Day 1 :
Keynote Forum
Shimon Slavin
International Center for Cell Therapy & Cancer Immunotherapy,Israel
Keynote: Innovative immunotherapy for prevention and treatment of relapse relapse following conventional chemotherapy or stem cell transplantation
Time : 10:00 AM - 10:30 AM
Biography:
Shimon Slavin, MD, Professor of Medicine, pioneered the use of personalized anti-cancer immunotherapy mediated by donor lymphocytes and innovative methods for stem cell transplantation for malignant and non-malignant disorders, including treatment of autoimmune diseases and induction of transplantation tolerance to bone marrow and organ allografts. More recently, Slavin pioneered the use of multi-potent mesenchymal stromal cell for regenerative medicine. Slavin authors 4 books, 660 scientific publications and serves on many editorial boards and many national and international advisory boards. Slavin received many international awards in recognition of his contributions for treatment of malignant and non-malignant disorders.
Abstract:
Immunotherapy represents the treatment of choice against chemo-radioresistant malignant cells and cancer stem cells that are a prioi resistant to anti-cancer modalities. The documented therapeutic effects of donor lymphocyte infusion (DLI) following maximally tolerated myeloablative chemo radiotherapy following allogeneic stem cell transplantation (SCT) suggests that cell-mediated immunotherapy may represent the treatment of choice for elimination of otherwise resistant malignant cells. Accordingly, we have developed a new approach for induction of graft-vs-malignancy (GVM) effects by intentionally mismatched IL-2 activated killers (IMAK) while avoiding GVHD following conventional chemotherapy or haploidentical SCT using reduced intensity conditioning (RIC) followed by post transplant elimination of host and donor’s alloreactive T cells for prevention of rejection and GVHD. Long-term GVM effect was induced post-SCT by IL-2 activated donor NK cells prepared by negative selection of CD3+ T cells or positive selection of CD56+ NK cells. Mismatched NK cells induced most effective GVM while avoiding GVHD in patients with resistant relapsed Leukemia. Short-term GVM effects with no prior SCT was accomplished by haploidentical or unrelated IMAK activated in vitro and in vivo following infusion with low dose IL-2 for 5 days. More effective and more selective GVM effects against residual cancer cells could be accomplished using monoclonal or bispecific antibodies bound to Fc receptors on killer cells targeting killer cells against antigens over-expressed on malignant cells (e.g. Rituximab or Pinatumomab against B cell malignancies). Using IMAK against MRD following conventional chemotherapy or SCT can result in cure of otherwise resistant hematological malignancies while avoiding GVHD.
- Blood Malignancies
Leukemia
Session Introduction
John Batchelor
Central Manchester Foundation Trust,United Kingdom
Title: The pathogenesis of spontaneous intrcranial haemorrhage in patients with haematological malignancy
Biography:
John Batchelor is currently Consultant in Emergency Medicine at Central Manchester Foundation Trust, England UK. He is also Honorary Lecturer at Manchester Metropolitan University. He graduated from Leeds University England, in 1982. He is a Fellow of the Royal College of Surgeons of Ireland and Fellow of the Faculty of Emergency Medicine of England. He undertook his MD thesis at University College London. He has written extensively on the subject of minor head injuries. He has presented a paper in Paris in 2012 on a Meta-analysis looking at the relationship between cerebral microbleeds and antiplatelet agents. He has also recently published a meta-analysis on the effect on mortality of platelet transfusions in adults with spontaneous or traumatic antiplatelet associated intracranial haemorrhage. His current research interest lies in the area of risk factors for intracranial haemorrhage in both adults and paediatrics secondary to coagulopathy and thrombocytopenia.
