Day 1 :
Innovative Cellular Therapeutics, China
Keynote: Potent anti-leukemia activities of chimeric antigen receptor modified T (CAR-T) cell therapy in Chinese patients with relapsed/refractory hematological malignances
Time : 13:35-14:20
Background: Patients with relapsed/refractory hematological malignances, including acute lymphocytic leukemia as well as lymphoma, have a poor prognosis. Chimeric antigen receptor modified T cells against CD19 have displayed anti-malignance activities. Autologous CD19CAR-T performed in our clinical trials induced remission in patients with r/r hematological malignances. 41 subjects (from 10 clinical centers, in China) with r/r B-ALL and two subjects with non-Hodgkin's Lymphoma (NHL) were treated by autologous CD19 murine CAR-T cells (NCT 02813837). Another two subjects with r/r B-ALL were treated by autologous CD19 humanized CAR-T cells.
Methods: 41 subjects with r/r B-ALL and two subjects with r/r NHL were treated with murine CAR-T cells from May 8, 2015 to January 30, 2017, while three subjects with r/r B-ALL were treated with humanized CAR-T cells from December 16, 2016 to December 27, 2016. Both the murine and humanized CAR-T cells were infused with dose range between 0.45 × 106 CAR-T cells/kg and 10.51 × 106 CAR-T cells/kg. All subjects were monitored closely during the trial. Both murine and humanized CAR-T cells were prepared according to in-house built robust protocol to ensure quality.
Results: Following treatment with CD19 murine/humanized CAR-T cells, the proliferation of CAR-T cells were detected with both qPCR and flow cytometry techniques in blood and bone marrow samples in all clinical subjects. 34/41(82.93%) subjects with B-ALL achieved complete remission (CR) between 7 to 14 days after murine CD19 CART cell infusion, and 33/41(80.49%) subjects arrived at MRD negative. Additionally, Severe Cytokine Release Syndrome (CRS) was observed in 12 subjects (29.3%) and another 21 subjects have shown low-grade CRS symptoms (51.2%). Severe CRS subjects were adequately managed by anti-IL6R Tocilizumab and corticosteroid anti-inflammatory drugs. Two subjects with NHL achieved CR after CD19 murine CAR-T cells infused and neither of them suffered from irreversible neurotoxicity. Both two subjects with B-ALL treated with humanized CAR-T cells achieved CR as well as MRD negative.
Conclusions: This is the first multicentre report to our knowledge of successful treatment of r/r B-ALL with CD19 CAR T cells in China. Even r/r B-ALL with high-burden leukaemia patients also was effective and associated with a high remission rate after autologous CD19 CAR-T infusion (NCT 02813837). In addition, though the follow-up is short, CD19 murine CAR-T cells showed potent efficacy in subjects with NHL, meanwhile subjects with r/r B-ALL might benefit from CD19 humanized CAR-T cells therapy.
Lei Xiao is the Chairman and CSO of Innovative Cellular Therapeutics Co., Ltd. His research interests include chimeric antigen receptor T cells therapy, iPS cell technology & human embryonic stem cells and Gene therapy. During October 2005 - September 2010 he worked as Principal Investigator in Shanghai Institute of Biochemistry and Cell Biology. During January 2007 - September 2010, he was the Director of Cell Bank/Stem Cell Bank of Chinese Academy of Sciences, Shanghai Institute for Biological Sciences. He was a Professor at Zhejiang University from 2010 to 2015. From August 2009 to present, he is a Chief Science Officer at the Innovative Cellular Therapeutics Co., Ltd., which was formerly Shanghai SiDanSai Biotechnology Co, Ltd.
