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Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to lymphoid malignancies. The majority of NBS patients are identified with a homozygous five base pair deletion in the Nibrin (NBN) gene (c.657_661del5, p.K219fsX19) with a founder effect observed in Caucasian European populations, especially of Slavic origin. We present here an analysis of a cohort of 136 NBS patients of Eastern Slav origin across Belarus, Ukraine, Russia, and Latvia with a focus on understanding the geographic distribution, incidence of malignancy, and treatment outcomes of this cohort. Our analysis shows that Belarus had the highest prevalence of NBS (2.3 per 1,000,000), followed by Ukraine (1.3 per 1,000,000), and Russia (0.7 per 1,000,000). Of note, the highest concentration of NBS cases was observed in the western regions of Belarus and Ukraine, where NBS prevalence exceeds 20 cases per 1,000,000 people, suggesting the presence of an “Eastern Slavic NBS hot spot.” The median age at diagnosis of this cohort ranged from 4 to 5 years, and delay in diagnosis was more pervasive in smaller cities and rural regions. A total of 62 (45%) patients developed malignancies, more commonly in males than females (55.2 vs. 34.2%; p=0.017). In 27 patients, NBS was diagnosed following the onset of malignancies (mean age: 8 years). Malignancies were mostly of lymphoid origin and predominantly non-Hodgkin lymphoma (NHL) (n=42, 68%); 38% of patients had diffuse large B-cell lymphoma. The 20-year overall survival rate of patients with malignancy was 24%. However, females with cancer experienced poorer event-free survival rates than males (16.6% vs. 46.8%, p=0.036). Of 136 NBS patients, 13 underwent hematopoietic stem cell transplantation (HSCT) with an overall survival of 3.5 years following treatment (range: 1 to 14 years). Indications for HSCT included malignancy (n=7) and immunodeficiency (n=6). Overall, 9% of patients in this cohort reac

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1-dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. Synergistic cell killing was also observed between A-1592668 or the related analog A-1467729, and venetoclax in a number of hematologic cell lines and primary NHL patient samples. Importantly, the CDK9 inhibitor plus venetoclax combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in mouse models of lymphoma and AML. These data indicate that CDK9 inhibitors could be highly efficacious in tumors that depend on MCL-1 for survival or when used in combination with venetoclax in malignancies dependent on MCL-1 and BCL-2.Copyright © 2019, The Author(s).

Despite overall improvements in cancer survival due to earlier diagnosis and better treatment, socio-economically disadvantaged people have lower cancer survival than more advantaged people. We aimed to examine differences in cancer survival by area-level socio-economic disadvantage in Victoria, Australia and assess whether these inequalities varied by year of diagnosis, age at diagnosis, time since diagnosis and sex. Cases diagnosed with a first primary cancer in 2001-2015 were identified using the Victorian Cancer Registry and followed to the end of 2016. Five-year net survival and the excess risk of death due to a cancer diagnosis were estimated. People living in more disadvantaged areas had lower five-year survival than residents of less disadvantaged regions for 21 of 29 cancer types: head and neck, oesophagus, stomach, colorectum, anus/anal canal, liver, gallbladder/ biliary tract, pancreas, lung, melanoma, connective/soft tissue, female breast, ovary, prostate, kidney, bladder, brain and central nervous system, unknown primary, non-Hodgkin lymphoma, multiple myeloma and leukemia. The observed lower survival in more deprived regions persisted over time, except head and neck cancer, for which the gap in survival has widened. Socio-economic inequalities in survival decreased with increasing age at diagnosis for cancers of connective/soft tissue, bladder and unknown primary. For colorectal cancer, the observed survival disadvantage in lower socio-economic regions was greater for men than for women, while for brain and central nervous system tumours, it was larger for women. Cancer survival is generally lower for residents of more socio-economically disadvantaged areas. Identifying the underlying reasons for these inequalities is important and may help to identify effective interventions to increase survival for underprivileged cancer patients.Copyright © 2020 Afshar et al. This is an open access article distributed under the terms of the Creative Commons Attribut