Abstract:
Spontaneous intracranial haemorrhage is a well recognised complication in patients with haematological disease. Intracranial haemorrhage is the second leading cuase of death in patients with acute myeliod leukaemia. The reported mortality is over 50% for patients with haematological malignancy and spontaneous intracranial haemorrhage. The reported incidence of spontaneous intracranial haemorrhage appears to be slightly higher in acute myeliod leukaemia (AML) and chronic myeloid leukaemia in blast crisis than in other forms of haemalogical malignancy. The distribution of ICH is as follows:- intraparenchymal haemorrhage accounts for about 60% of the reported case series. The remaining sites are distributed between the cerebellum, brainstem, basal ganlia, subarachnoid, subdural, intraventricular and epidural regions. Over 50% of patients will having more than one intracranial bleeding site on CT. Previously proposed risk factors for spontaneous intracranial bleeding include: direct invasion by tumour cells, invasive intracranial sepsis, hyperleukocytosis, and coagulopathy. Abnormalities of clotting include DIC, thrombocytopenia and pronlonged prothrombin time. Coagulopathy and thrombocytopenia are probably not the main factors reponsible for spontaneous intracranial haemorrhage in view of the fact that neither platelets nor clotting factors are responsible for maintianing cerebral vessel integrity under normal physiological conditions. Cohort studies from patients with idiopathic thrombocytopenia have shown a poor correlation between platelet count and the risk of spontaneous intracranial haemorrhage in both adults and children. Batchelor (2015) has shown that coagulopathy in patients with traumatic intracranial bleeding increases the risk of progressive haematoma progression by an odds ratio of 6.176 (95% CI: 4.727 – 8.069). This paper aims to explore other factors which may account for spontaneous ICH in patients with haematological malignancy .
Jean Jacques Fournie
Cancer Research Center of Toulouse,France
Title: Stratifying patients for Immune checkpoint blockade cancer therapies
Biography:
Jean Jacques Fournié completed his PhD (Biochemistry and Immunology) from Toulouse University and a Post-doctoral stay at the Clinical Immunology Research Center of University of Sydney, Australia. He is the Founding Director of Cancer Research Center of Toulouse, an international cancer research laboratory from INSERM, University of Toulouse 3 and CNRS, and leads the research team ‘Innovating Therapeutics Strategies in Lymphomas’ of Laboratoire d’Excellence Toulouse Cancer at Institut Universitaire du Cancer of Toulouse-Oncopole, France. He published more than 150 papers in reputed journals, produced 21 patents and co-founded the Innate Pharma Company (www.innate-pharma.com).
Abstract:
Non-Hodgkin’s B-cell lymphomas (B-NHL) are aggressive lymphoid malignancies which develop in patients due to oncogenic activation, chemo-resistance and immune evasion. Tumor biopsies show that B-NHL frequently deploys several immune escape strategies, a problem for the development of checkpoint blockade immunotherapies in these diseases. In particular, there are currently no means to identify those B-NHL patients most likely to respond to the new therapeutic antibodies. Meta-analysis of large series of microarrays from B-NHL biopsies is necessary to assess their immuno-edition, but material (single datasets) and methods to do this are currently lacking. This talk will present a new data mining strategy to do so, and their results in large cohorts of ~1500 patients with B-NHL. This approach was validated by producing scores fully matched to phenotypic hallmarks of B-NHL. Then, immune escape in patients was investigated by this method, and revealed a significant immune escape in most samples of DLBCL and FL, but fewer in MCL and MZL. Both gene expression patterns and overall survival data evidence four stages of cancer immuno-editing in B-NHL: • Non-immunogenic tumors (stage 1) • Immunogenic tumors without immune escape (stage 2) • Immunogenic tumors with immunoescape (stage 3) • Fully immunoedited tumors (stage 4) Scores characterizing immunoescape stages 3 and 4 (76% of FL and DLBCL samples in the dataset) identify those B-NHL patients relevant for immune checkpoint blockade therapeutics. Beyond, the consequences of these findings will be discussed in the more general context of molecular profilings for cancer treatment.
