL the optimal treatment strategy for this patients (pts) remains unknown. Objective: The
Bochum, Germany; 4Piqur Pharmaceuticals, Basel, Switzerland; 5
University Hospital Munich, Munich, Germany; 6University Hospital
Bonn, Bonn, Germany
Context: The prognosis of PCNSL remains worse than that of other diffuse-large B-cell lymphomas. Thus, there is a big need for further therapeutic improvement. Dysregulation of various cellular pathways, such as NFkB, toll-like receptor or B-cell receptor signaling have been reported in PCNSL and constitute a potential therapeutic target. Objective: To determine efficacy and safety of mTOR/PI3K inhibitors in PCNSL. Design: Temsirolimus, an allosteric mTOR inhibitor targeting mTORC1, was tested in a phase II study. Patients: Histologically confirmed relapsed/refractory (r/r) PCNSL after high-dose methotrexate based chemotherapy and failure or ineligibility for high-dose chemotherapy with autologous stem-cell transplant failure were main eligibility criteria. Thirty-seven eligible patients (median age, 70 years) were included. The median time since last treatment was 3.9 months. Interventions: The first cohort (n ¼ 6) received 25 mg, all consecutive patients 75 mg temsirolimus intravenously once per week. Main Outcome Measures: Response rate was the primary
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S107
Abstracts end-point. Results: Complete response (CR) was achieved in 5 patients (13.5%), CR unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent CTC 3 adverse events were: hyperglycemia (29.7% patients), thrombocytopenia (21.6%), infection (19%) and anemia (10.8%). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/ mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient (75 mg cohort) and not detectable in all others. Conclusions: Single-agent temsirolimus at a weekly dose of 75 mg was active in r/rPCNSL; however, responses were usually short lived. Cellular feedbacks resulting in e.g. upregulation of AKT could be the reason of resistance to temsirolimus. Dual pan-PI3K/mTOR inhibitors of both mTORC1/TORC2 and the upstream PI3K isoforms lead to a G1/ S arrest and robust autophagy without unintended upregulation of AKT. A trans-atlantic study with an oral dual PI3K/mTOR inhibitor PQR309 in r/rPCNSL (NCT02669511) is currently ongoing with 5 patients recruited thus far. At the meeting, first experience will be presented.
NHL-128 RELINFO - Brazilian Network for Lymphoma Registry in Rio de Janeiro: Preliminary Results Leonardo Gomes ,7,10 Adriana Scheliga,1 Marcio Hori,2 Monica Prexedes,3 Fernando Monteiro,4 Marilza Magalhães,5 Rita Spariz,6 Kellen Blanco,8 Luciana Conti,9 Glaucia Guasti,10 Solange Elehep11 1
Instituto Nacional Do Cancer, Rio de Janeiro, Brazil; 2Instituto COI de Educação e Pesquisa, Rio de Janeiro, Brazil; 3Hospital Universitário
Figure 1 Most Common NHL Subtypes in RELINFO Registry
HL. The majority was female (52.2%). The mean age was 47 years. Most common NHL subtypes are shown in Figure 1. Nodular sclerosis represented the most common HL subtype (64.2%). The average time between the symptons onset and diagnosis was 5.3 months. Median time between diagnosis and start of treatment was 24 days. Four pts died before receiving any treatment due to advanced disease. Among HL 96% had primary nodal disease most frequently in the cervical region (33.8%). High IPS3 observed in 32%. Among NHL pts, 23.6% had extranodal disease. High/High intermidiate IPI were identified in 34 pts with NHL. Conclusion: RELINFO is to become a reliable lymphoma registry and a menagement model to be replicated nationwide, providing subsidies for the development of clinical studies, given the large number of new strategies and therapeutic options. Financial Support: FAPERJ Proc E-26/111.429/2012
Antônio Pedro (HUAP/UFF); 4Hospital Federal da Lagoa (HFL), Rio de Janeiro, Brazil; 5Hospital Universitário Gaffrée e Guinle (HUGG/UNIRIO), Rio de Janeiro, Brazil; 6Hospital Federal Cardoso Fontes 7
(HFCF), Rio de Janeiro, Brazil; IDOR - Instituto D’Or Pesquisa e Ensino, Rio de Janeiro, Brazil; 8Hospital de Força Aérea do Galeão (HFAG), Rio de Janeiro, Brazil; 9Oncoclínica Centro de Tratamento Oncológico Ltda., Rio de Janeiro, Brazil; 10Hospital Central do Exercito (HCE), Rio de Janeiro, Brazil; 11Hospital Central da Policia Militar do Estado do Rio de Janeiro (HCPM), Rio de Janeiro, Brazil
Introduction: There are few data in the incidence, monitoring and prognosis of lymphomas patients in Brazil. Objective: Describe the lymphoma patients (pts) clinical profile enrolled in 11 different public and private institutions paticipating at RELINFO in 2014. Methodology: RELINFO (ClinicalTrials.gov:NTC02265497) is a multicenter, observacional, prospective study intended to collect clinical, histopathological, molecular and treatment data from pts diagnosed with Hodgkin’s Lymphoma (HL) and non-Hodgkin’s Lymphoma (NHL). The web-based platform was developed using OpenClinica case report forms. INCA is the Coodinator Center. Results: There were 180 eligible pts, 127 (70%) with NHL and 53 (30%) with
S108
-
Clinical Lymphoma, Myeloma & Leukemia September 2016
NHL-131 Novel BRD4-Degrading Proteolysis Targeting Chimera (PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma (MCL) Cells Kapil Bhalla , Baohua Sun, Warren Fiskus, Liang Zhang, Dyana Saenz, Christopher Mill, Michael Wang Departments of Leukemia and Lymphoma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