Umm Al Qura University, Saudi Arabia
Keynote: Soluble carcinoembryonic antigen cell adhesion molecule 1,6 and 8 in acute myeloid leukemia: their relation to survival and prognosis
Time : 09:30-10:15
Amal zaghloul has completed her medical doctorate in clinical pathology with specialty in hematology at the age of 34 years from faculty of medicine Ain shams University Cairo Egypt. She is a professor of clinical pathology (hematology) at faculty of medicine Umm Alqura University (Saudi Arabia) and at faculty of medicine Ain Shams university (Cairo Egypt). She has participated in both theoretical and practical teaching of Hematology. Also, supervising research works of under and postgraduate students. She has experience in the flow cytometry, immunohistochemistry and ELISA . She has published more than 25 papers in reputed journals
- Hematologic Oncology/ Cancer/ Hematology and Oncology Experts meeting
King Faisal Specialist Hospital and Research Center, Saudi Arabia
Murugan A K completed his PhD from the Department of Molecular Oncology, Tokyo Medical and Dental University, Tokyo, Japan and Postdoctoral studies from Hoshi University, Tokyo, Japan and The Johns Hopkins University School of Medicine, Baltimore, USA. Currently, he is a Scientist in the Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. He has published more than 35 papers in reputed journals and holds a patent for identification of novel ALK mutations in anaplastic thyroid cancer. His research focuses on molecular biology of head and neck squamous cell carcinoma and thyroid cancer identifying molecular therapeutic targets and biomarkers. He has been serving as Reviewer in Thyroid, PLOS One, Oncogene, Cancer Research, Tumor Biology, Endocrine Related Cancer, Oral Oncology, etc.
Thyroid cancer is the most common endocrine malignancy. In the past 4 decades, the incidence of thyroid cancer is consistently increasing in all parts of the world. Recently, mutations in the genes of GPCR signaling pathway were reported in thyroid cancer patients of mixed ages. However, the prevalence of mutations of the GPCR signaling pathway genes its significance is completely unknown in pure pediatric and adult DTCs. In this study, we determine the prevalence of the GPCR pathway genes (LPAR4, PIK3CA and PTEN) mutation in pure pediatric and adult DTCs. A total of 310 samples consisting of 17 multi nodular goiters (MNG), 89 pediatric (age < 18 years) and 204 adult (age > 18 years) DTC samples were analyzed for mutations in genes LPAR4 (exon 1), PIK3CA (exons 9 and 20) and PTEN (exons 5, 6, 7 and 8) of the GPCR pathway by PCR amplification of tumor genomic DNAs and direct sequencing of amplicons using Sanger sequencing. Overall, we found 2.7% (2/72) of PIK3CA and 1.4% (1/72) of PTEN in pediatric CPTC (classical papillary thyroid cancer). We identified 3.6% (2/55) of PIK3CA in FV-PTC (Follicular Variant PTC), 3.5% (1/29) of PIK3CA in TPC (Tall-cell PTC), and 1% (1/114) in CPTC of adult thyroid cancer. We did not find any mutations in LPAR4 gene in both pediatric and adult thyroid cancer. We also found two novel mutations one in the PIK3CA gene (C984Y) of a pediatric CPTC and the other in the PTEN gene of an adult CPTC sample. Our study is the first to report GPCR pathway mutations in a pure and adult DTC samples. Our results show a common occurrence of PIK3CA and PTEN mutations but not the LPAR4 mutations in both pediatric and adult DTCs suggest PIK3CA and PTEN genes of the GPCR pathway play a significant role in thyroid carcinogenesis and pave attractive target for therapeutic prevention.
Decision Resources Group, India
Swarali Tadwalkar has completed her Master’s in Public Health (MPH) from University of South Florida, Tampa in 2015. She has an extensive experience in primary and secondary healthcare research stemming from projects in digital health, health policy and management, and health economics and outcomes research (HEOR). She currently works with Decision Resources Group (DRG) as an Associate Epidemiologist with the Epidemiology team and develops epidemiological population forecasts for different infectious and non-communicable diseases with particular interests in the oncology space.
Objective: The objective of the present study is to estimate the global incidence and prevalence of Chronic Myeloid Leukemia (CML) by world regions over the next ten years using a multi-factorial forecast model.