Slobodanka Ostojic Kolonic
Clinical Hospital Merkur,Europe
Title: Rituximab maintenance in follicular lymphoma
Biography:
Slobodanka Ostojic Kolonic is a Professor of Internal Medicine at the School of Medicine of University of Zagreb, Croatia. She is an attending physician in Internal Medicine and Hematology at Clinical Hospital Merkur and Head of the Internal Medicine Department since 2011. She is the President of the myelodysplastic syndrome working group as part of Croatian Cooperative Group for Hematologic Diseases (KROHEM). Her research and interest is focused on lymphoproliferative disorders, myelodysplastic syndrome, chronic leukemias and multiple myeloma. She has given numerous invited lectures at domestic and international meetings, has authored many scientific papers in peer-reviewed journals, and the author of several chapters in internal medicine, pharmacology and oncology medical textbooks
Abstract:
Follicular lymphoma is an indolent B-cell malignancy which represents 15 to 20% of newly diagnosed non-Hodgkin lymphomas. Therapeutic options for patients with untreated FL include observation for asymptomatic and low tumor burden and multiagent chemotherapy for symptomatic and high tumor burden patients. Despite slow growth and high initial response rate, many patients experience disease progression and relapse. Rituximab has significantly improved the outcomes of patients with B-cell lymphomas, as well as in patients with advanced FL. Results of randomized studies have shown that the combination of the anti-CD20 monoclonal antibody rituximab with various chemotherapy regimens, can improve patients' overall survival and progression free survival. Maintenance therapy with rituximab in patients with any previous induction therapy improves progression free survival and statistically significant survival benefit for patients with advanced disease. There have been several reports that demonstrated similar benefits for FL patients who received rituximab maintenance every 2 or every 3 months for 2 years. Most of patients had beneficial effect by prolonging response duration in first remission and in case of recurrent disease. In low tumor burden FL patients, there have been no survival benefit and no changing the natural course of disease if rituximab was given as an induction therapy. In conclusion, maintenance therapy with rituximab is efficacious in advanced stage FL patients, with significant benefit in PFS and OS.
Ashutosh Wechalekar
University College London ,UK
Title: Systemic AL amyloidosis - novel approaches to treatment
Biography:
Ashutosh Wechalekar is a Reader in Haematology and Medicine at University College London. He is a Consultant Haematologist at University College London Hospitals and the Royal Free London NHS Foundation Trust. He was trained in Haematology in UK and Canada. His clinical and academic interests are focused on amyloidosis and multiple myeloma. He is one of the world leaders in systemic amyloidosis; in particular AL amyloidosis. His work has defined this disease in a prognostic way and shaped the treatment algorithms. He is interested in characterization and treatment of systemic AL amyloidosis, and runs the national trials in AL amyloidosis. He has interest in multiple myeloma particularly with renal impairment and is involved in clinical trials of new and novel agents in these disorders.
Abstract:
Light chain (AL) amyloidosis is a rare but increasingly recognized complex disorder. It is a consequence of tissue deposition of misfolded monoclonal immunoglobulin light chains protein which forms amyloid fibrils. Most patients have an underlying plasma cell dyscrasia and a small proportion have a lymphoplasmacytic lymphoma. The clinical features are determined by the organs affected by the tissue amyloid deposition. The main organs affected by systemic AL amylolidosis are heart, kidneys, liver, peripheral/autonomic neuropathy and soft tissues. The diagnosis is made by histological demonstration of amyloid deposition on a tissue biopsy (or abdominal fat aspirate) by Congo red staining followed by amyloid fibril typing by immunohistochemistry or mass spectrometry. This is followed by assessing the extent of organ damage (particularly cardiac) to decide a risk stratified approach to treatment. There have been exciting advances in treatment with improvement in survival from 2 years to over 5 years. Baseline therapy is risk stratified. Autologous stem cell transplant is considered for selected fit patients. Most patients treated with it are assessed at baseline, weighing the reversible or non-reversible contraindications, toxicity of treatment and chemotherapy alternatives available. Chemotherapy typically involves a proteasome inhibitor based approach (CyBorD is the commonest front line regime used). Other options include melphalan, thalidomide, lenalidomide, bendamustine in combination with dexamethasone. Attaining a very good partial response or better is the treatment goal. Novel anti-amyloid therapies using small molecules and monoclonal antibodies are in advanced phase trials offering hope of rapid organ improvement. The prognosis of AL amyloidosis has improved from a median survival of ~2 years in the early part of the last decade to over 5 years but high early cardiac mortality still remains problematic. Early diagnosis coupled with use of highly effective chemotherapy regimens and the availability of novel anti-amyloid agents has changed natural history of this disease.