MCL cells exhibit chronic-active BCR signaling and downstream pro-growth and pro-survival NFkB activity. Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase (BTK) yields high overall response rate in relapsed/refractory MCL, but approximately 40% of patients demonstrate primary refractory/resistant disease. Mutations in CARD11/IKBKB/
aim of our study to determine efficacy and safety assessment of the modified chemotherapy protocol NHL-BFM-90 (m NHL-BFM90) in the treatment of the PIAL with AF. Patients: 29 previously untreated pts with PIAL underwent mNHL-BFM-90 treatment between 2002 e 2012 years: 20 (69%) - DLBCL, 9 (31%) BL; mean age 35 years (range 15-65); M/F¼20/9; stage >I 26 pts (89,6%); all pts had one or more AF. Isolated colon involvement were revealed in 8 (27, 5%), small intestine in 4 (13, 7%) and combined small and large bowel in 18 (58, 6%) pts. LDH level was elevated in 21 (72%), Bulky disease (>10 cm) in 16 (55%) cases. 17 (58, 6%) patients received surgical treatment before chemotherapy. NHL-BFM-90 program modified in the following way: doxorubicin (50mg/m2) added on the third day of course A. All pts underwent from 4 to 6 courses. Results: Complete remission achieved in 26 (89%) pts: BL - 9 from 9 (100%) pts, all alive in remission; DLBCL - 17 from 20 (85%) pts. Three of DLBCL pts without remission: two of them died due to progression and treatment complications and one alive in remission for 8 years after salvage therapy. With a median follow-up of 84 months, (range 1154) progression-free and overall survival of 29 pts constituted 89% and 93%, respectively. Hematologic toxicity of grade 3 and 4 observed in 80% of pts. Severe complications became the reason for subsequent switch to CHOP therapy after two courses in 3 pts. Conclusions: The mNHL-BFM-90 demonstrated acceptable toxicity and high efficacy in patients with PIAL with AF.
NHL-127 Targeting mTOR/PI3K in Primary CNS Lymphoma (PCNSL) Agnieszka Korfel ,1 Elisabeth Schorb,2 Uwe Schlegel,3 Dimitrijevic ,4 Saana D’Allonzo,4 Sa sa Dimitrijevic 5 Martin Dreyling, Ullrich Herrlinger,6 Philipp Kiewe1 1
University Hospital Charité Berlin, Berlin, Germany; 2University
Hospital Freiburg, Freiburg, Germany; 3University Hospital Bochum,
NHL-126 Long-Term Follow-Up of Primary Intestinal Aggressive Lymphomas Treated with mNHL-BFM-90 Evgeniy Zvonkov, Nelli Gabeeva, Anna Sidorova, Anna Morozova, Olga Gavrilina, Hunan Julhakyan , Darya Koroleva, Alla Kovrigina, Tatyana Obukhova, Elena Parovichnikova, Valeriy Savchenko National Research Center for Hematology of the Ministry of Healthcare of the Russian Federation, Moscow, Russia
Context: The primary intestinal aggressive lymphomas (PIAL) account about 70% of all intestinal lymphomas. Among them, diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) is the most frequent. R-CHOP chemotherapy can induce favorable results for localized-stage. However, the presence of adverse factors (AF) and advanced stages decrease the efficacy of this therapy: 5-year progression-free survival (PFS) and overall survival (OS) are about 50%. Due to the rarity PIAL the optimal treatment strategy for this patients (pts) remains unknown. Objective: The
Bochum, Germany; 4Piqur Pharmaceuticals, Basel, Switzerland; 5
University Hospital Munich, Munich, Germany; 6University Hospital
Bonn, Bonn, Germany
Context: The prognosis of PCNSL remains worse than that of other diffuse-large B-cell lymphomas. Thus, there is a big need for further therapeutic improvement. Dysregulation of various cellular pathways, such as NFkB, toll-like receptor or B-cell receptor signaling have been reported in PCNSL and constitute a potential therapeutic target. Objective: To determine efficacy and safety of mTOR/PI3K inhibitors in PCNSL. Design: Temsirolimus, an allosteric mTOR inhibitor targeting mTORC1, was tested in a phase II study. Patients: Histologically confirmed relapsed/refractory (r/r) PCNSL after high-dose methotrexate based chemotherapy and failure or ineligibility for high-dose chemotherapy with autologous stem-cell transplant failure were main eligibility criteria. Thirty-seven eligible patients (median age, 70 years) were included. The median time since last treatment was 3.9 months. Interventions: The first cohort (n ¼ 6) received 25 mg, all consecutive patients 75 mg temsirolimus intravenously once per week. Main Outcome Measures: Response rate was the primary
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S107
Abstracts end-point. Results: Complete response (CR) was achieved in 5 patients (13.5%), CR unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent CTC 3 adverse events were: hyperglycemia (29.7% patients), thrombocytopenia (21.6%), infection (19%) and anemia (10.8%). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/ mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient (75 mg cohort) and not detectable in all others. Conclusions: Single-agent temsirolimus at a weekly dose of 75 mg was active in r/rPCNSL; however, responses were usually short lived. Cellular feedbacks resulting in e.g. upregulation of AKT could be the reason of resistance to temsirolimus. Dual pan-PI3K/mTOR inhibitors of both mTORC1/TORC2 and the upstream PI3K isoforms lead to a G1/ S arrest and robust autophagy without unintended upregulation of AKT. A trans-atlantic study with an oral dual PI3K/mTOR inhibitor PQR309 in r/rPCNSL (NCT02669511) is currently ongoing with 5 patients recruited thus far. At the meeting, first experience will be presented.