Aim: Patients with haematologic malignancies are major recipients of blood products; however comprehensive Australian data about clinical outcomes of transfusion are limited. As part of a feasibility study to establish a national comprehensive dataset of all transfusions and their outcomes, we analysed transfusion data for adult haematology/oncology patients from the first pilot site. Method(s): Hospital electronic data on adult patients receiving any blood product (>=1 RBC [red blood cells], platelet, FFP [fresh frozen plasma], cryoprecipitate, or plasma derivative) during 2017 were imported, linked and analysed using the expanded platform of the Australian and New Zealand Massive Transfusion Registry. Data included laboratory (for transfusion and blood tests) and hospital information systems records (for patient demographics, co-morbidities, admission and clinical outcome data). Haematology/oncology patients were identified by ICD-10-AM diagnostic codes. Analyses were performed using Stata software. Result(s): Of 5859 transfused admitted patients, 767 (13%) were haematology/ oncology patients. Of these 38% were acute leukaemias, 25% myeloma, 15% NHL (non-Hodgkin lymphoma), 7% chronic leukaemias, and 15% MDS and other haematopoietic neoplasms. Patient median age was 66.7y, [IQR, 57, 74], and 58% were male. Haematology/oncology patients were 30% (3365/11201) of all admissions where a transfusion was performed; of which 56% were day-admissions. 61% of patients were admitted only once; 34% had 2-10 admissions and 5% had 11-100 admissions. They accounted for 33% RBCs, 69% platelets, 20% cryoprecipitate, 5% FFP and 13% IVIg (intravenous immunoglobulin; in grams) transfused. For outpatients receiving platelet transfusions, median [IQR] platelet count was 17 x109/L [10, 51]. Conclusion(s): Haematology/oncology patients represented 13% of all transfused patients, but required significant proportions of the transfusion product inventory, including 69% of all platelets, cons

ES is a 7-month-old female born to a non-consanguineous Caucasian couple at 35 weeks of gestation following a pregnancy that was complicated by Maternal Non-Hodgkin's Lymphoma requiring R-CHOP (Chemotherapy) from 17 to 35 weeks antenatally. At 12 weeks of age ES progressively deteriorated following a respiratory illness requiring invasive respiratory support. Initial investigations showed marked lymphopenia of 1.5 x 10^9/L and a search for opportunistic organisms revealed elevated Pneumocystis Jiroveci counts in her BAL. Following this she was started on a combination of Primaquine, Lincomycin and Bactrim treatment. Apart from the lymphopenia, her IgG was noted to be extremely low at <1.0 g/L. There were concerns of a primary immunodeficiency, however this was confounded by the possibility of a secondary immunodeficiency due to the use of maternal R-CHOP antenatally. Her recent thymic emigrants were noted to be 53% suggestive of adequate output from the thymus and her PHA was also normal suggestive of adequately functioning T cells. Recovery of lymphocyte counts to 7.2 x 109/L and IgG to 3.2 g/L post supportive management including intravenous immunoglobulin over the ensuing months confirmed the likelihood of a secondary immunodeficiency in her presentation. She is currently on low flow oxygen and her immunoglobulin levels have stabilized without ongoing IVIG, as her own production of immunoglobulins takes over. This case illustrates the importance of monitoring of babies born to mothers on chemotherapy and consideration of supportive management which may include antimicrobial prophylaxis and intravenous immunoglobulins during the first 6-12 months of life.

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1-dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. Synergistic cell killing was also observed between A-1592668 or the related analog A-1467729, and venetoclax in a number of hematologic cell lines and primary NHL patient samples. Importantly, the CDK9 inhibitor plus venetoclax combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in mouse models of lymphoma and AML. These data indicate that CDK9 inhibitors could be highly efficacious in tumors that depend on MCL-1 for survival or when used in combination with venetoclax in malignancies dependent on MCL-1 and BCL-2.Copyright © 2019, The Author(s).