Biography:
Michael Keng received his BS and MD degrees from Michigan State University in East Lansing, Michigan. He completed his Internal Medicine residency at University of Southern California in Los Angeles, California, and Hematology and Medical Oncology fellowship at the Cleveland Clinic in Cleveland, Ohio. He then joined the University of Virginia (Charlottesville, Virginia) in 2014. He currently holds a faculty appointment in Medicine in the Division of Hematology/Oncology at University of Virginia. His clinical areas of interest are focused on clinical trials in hematologic malignancies, including myelodysplastic syndromes, leukemia, and other myeloid malignancies and bone marrow failures. He has a special interest in treating the elderly population, determining optimal combinations and timing of targeted agents, and studying patient safety and quality improvement
Abstract:
Acute myeloid leukemia (AML) is the most common acute leukemia, a disease primarily seen in the elderly with a median age of 67 years. Since the 1970s, treatment with cytarabine and an anthracycline in a “7+3” manner has remained the foundation of curative intent therapy for AML. However, only one-third of patients defined as “old” receive this definitive AML therapy due to concerns of overall performance status and potential treatment-related mortality. Recent data have shown that older AML patients both can tolerate and survive longer than those untreated. A wide spectrum of treatment options is available for elderly AML patients: Intensive chemotherapy, hypomethylating agents, low-dose cytarabine, investigational agents, and supportive care with hydroxyurea and transfusions. There has been great debate regarding the assessment of fitness for chemotherapy and selection of appropriate treatment regimens. Due to diversity of the geriatric patient population and heterogeneity of AML disease, treatment of elderly AML patients to maximize both quantity and quality of life remain challenging and controversial.
Malak Yahia Qattan
King Saud University, KSA
Title: Stem cells microenvironment and its effects on leukemia treatment
Biography:
Malak Yahia Qattan has completed her PhD in Leukemia and Stem Cells Research in 2014 from University of Manchester, UK. She is a Vice Director of Health Sciences Department in King Saud University, Riyadh. Her research focuses on the investigation of mechanisms of gene regulation and cancer biology research. Her long term interests are in investigating the mechanisms by which clinically relevant drugs mediate their therapeutic effects in order to improve available treatments and to develop novel pharmacologically beneficial approaches.
Abstract:
Although the survival rates of 80% in Acute Lymphocytic Leukemia (ALL) are remarkable achievement, the 20% of affected children are facing the risk of death and toxicity of the treatment is significant. The drugs used in ALL are anthracyclines and steroids. The exact mechanisms of action of those drugs are not well understood and significant proportion of children develops drug resistance. Moreover, it has recently been described that microenvironment can also contribute to leukemia cell survival and protect leukemia cells from the cytotoxic effect of drugs. Increased understanding of the mechanisms that lead to 80% curable rate will help bring curable rate to this level in other cancer types as well. So the research aimed to better understand of the role played by Glucocorticoid Receptor (GR) in improving the treatment and the role of bone marrow environment in inducing resistance. We have used ALL cell lines in the absence and presence of conditioned media (CM) obtained from bone marrow cells thus mimicking clinical settings. Our results demonstrate possibility of alternative pathways being utilized for apoptosis when both drugs are used. Furthermore, data indicates that Glucocorticoids (GC) induces autophagy as well as apoptosis in leukemia cells. In addition, Receptor Interacting Protein 1(RIP-1) is significantly repressed in cells grown in CM media and it has been linked to not only apoptosis, but also with other forms of cells death including autophagy and necroptosis. That may highlight new targets of glucocorticoids and open new therapeutic possibilities.