Methods: Using a critically appraised set of country-specific cancer registries, CML incidence was estimated for 45 countries, representing approximately 90% of the world’s population in 2017. Measures of economic development across countries such as gross domestic product (GDP) were considered as key indicators for access to healthcare and the adoption of potentially leukemogenic dietary patterns and lifestyles. Observed correlations between GDP, CML risk, and survival were used to trend CML incidence over the next ten years. CML survival was trended using an attenuated function of the historical trend, representing the continuing optimization of tyrosine kinase inhibitor-based treatment. Prevalence was estimated as a cumulative incidence over preceding twenty years with adjustments for disease-specific and competing-cause mortality for each year. To estimate incident and prevalent CML globally, aggregate estimates for each region were divided by the proportion of countries in that region for which direct estimates were made using the methods described above.
Results: The incidence of CML in Africa, Latin America, lower-income Asia Pacific countries, high-income Asia Pacific countries, Europe, and North America is 0.4, 0.7, 0.7, 1.2, 1.4, and 2 cases per 100,000/year. The prevalence of CML in Africa, Latin America, lower-income Asia Pacific countries, high-income Asia Pacific countries, Europe, and North America is 3, 5, 6, 10, 11, and 15 cases per 100,000 in 2017. Latin America is expected to see the highest growth in prevalent cases over the next ten years: 36% by 2027.
Conclusion: The incidence and prevalence of CML is expected to increase globally. Improvements in the survival of CML patients will result in 20000 additional cases surviving by 2027 worldwide.
Maulana Azad Medical College and associated Lok Nayak Hospital, India
Jahnavi Dhar is a third year post graduate student in the Department of Medicine, currently pursuing DOCTOR OF MEDICINE (M.D.) degree from Maulana Azad Medical College (M.A.M.C.) and associated Lok Nayak Hospital, New Delhi, since 2015. I have also worked as an intern in the prestigious 1600 bedded Lok Nayak Hospital in 2014. I have completed my Bachelor of Medicine, Bachelor of Surgery (M.B.B.S.) from Maulnana Azad Medical College (M.A.M.C.), University of Delhi in 2013. I am a student in medicine, interested in exploring the mechanisms of pathological processes and how they come together to manifest as a disease. I intend to learn all that I can so as to enhance my understanding of how our bodies function. I aim to use this knowledge to enable research and real world implementation to solve problems we face in clinic and beyond. I stood first in the University of Delhi in my final professional examination in 2013 with an aggregate of 72.4%, with a Roll of honors and 8 gold medals. I secured All India rank 1 in class 10th board conducted by C.B.S.E. in 2007. I have a publication of “Chronic myeloid leukemia – an overview” in API textbook medicine in January 2017. I also secured first position in a Case presentation on “familial type 2a hyperlipoprotenemia” in 2016 at API DSC conference 2016 held at Ashoka hotel, Chanakyapuri, New Delhi.
Background: CML is the most common adult leukemia in India, accounting for 50-70% of all leukemias in our country. The median age of presentation in India is 40-50 years which is a decade younger compared to the age of presentation in the western countries, which is around 66 years. The introduction of Tyrosine Kinase inhibitors (TKIs) mostly Imatinib mesylate has greatly enhanced survival from <30% to 85% in developing countries.
Aims and Objectives: This study was undertaken to analyze the newly diagnosed, treatment naïve CML patients based on the symptomology, hematological, clinic-pathological and cytogenetic analysis at the time of diagnosis and to compare these parameters post 6 weeks of chemotherapy (Imatinib). A comparison of the data obtained was done with data of the western world to analyze any differences.
Methods: 33 newly diagnosed CML patients (>18 years) were recruited from January 2015 to January 2017. Every patient underwent a complete set of hematological, radiological and cytogenetic analysis at the time of diagnosis. The patients were started on Imatinib Mesylate. The patients underwent an analysis of the hematological parameters after 6 weeks of chemotherapy to assess for Hematological remission (HR). Outcome of the patients was also noted.
Results: Total 33 newly diagnosed treatment naïve CML patients were recruited in 2 years. The range of age distribution was between 18-50 years. 23 (69.69%) of them were in the age group of 18-40 years. There were 20 (60%) males and 13(40%) females.
11 (34%) patients had presented with a duration of 3-4 months. The most symptom of the patients at the time of diagnosis was fatigue (88%) which was followed by pain/discomfort in the left hypochondrium (79%) and unexplained weight loss (64%).