Despite overall improvements in cancer survival due to earlier diagnosis and better treatment, socio-economically disadvantaged people have lower cancer survival than more advantaged people. We aimed to examine differences in cancer survival by area-level socio-economic disadvantage in Victoria, Australia and assess whether these inequalities varied by year of diagnosis, age at diagnosis, time since diagnosis and sex. Cases diagnosed with a first primary cancer in 2001-2015 were identified using the Victorian Cancer Registry and followed to the end of 2016. Five-year net survival and the excess risk of death due to a cancer diagnosis were estimated. People living in more disadvantaged areas had lower five-year survival than residents of less disadvantaged regions for 21 of 29 cancer types: head and neck, oesophagus, stomach, colorectum, anus/anal canal, liver, gallbladder/ biliary tract, pancreas, lung, melanoma, connective/soft tissue, female breast, ovary, prostate, kidney, bladder, brain and central nervous system, unknown primary, non-Hodgkin lymphoma, multiple myeloma and leukemia. The observed lower survival in more deprived regions persisted over time, except head and neck cancer, for which the gap in survival has widened. Socio-economic inequalities in survival decreased with increasing age at diagnosis for cancers of connective/soft tissue, bladder and unknown primary. For colorectal cancer, the observed survival disadvantage in lower socio-economic regions was greater for men than for women, while for brain and central nervous system tumours, it was larger for women. Cancer survival is generally lower for residents of more socio-economically disadvantaged areas. Identifying the underlying reasons for these inequalities is important and may help to identify effective interventions to increase survival for underprivileged cancer patients.Copyright © 2020 Afshar et al. This is an open access article distributed under the terms of the Creative Commons Attribut

PURPOSE To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the doseresponse relationship, and explore associations with moderate- and vigorous-intensity physical activity. METHODS Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend (P <.05) and 95% CIs (<1.0). RESULTS A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types. CONCLUSION Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multip

Aim: Patients with haematologic malignancies are major recipients of blood products; however comprehensive Australian data about clinical outcomes of transfusion are limited. As part of a feasibility study to establish a national comprehensive dataset of all transfusions and their outcomes, we analysed transfusion data for adult haematology/oncology patients from the first pilot site. Method(s): Hospital electronic data on adult patients receiving any blood product (>=1 RBC [red blood cells], platelet, FFP [fresh frozen plasma], cryoprecipitate, or plasma derivative) during 2017 were imported, linked and analysed using the expanded platform of the Australian and New Zealand Massive Transfusion Registry. Data included laboratory (for transfusion and blood tests) and hospital information systems records (for patient demographics, co-morbidities, admission and clinical outcome data). Haematology/oncology patients were identified by ICD-10-AM diagnostic codes. Analyses were performed using Stata software. Result(s): Of 5859 transfused admitted patients, 767 (13%) were haematology/ oncology patients. Of these 38% were acute leukaemias, 25% myeloma, 15% NHL (non-Hodgkin lymphoma), 7% chronic leukaemias, and 15% MDS and other haematopoietic neoplasms. Patient median age was 66.7y, [IQR, 57, 74], and 58% were male. Haematology/oncology patients were 30% (3365/11201) of all admissions where a transfusion was performed; of which 56% were day-admissions. 61% of patients were admitted only once; 34% had 2-10 admissions and 5% had 11-100 admissions. They accounted for 33% RBCs, 69% platelets, 20% cryoprecipitate, 5% FFP and 13% IVIg (intravenous immunoglobulin; in grams) transfused. For outpatients receiving platelet transfusions, median [IQR] platelet count was 17 x109/L [10, 51]. Conclusion(s): Haematology/oncology patients represented 13% of all transfused patients, but required significant proportions of the transfusion product inventory, including 69% of all platelets, cons