- Myeloma
Myelodysplastic Syndrome
Childhood Hematological Cancers
Session Introduction
Inga Mandac Rogulj
Clinical Hospital Merkur,Europe
Title: Management of higher risk myelodysplastic syndrome
Biography:
Inga Mandac Rogulj is attending physician in internal medicine and hematology at Clinical Hospital Merkur in Zagreb, Croatia. She graduaded from School of Medicine at the University of Zagreb in 2004., and in 2006. joined the clinical faculty in the Division of Hematology at Clinical Hospital Merkur where she continues her clinical practice. Her research and interest is focused on lymphoproliferative disorders, myelodysplastic syndrome, chronic leukemias and multiple myeloma. Dr Mandac Rogulj has given invited lectures at domestic and international meetings and has authored several abstracts and scientific papers in peer-reviewed journals.
Abstract:
Higher risk myelodysplastic syndromes (MDS) include patients in the Intermediate-2 and high-risk categories of the International Prognostic Scoring System and are associated with excess blasts, poor-risk cytogenetics and multiple cytopenias. Survival in untreated higher-risk MDS patients is 6 months following diagnosis, and for that reason the goal of therapy is to prolong survival and delay progression to acute myeloid leukemia. At present time, different guidelines recommend initial treatment with one of the hypomethylating agents (HMA), azacitidine or decitabine. Only azacitidine has been shown to prolong survival in comparison to conventional care regimens, but results have shown that the median survival advantage is only 9,5 months. Among patients with initial responses to HMAs, the median response duration is 9-15 months. Many data indicate that as many as 40% of patients do not respond to treatment or subsequently relapse. After HMA failure, no standard of care has been defined, and many combination treatment strategies have shown variety results. Suggested treatment options for HMA failure include allogeneic stem cell transplantation (in case of eligible patient), addition of other drugs to HMA, enrollment in clinical trials if available or best supportive care. Patients who progress to AML should be offered intensive chemotherapy, but data suggest poor response rates. Allogeneic SCT is the only treatment option with a possibility of cure in front line or for relapsed/refractory HR-MDS suitable patients . In conclusion, HR-MDS patients who face a poor prognosis, need new treatment options to improve their outcomes.
Lamya Mohamed Ibrahim
Advanced Center For Daycare Surgery, UAE
Title: Association of MDR1 Gene Polymorphism (G2677T) with Imatinib Response in Egyptian Chronic Myeloid Leukemia patients
Biography:
Lamya Mohamed Ibrahim completed her doctorate in clinical pathology and hematology at Mansoura faculty of medicine, Egypt in 2010. She joined the clinical pathology department from 2000 till now, promoted from assistant lecturer to lecturer and finally Assistant professor. She published regularly in international and national journals with about publications. She is also working as a reviewer of many peer- reviewed medical journals. Dr. Lamia Ibrahim also contributed and presented her work to many international conferences such as European Hematology Association 2014. She is also a member of many organizations such as European Hematology Association (EHA), American Hematology Association (ASH), Emirates Medical Hematology Association (EMHA), Egyptian Society of Hematology (ESH), Egyptian Society of Laboratory Medicine (ESLM), and Pan- Arab Hematology Associations.