On examination, pallor was present in all 33 (100%) patients and hepatomegaly and splenomegaly was noted in all the cases (100%). On ultrasound, the average size of the liver was around 15.47 ± 1.66 cm and the average size of the spleen was 19.80 ± 2.48 cm. HIV status was negative in 32 (97%) patients.
All the cases underwent a complete blood analysis at the time of diagnosis. Total leucocyte count (TLC in lacs) was significantly raised to the value of 319537+180886. Basophils accounted for 4.51+2.76%, myelocytes for 16.85+10.31% and blasts for 9.81+11.39% of the TLC. LDH (IU/L) and uric acid (mg/dl) were raised significantly to a value of 1567+541.4 and 10.67+6.83, respectively. L.A.P. score was reduced to a value of 7.54+1.88. Bone marrow aspirate and biopsy was done in all patients of CML. 22 (67%) patients were in the chronic phase, 7 (21%) in the accelerated phase and 4 (12%) were in blast crisis. Four cases had presented in Tumour lysis syndrome out of which one was in chronic phase, one in accelerated and 2 in blast crisis. BCR-ABL Mutation was positive in 32 (97%) patients.
Follow up of all the 33 patients was done after starting them on chemotherapy (Imatinib). Two of them died. Hence, 31 cases underwent a complete blood analysis after 6 weeks of chemotherapy. All the parameters were analysed along with hematological remission. 4 cases had presented in tumour lysis syndrome, in which one died (in blast crisis) and the remaining 3 did not achieve hematological remission (HR).
Majority of the parameters showed significant improvement after chemotherapy (p value <0.0001). TLC (lakhs) showed marked improvement from 319537+180886 to 8965+4373 (p value <0.0001), basophils (%) from 4.51+2.76 to 0.87+0.99 (p value <0.0001), myelocytes (%) decreased from 16.85+10.31 to 0.41+1.40 (p value <0.0001) and blasts (%) showed marked improvement from 9.81+11.39 to 0.61+2.04 (p value <0.0001).
Out of 33 cases, 2 (6%) had died. In the remaining 31 cases, hematological remission was assessed after 6 weeks of Imatinib mesylate. 27 (87%) out of 31 patients achieved HR and 4 (13%) did not. Out of the 4 cases who did achieve HR, 1 was in chronic phase, 1 in accelerated phase and 2 in blast crisis.
Conclusions: In our study, a prospective analysis was made for newly diagnosed, treatment naïve CML patients at the time of diagnosis and after 6 weeks of Imatinib mesylate. The mean age of presentation is a decade younger than the west. The patients hardly get detected in the asymptomatic stage in our country. There is a higher proportion of patients in the accelerated and blast crisis. Furthermore, TKIs (mostly Imatinib) is the chemotherapy available in majority. All these factors combined herald dismal prognosis for patients in a developing country as compared to the West.
In our study, majority of the hematological parameters showed remarkable improvement on Imatinib, which highlights the importance of an early diagnosis and timely institution of chemotherapy in all the patients of CML.
Maulana Azad Medical College and associated Lok Nayak Hospital, India
Jahnvi Dhar is a third year Post-graduate student in the Department of Medicine, currently pursuing Doctor of Medicine (MD) degree from Maulana Azad Medical College (MAMC) and associated with Lok Nayak Hospital, New Delhi, since 2015. She also worked as an Intern in the prestigious 1600 bedded Lok Nayak Hospital in 2014. She completed her Bachelor of Medicine, Bachelor of Surgery (MBBS) from Maulnana Azad Medical College, University of Delhi in 2013. She is interested in exploring the mechanisms of pathological processes and how they come together to manifest as a disease. She intends to learn all that can be done to enhance her understanding of how our bodies function. She aims to use this knowledge to enable research and real world implementation to solve problems we face in clinic and beyond.
Background: Most common manifestations in CML patients are fatigue, fever, unexplained weight loss and abdominal distension. Though rare, otoneurological manifestations have been reported in 15–40 % of all leukemic patients. The prevalence of self-reported hearing loss in CML patients is around 22.4%. But audiometry assessments have shown a higher prevalence of 65.5%. Hence, presence of otoneurological findings in CML makes it a rare and exciting presentation.