ES is a 7-month-old female born to a non-consanguineous Caucasian couple at 35 weeks of gestation following a pregnancy that was complicated by Maternal Non-Hodgkin's Lymphoma requiring R-CHOP (Chemotherapy) from 17 to 35 weeks antenatally. At 12 weeks of age ES progressively deteriorated following a respiratory illness requiring invasive respiratory support. Initial investigations showed marked lymphopenia of 1.5 x 10^9/L and a search for opportunistic organisms revealed elevated Pneumocystis Jiroveci counts in her BAL. Following this she was started on a combination of Primaquine, Lincomycin and Bactrim treatment. Apart from the lymphopenia, her IgG was noted to be extremely low at <1.0 g/L. There were concerns of a primary immunodeficiency, however this was confounded by the possibility of a secondary immunodeficiency due to the use of maternal R-CHOP antenatally. Her recent thymic emigrants were noted to be 53% suggestive of adequate output from the thymus and her PHA was also normal suggestive of adequately functioning T cells. Recovery of lymphocyte counts to 7.2 x 109/L and IgG to 3.2 g/L post supportive management including intravenous immunoglobulin over the ensuing months confirmed the likelihood of a secondary immunodeficiency in her presentation. She is currently on low flow oxygen and her immunoglobulin levels have stabilized without ongoing IVIG, as her own production of immunoglobulins takes over. This case illustrates the importance of monitoring of babies born to mothers on chemotherapy and consideration of supportive management which may include antimicrobial prophylaxis and intravenous immunoglobulins during the first 6-12 months of life.

PURPOSE To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the doseresponse relationship, and explore associations with moderate- and vigorous-intensity physical activity. METHODS Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend (P <.05) and 95% CIs (<1.0). RESULTS A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types. CONCLUSION Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multip

The significant morbidity and mortality associated with iron overload can be reduced by effective iron chelation. Magnetic resonance imaging (MRI) provides accurate and reproducible iron load assessment. The aim of this epidemiological study was to assess the prevalence and severity of cardiac and hepatic siderosis by MRI and to evaluate the impact of MRI on clinical management in patients with transfusion-dependent anemia and non-transfusion-dependent thalassemia (NTDT). We enrolled 243 patients with myelodysplastic syndromes (MDS), thalassemia major (TM), NTDT or other chronic anemia. Overall, 10% and 48% had cardiac and hepatic siderosis, respectively. Mean liver iron concentration (LIC) was above target range in all groups; mean myocardial T2* was normal. Hepatic siderosis was more prevalent than myocardial siderosis in patients with MDS, occurring in 54.4% and 4.4% of patients, respectively. As also observed in patients with NTDT or other anemia, hepatic siderosis was present in a large proportion of MDS patients who were chelation naive (57.7%), as well as in patients receiving iron chelation therapy (ICT) (52.4%), despite a lower transfusion load compared with TM. Correlation between LIC and serum ferritin was observed across diseases; however, not all patients requiring ICT could be identified with serum ferritin alone, as serum ferritin underestimated LIC in 4.4% and overestimated LIC in 7.5% of patients. Exploratory analyses showed serum ferritin thresholds for liver siderosis detected by MRI at approximately 300 ng/mL higher in MDS than in TM. Most patients reported low-medium adherence to ICT; MRI assessment led to change in ICT in 46% of evaluable patients, including 52% of MDS patients. Accurate organ iron monitoring by MRI facilitated appropriate initiation of chelation, dose optimization and clinical decision making.Trial registration: ClinicalTrials.gov: NCT01736540.Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.

DISCLOSURES: Schuster: Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Nordic Nanovector: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding. Bartlett:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yoon:Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Janssen: Consultancy; Yuhan Pharma: Research Funding. Bosch:Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory c

Background CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. Dual inhibition of CD73 and A2aR improves anti-tumor immune responses in mouse tumor models[1]. CPI-006 is a humanized IgG1 Fc gamma receptor binding-deficient anti-CD73 antibody that has a dual mechanism of action. It blocks CD73 catalytic activity and adenosine production. In addition, it has immunomodulatory activity on CD73 positive immune cells including B cells, T cells and antigen presenting cells. CPI-006 relieves adenosine-mediated immunosuppression in vitro as a single agent and in combination with ciforadenant[2]. CPI-006 is now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA), in combination with ciforadenant, an oral, small molecule, selective A2aR antagonist and in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients with: non-small cell lung cancer (NSCLC), renal cell carcinoma cancer (RCC), urothelial bladder cancer, cervical cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, head and neck cancer, triple-negative breast cancer, endometrial cancer, select sarcomas and non-Hodgkin lymphoma (NHL) who are relapsed, refractory or intolerant to 1 to 5 standard therapies; aged >= 18 yo; with adequate organ function and measurable disease. Study details is presented in Figure 1. The primary objective of the dose escalation is to assess safety/ tolerability, MTD or MDL of CPI-006 SA, in combination with ciforadenant and with pembr