Abstract:
Despite the excellent efficacy results of IM treatment in CML patients, resistance to IM has emerged as a significant problem. Genetic variations in genes involved in drug transportation might influence the pharmacokinetic and metabolism of IM. The genotype of a patient is increasingly recognized in influencing the response to the treatment. The aim of this study was to investigate the genotype frequencies of SNPs G2677T in CML patients undergoing IM treatment and to determine whether different genotype pattern of these SNPs have any influence in mediating good response and resistance to IM. A total of 96 CML and 30 control samples were analyzed for MDR1 gene (G2677T) polymorphism using PCR- RFLP technique. Genotype distribution revealed increase in GG, GT (34.4%, 46.9%) and significant decrease in TT (18.8%) genotype frequencies in CML patients compared to controls(p=0.257, 0.326, 0.017 respectively). Patients in accelerated and blastic phases had higher GT genotype frequency compared to patients in early phases (p<0.001). The resistance incidence correlated with G allele. GG and GT genotypes were higher in CML patients showing imatinib resistance compared to sensitive CML patients (P = 0.893, 0.002). Meanwhile TT genotype was shown significantly to be higher among imatinib sensitive group with (p<0.001). GT genotype was found to be a significant predictor of IM resistance risk (p=0.002). GG genotype was not proved to be significant indicator of resistance risk (p=0.893). On the other hand, TT may be a protective factor against imatinib resistance in CML patients (P<0.001). Determination of G2677T MDR1 polymorphisms might be useful in response prediction to therapy with Imatinib in patients with CML.
Chhaya Rani Shevra
MLB Medical College,India
Title: Recent advances in the diagnosis of multiple myeloma
Biography:
Chhaya Rani Shevra is an Assistant Professor at MLB Medical College and have Published many papers in many reputed journals.
Abstract:
Multiple myeloma (MM) is a malignant tumor of plasma cells. It accounts for 1% of all cancer death in Western countries. Clinically it is characterized by severe bone pain, spontaneous fractures due to lysis of bone, which give rise to spinal cord compression, bone pain, numbness, weakness and paraplegia. Besides this patients may manifests with symptoms related to hypercalcemia, and hyperviscosity syndrome,renal failure and infection. Most of these symptoms are due to monoclonal protein in serum and urine. It is predominantly a disease of seventh and eighth decades, but 7.86% cases can be seen under 40 years of age. The disease is diagnosed with serum or urine protein electrophoresis or immunofixation and bone marrow aspirate analysis. Skeletal radiographs are important in staging multiple myeloma and revealing lytic lesions, vertebral compression fractures, and osteoporosis. Magnetic resonance imaging and positron emission tomography or computed tomography are emerging as useful tools in the evaluation of Patients with myeloma; The differentialdiagnosis of monoclonal gammopathies includes monoclonal gammopathy of uncertain significance, smoldering (asymptomatic) and symptomatic multiple myeloma, amyloidosis, B-cell non-Hodgkin lymphoma, Waldenström macroglobulinemia, and rare plasma cell leukemia and heavy chain diseases. Five-year survival rates approach 33 percent, and the median survival rate is 33 months. Resent research have implicated that there is a cytokine network in the pathogenesis of MM especially in bony lesions, which are the predominant features of plasma cell dyscrasia.
Amani Mahbub
Umm Al Qura University,Saudi Arabia
Title: Polyphenols Act Synergistically with Doxorubicin and Etoposide in leukaemia cell lines
Biography:
Amani Mahbub has completed M.Sc. in Biomedical Basis of Disease in 2010 and PhD in Anti-Cancer Potential of Polyphenols in Treatment of Leukemia in 2015 at the Sheffield Hallam University of Biomedical Research Centre – Cancer Research, Sheffield, UK. She has been interested in investigating the biological effects of a number of nutraceutical compounds such as polyphenols alone and in combination with chemotherapies on the induction of apoptosis, reduced cell proliferation and signalling pathways that involved in the pathogenesis of leukaemias. She also has four published papers in the Journal of Pathology (2012), the Journal of Anti-cancer Agents in Medicinal Chemistry (2013) and recently two in Nature (2015). In addition, she was awarded, the Alastair Currie prize for the best poster presentation at the Pathological Society of Great Britain & Ireland Conference in 2012, Sheffield, UK. Currently, she is working at Umm Al-Qura University in Applied Medical Sciences College– Pathology Department, Makkah, KSA.