Aims and Objectives: To analyze the prevalence of otoneurological complaints in patients of CML and to compare it with the age and sex matched healthy control population.
Methods: 33 newly diagnosed, treatment naïve CML cases and age and sex matched controls were recruited from October 2015 to January 2017. Otological complaints were noted at the time of presentation along with a complete otological examination. All the cases and controls were subjected to PTA (Pure tone audiometry) and BERA (Brainstem evoked response audiometry) to assess the prevalence of sensorineural hearing loss (SNHL) and the results were compared.
Results: Tinnitus was noted in 5 (15.2%), vertigo in 1 (3%) and subjective hearing loss in 10 (30.3%) cases as compared to no controls. 7 (21.2%) cases had speech frequency hearing loss (>25 dB) on Pure tone audiometry (PTA) as compared to no controls (p value 0.01). The hearing loss among the cases (n=33) was quantified as 18.30+15.05 dB and 19.39+14.68 dB in the left and right ear, as compared to the controls (n=33) having 7.34+2.64 dB and 8.22+3.27 dB, respectively, which was statistically significant for p value <0.0001.
Similarly, 22 (66.7%) cases had high frequency hearing loss on PTA and Brainstem evoked response audiometry (BERA), each as compared to only 2 (6%) controls (p value <0.0001). The hearing loss (based on PTA) for cases (n=33) was 43.94+23.41 dB (left ear) and 44.55+23.56 dB (right ear) among the cases as compared to control (n=33) having 12.27+6.26 dB (left ear) and 12.42+7.08 dB (right ear), which was significant (p value <0.0001). All the 33 cases underwent BERA at the time of diagnosis and SNHL was quantified, but it was done only in 2 controls having objective evidence of SNHL on PTA, so p value was not calculated. The amount of SNHL on BERA for the cases (n=33) was 47.88+25.59 dB and 47.88+25.59 dB in the left and right ear, respectively.
Conclusions: In our study, 22 (66.7%) CML patients had SNHL as compared to the 2 (6%) in control group which shows a higher prevalence of both, self-reported and audiologically proven SNHL in CML which is most likely due to leukocytosis and/or leukemic infiltration of the cochlea. BERA is a more sensitive technique in identifying these at risk individuals.
No study had been done till date based on newly diagnosed, treatment naïve CML patients regarding their otoneurological manifestations in comparison with a age and sex matched healthy control group. Based on the analysis of our study, it is recommended that there should be a baseline audiological profile of every CML patient at the time of diagnosis, so the timely institution of chemotherapy (Imatinib) can lead to prevention and/or treatment of SNHL.
Zareen Irshad is a Hematologist from Pakistan. She graduated from Sindh Medical College, Karachi in 2005 and got distinction in Pediatrics. She has done fellowship in Hematology from College of Physicians and Surgeons, Pakistan. Currently, she is working as Assistant Professor in Pathology department being involved in Under and Post-graduate medical students teaching and also Head of Department in Jinnah Sind Medical University Laboratory. She attended as organizer and active participant in many seminars and workshops. She is interested in research work and wants to continue her research studies in the field of Coagulation Studies and Transfusion Medicine.
Background: Over the last few years dengue has become a major health problem in tropical and subtropical regions around the world. Dengue fever is an acute febrile disease caused by an arbrovirus in Flavivirus genus. Dengue viral infection is known to cause a wide spectrum of disease manifestations, from mild undifferentiated fever, classical dengue fever to dengue haemorrhagic fever (DHF)/ dengue shock syndrome (DSS). Haematological manifestations include thrombocytopenia, leucopenia, and deranged prothrombin time, activated partial thromboplastin time.
Objective: The study was aimed to find out frequency of haemostatic manifestations in dengue and clinical outcome of patients
Material and Methods:
Sample Size: 135
Study design: Descriptive study. Cross Sectional.
Place of study: The study was conducted in Pathology department at PNS Shifa, Karachi.