The significant morbidity and mortality associated with iron overload can be reduced by effective iron chelation. Magnetic resonance imaging (MRI) provides accurate and reproducible iron load assessment. The aim of this epidemiological study was to assess the prevalence and severity of cardiac and hepatic siderosis by MRI and to evaluate the impact of MRI on clinical management in patients with transfusion-dependent anemia and non-transfusion-dependent thalassemia (NTDT). We enrolled 243 patients with myelodysplastic syndromes (MDS), thalassemia major (TM), NTDT or other chronic anemia. Overall, 10% and 48% had cardiac and hepatic siderosis, respectively. Mean liver iron concentration (LIC) was above target range in all groups; mean myocardial T2* was normal. Hepatic siderosis was more prevalent than myocardial siderosis in patients with MDS, occurring in 54.4% and 4.4% of patients, respectively. As also observed in patients with NTDT or other anemia, hepatic siderosis was present in a large proportion of MDS patients who were chelation naive (57.7%), as well as in patients receiving iron chelation therapy (ICT) (52.4%), despite a lower transfusion load compared with TM. Correlation between LIC and serum ferritin was observed across diseases; however, not all patients requiring ICT could be identified with serum ferritin alone, as serum ferritin underestimated LIC in 4.4% and overestimated LIC in 7.5% of patients. Exploratory analyses showed serum ferritin thresholds for liver siderosis detected by MRI at approximately 300 ng/mL higher in MDS than in TM. Most patients reported low-medium adherence to ICT; MRI assessment led to change in ICT in 46% of evaluable patients, including 52% of MDS patients. Accurate organ iron monitoring by MRI facilitated appropriate initiation of chelation, dose optimization and clinical decision making.Trial registration: ClinicalTrials.gov: NCT01736540.Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.

DISCLOSURES: Schuster: Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Nordic Nanovector: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding. Bartlett:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Incyte: Research Funding; Janssen: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Forty Seven: Research Funding; Genentech, Inc.: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yoon:Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MSD: Consultancy; Janssen: Consultancy; Yuhan Pharma: Research Funding. Bosch:Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory c

Background CD73 expression is elevated in tumors and contributes to increasing levels of immunosuppressive adenosine in the tumor microenvironment. CD73 knockout mice exhibit reduced tumor growth and resistance to experimental metastasis. Inhibition of CD73 activity with an anti-CD73 antibody blocks adenosine production, shown to inhibit tumor growth in syngeneic models. Dual inhibition of CD73 and A2aR improves anti-tumor immune responses in mouse tumor models[1]. CPI-006 is a humanized IgG1 Fc gamma receptor binding-deficient anti-CD73 antibody that has a dual mechanism of action. It blocks CD73 catalytic activity and adenosine production. In addition, it has immunomodulatory activity on CD73 positive immune cells including B cells, T cells and antigen presenting cells. CPI-006 relieves adenosine-mediated immunosuppression in vitro as a single agent and in combination with ciforadenant[2]. CPI-006 is now being investigated in this Phase 1/1b multicenter, open label trial as single agent (SA), in combination with ciforadenant, an oral, small molecule, selective A2aR antagonist and in combination with pembrolizumab, an anti-PD1 indicated for the treatment of patients across a number of malignancies (NCT03454451). Methods Up to 462 subjects will be enrolled at approximately 35 sites in the US, Canada and Australia. Eligible patients with: non-small cell lung cancer (NSCLC), renal cell carcinoma cancer (RCC), urothelial bladder cancer, cervical cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, head and neck cancer, triple-negative breast cancer, endometrial cancer, select sarcomas and non-Hodgkin lymphoma (NHL) who are relapsed, refractory or intolerant to 1 to 5 standard therapies; aged >= 18 yo; with adequate organ function and measurable disease. Study details is presented in Figure 1. The primary objective of the dose escalation is to assess safety/ tolerability, MTD or MDL of CPI-006 SA, in combination with ciforadenant and with pembr