NHL-128 RELINFO - Brazilian Network for Lymphoma Registry in Rio de Janeiro: Preliminary Results Leonardo Gomes ,7,10 Adriana Scheliga,1 Marcio Hori,2 Monica Prexedes,3 Fernando Monteiro,4 Marilza Magalhães,5 Rita Spariz,6 Kellen Blanco,8 Luciana Conti,9 Glaucia Guasti,10 Solange Elehep11 1
Instituto Nacional Do Cancer, Rio de Janeiro, Brazil; 2Instituto COI de Educação e Pesquisa, Rio de Janeiro, Brazil; 3Hospital Universitário
Figure 1 Most Common NHL Subtypes in RELINFO Registry
HL. The majority was female (52.2%). The mean age was 47 years. Most common NHL subtypes are shown in Figure 1. Nodular sclerosis represented the most common HL subtype (64.2%). The average time between the symptons onset and diagnosis was 5.3 months. Median time between diagnosis and start of treatment was 24 days. Four pts died before receiving any treatment due to advanced disease. Among HL 96% had primary nodal disease most frequently in the cervical region (33.8%). High IPS3 observed in 32%. Among NHL pts, 23.6% had extranodal disease. High/High intermidiate IPI were identified in 34 pts with NHL. Conclusion: RELINFO is to become a reliable lymphoma registry and a menagement model to be replicated nationwide, providing subsidies for the development of clinical studies, given the large number of new strategies and therapeutic options. Financial Support: FAPERJ Proc E-26/111.429/2012
Antônio Pedro (HUAP/UFF); 4Hospital Federal da Lagoa (HFL), Rio de Janeiro, Brazil; 5Hospital Universitário Gaffrée e Guinle (HUGG/UNIRIO), Rio de Janeiro, Brazil; 6Hospital Federal Cardoso Fontes 7
(HFCF), Rio de Janeiro, Brazil; IDOR - Instituto D’Or Pesquisa e Ensino, Rio de Janeiro, Brazil; 8Hospital de Força Aérea do Galeão (HFAG), Rio de Janeiro, Brazil; 9Oncoclínica Centro de Tratamento Oncológico Ltda., Rio de Janeiro, Brazil; 10Hospital Central do Exercito (HCE), Rio de Janeiro, Brazil; 11Hospital Central da Policia Militar do Estado do Rio de Janeiro (HCPM), Rio de Janeiro, Brazil
Introduction: There are few data in the incidence, monitoring and prognosis of lymphomas patients in Brazil. Objective: Describe the lymphoma patients (pts) clinical profile enrolled in 11 different public and private institutions paticipating at RELINFO in 2014. Methodology: RELINFO (ClinicalTrials.gov:NTC02265497) is a multicenter, observacional, prospective study intended to collect clinical, histopathological, molecular and treatment data from pts diagnosed with Hodgkin’s Lymphoma (HL) and non-Hodgkin’s Lymphoma (NHL). The web-based platform was developed using OpenClinica case report forms. INCA is the Coodinator Center. Results: There were 180 eligible pts, 127 (70%) with NHL and 53 (30%) with
S108
-
Clinical Lymphoma, Myeloma & Leukemia September 2016
NHL-131 Novel BRD4-Degrading Proteolysis Targeting Chimera (PROTACs) Exert Potent Single Agent and Synergistic Activity with Ibrutinib and Venetoclax Against Human Mantle Cell Lymphoma (MCL) Cells Kapil Bhalla , Baohua Sun, Warren Fiskus, Liang Zhang, Dyana Saenz, Christopher Mill, Michael Wang Departments of Leukemia and Lymphoma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
MCL cells exhibit chronic-active BCR signaling and downstream pro-growth and pro-survival NFkB activity. Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase (BTK) yields high overall response rate in relapsed/refractory MCL, but approximately 40% of patients demonstrate primary refractory/resistant disease. Mutations in CARD11/IKBKB/