Inclusion criteria: The study was conducted on all patients of serologically proven dengue infection.
Results: A total of 135 patients were evaluated in the study. The mean age of the patients was 29 years (Range: 2 – 63years). Out of these patients, 111(82.22%) were male and 24(17.78%) were female patients. The most common haemostatic manifestations in dengue patients were thrombocytopenia in 111(82.2%) patients. Severe thrombocytopenia was observed in 9(6.7%) cases, moderate thrombocytopenia was found in 30(22.2%) cases and mild thrombocytopenia was observed in 72(53.3%) cases. Bleeding time more than 9 minutes was observed only in 1 case. Prolonged prothrombin time observed in 8(5.6%) cases and deranged APTT was observed in 57(42.2%) cases. Increased level of fibrin degradation product (D-dimer) was in 30(22.2%) cases. Out of 135 patients, 2(1.48%) were expired and 133(98.52%) were survived and discharged
Conclusion: Dengue continues to be a significant health problem in Pakistan. It is extremely important to implement and maintain an effective, sustainable and community based disease prevention program.
Dr. Lixin Rui trained as an oncologist in China and completed his PhD at the Australian National University. In 2006, he received a CJ Martin Postdoctoral Fellowship and started lymphoma research in Louis Staudt's lab at the National Cancer Institute. In December 2012, Dr. Rui joined the Division of Hematology/Oncology as an Assistant Professor in the Department of Medicine at the University of Wisconsin-Madison. Dr. Rui's research in his lab focuses on lymphoma biology, with an emphasis on JAK-STAT signaling in lymphomagenesis.
The Janus kinas (JAK)/signal transducer and activator of transcription (STAT) pathway is central to signaling by receptors of diverse cytokines, growth factors and related molecules, which is critical for normal hematopoiesis and immune response. However, this signaling pathway is deregulated in several B cell lymphomas. In activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL), autocrine production of IL-6 and IL-10 can result from high NF-kappaB activity, which is caused by a variety of genetic alterations, such as mutations in MYD88 and CARD11. Our recent work has demonstrated that JAK1 is an active kinase downstream of IL-6 and IL-10 signaling that activates STAT3. Interestingly, JAK1 can function in the nucleus to regulate gene expression through phosphorylating histone H3 on tyrosine 41. There are nearly 3,000 JAK1 epigenetic target genes including MYD88, IRF4 and MYC, of which expression is essential for cancer cell survival and proliferation.
Here we have investigated the canonical gene regulatory mechanism by STAT3 in ABC DLBCL cells. We performed STAT3 ChIP-seq assay in two ABC DLBCL cell lines TMD8 and OCI-Ly10 and identified 4,746 potential STAT3 target genes in TMD8 cells and 6,058 in OCI-Ly10 cells. RNA-seq analysis demonstrated that 53% of those in TMD8 cells and 68% of those in OCI-Ly10 cells changed their expression, suggesting direct STAT3 target genes. Of note, 2,251 genes overlapped between the two cell lines. Gene ontology analysis of these common STAT3 target genes showed the enrichment of gene signatures that involve B cell activation, proliferation, differentiation, and apoptosis. Further gene set enrichment analysis (GSEA) revealed the type 1 interferon pathway regulated by STAT3. Indeed, RNA-seq data showed increased expression of genes in this pathway including STAT1, STAT2, IRF7, and IRF9 following knockdown of STAT3 by shRNAs. These results were further confirmed by immunoblot analysis, suggesting inhibition of type 1 interferon by STAT3. It is known that the type 1 interferon pathway is proapoptotic and is suppressed by IRF4 in ABC DLBCL cells. This pathway can be activated by Lenalidomide due to inhibition of IRF4 expression. Based on these findings, we performed in vitro cell survival assay and found that Lenalidomide indeed enhanced cell killing by STAT3 shRNA or the JAK inhibitor Ruxolitinib. We will test this synergism using an ABC DLBCL xenograft animal model. Our study provides a novel suppressive mechanism of type 1 interferon signaling by STAT3, which supports a potential targeted therapy for ABC DLBCL.