Introduction Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion (Rickert, 2013; Aalipour, 2013; Choe, 2016). The BCR pathway is an established therapeutic target in multiple subtypes of non-Hodgkin's lymphoma (NHL). BGB-3111 is a potent, highly specific, and irreversible BTK inhibitor, with greater selectivity for BTK vs other TEC- and EGFR-family kinases and demonstrates favorable pharmacokinetic and pharmacodynamic properties. We have previously shown complete and sustained BTK occupancy in both peripheral blood mononuclear cells (PBMCs) and lymph nodes (LN) in patients (pts) treated at the 160 mg BID dose in a phase 1 trial (Tam et al. ASH 2016). A recent update of clinical data suggests that complete and sustained BTK occupancy is associated with durable responses in pts with CLL/SLL and Waldenstrom's macroglobulinemia (Seymour et al. ICML 2017; Trotman et al. ICML 2017). Here, we present early safety and efficacy data in pts with other NHL subtypes: relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Methods This is an open-label, multicenter, phase 1b study of BGB-3111 in pts with B-cell malignancies. Dose escalation included pts with R/R B-cell malignancies, while the expansion phase enrolled disease-specific cohorts at the recommended phase 2 dose (320 mg/d, given once daily [QD] or split as 160 mg twice-daily [BID]). Response was assessed per ICML criteria (Cheson 2014). Results As of 18 May 2017, 75 pts with NHL were enrolled, including 23 DLBCL, 31 MCL, 14 FL, and 7 MZL pts. Patient characteristics are shown in the Table. With the exception of 1 pt with treatment-naive MCL, all pts had R/R disease. Safety: Median follow - up was 7 months (range, 0.3-31.9). The most frequent adverse events (AEs) of any cause were contusion (22.7%), upper respiratory tract infe

Introduction Bruton's Tyrosine Kinase (BTK) plays a critical role in B-cell receptor (BCR) signaling, which mediates B-cell proliferation, migration, and adhesion (Rickert, 2013; Aalipour, 2013; Choe, 2016). The BCR pathway is an established therapeutic target in multiple subtypes of non-Hodgkin's lymphoma (NHL). BGB-3111 is a potent, highly specific, and irreversible BTK inhibitor, with greater selectivity for BTK vs other TEC- and EGFR-family kinases and demonstrates favorable pharmacokinetic and pharmacodynamic properties. We have previously shown complete and sustained BTK occupancy in both peripheral blood mononuclear cells (PBMCs) and lymph nodes (LN) in patients (pts) treated at the 160 mg BID dose in a phase 1 trial (Tam et al. ASH 2016). A recent update of clinical data suggests that complete and sustained BTK occupancy is associated with durable responses in pts with CLL/SLL and Waldenstrom's macroglobulinemia (Seymour et al. ICML 2017; Trotman et al. ICML 2017). Here, we present early safety and efficacy data in pts with other NHL subtypes: relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Methods This is an open-label, multicenter, phase 1b study of BGB-3111 in pts with B-cell malignancies. Dose escalation included pts with R/R B-cell malignancies, while the expansion phase enrolled disease-specific cohorts at the recommended phase 2 dose (320 mg/d, given once daily [QD] or split as 160 mg twice-daily [BID]). Response was assessed per ICML criteria (Cheson 2014). Results As of 18 May 2017, 75 pts with NHL were enrolled, including 23 DLBCL, 31 MCL, 14 FL, and 7 MZL pts. Patient characteristics are shown in the Table. With the exception of 1 pt with treatment-naive MCL, all pts had R/R disease. Safety: Median follow - up was 7 months (range, 0.3-31.9). The most frequent adverse events (AEs) of any cause were contusion (22.7%), upper respiratory tract infe