Abstract:
The study aimed to assess the effects of polyphenol when used in combination with doxorubicin and etoposide, and determine whether polyphenols sensitized leukaemia cells, causing cell-cycle arrest, inhibition of cell proliferation and induction of apoptosis. The rationale being that in some solid tumours, polyphenols have been shown to sensitize cells to apoptosis and/or cell-cycle arrest, potentially reducing doses, whilst maintaining efficacy. Method: Quercetin, apigenin, emodin, rhein, cis-stilbene were investigated alone and in combination with etoposide and doxorubicin in two lymphoid (JURKAT and CCRF-CEM) and two myeloid (THP-1 and KG-1a) leukaemia cells lines. Measurements were made of ATP levels (CellTiter-Glo®assay), cell-cycle progression (propidium iodide (PI) staining and flow cytometry) and apoptosis (NucView-caspase-3 assay and Hoechst 33342/PI staining). The effects of these combinations on the apoptotic pathway (caspases-3, -8 and -9 Glo®luminescent assays), glutathione levels (GSH-Glo™-glutathione assay and cell tracker™ green-5-chloromethylfluorescein-diacetate-glutathione staining) and DNA damage (Alexa Fluor® 647 Mouse anti-H2AX staining) were also determined. Results: Doxorubicin and etoposide in combination with polyphenols synergistically reduced ATP levels, induced apoptosis and increased S- and/or G2/M-phase cell-cycle arrest in lymphoid leukaemia cell lines. In the myeloid cell lines doxorubicin and etoposide displayed differential effects. Doxorubicin had a synergistic or additive effect when combined with quercetin, apigenin, emodin, and cis-stilbene, but had an antagonistic effect when combined with rhein. Combination treatment caused a synergistic down regulation of glutathione (GSH) levels and increased DNA damage, driving apoptosis via caspase 8 and 9 activation. However, in myeloid cells were an antagonist effect this was associated with an up-regulation of GSH levels, a reduction in DNA damage and apoptosis. Conclusion: Doxorubicin and etoposide activity can be enhanced by polyphenols, particularly in lymphoid leukaemia cells, although effects were strongly dependent on type of cell line, with some interactions were antagonistic in myeloid cell lines.
Mehrdad Payandeh
Kermanshah University of Medical Sciences, Kermanshah, Iran
Title: Treatment and survival in patients with chronic myeloid leukemia in chronic phase (CML-CP) in West Iran
Biography:
Mehrdad Payandeh is a MD from Kermanshah University of medical science (KUMS). He is a Chair of Hemophilia Center of Kermanshah city and Chair ofBone Marrow Transplantation Center of Kermanshah city. He has Eight years of experience in diagnoses and treatment of hematology, oncology, coagulative, BMT patient's disorder in private and university Hospital. He has published more than 70 papers in reputed journals and has been serving as an editorial board member of repute.
Abstract:
CML includes 30% of all leukemias, and occurs from childhood to old age. The present study was a retrospective analysis of chronic phase CML patients registered to Hematology Clinic in Kermanshah, Iran, with checking of treatment options in this disease. Between of 2002 to 2014, 85 CML patients referred to Hematology Clinic that selected them for our study. We surveyed age, sex, B-symptoms, Splenomegaly, sokal score, hasford score, treatment and survival in all patients. Philadelphia chromosome analysis was done for each patient by conventional cytogenetics. We compared treatment in the patients with three drugs (Imatinib, hydroxyurea (HU) and Interferon alpha (IFN-α)). The mean age of the patients at diagnosis was 47.5±14.5 years (range, 23-82 years), with 43 patients (50.6%) male. 13 patients (15.3%) referred to clinic for the first time with B-symptoms and 44 patients (51.8%) had splenomegaly. Sokal Score for 77 patients (90.6%) was low, 4(4.7%) was intermediate and 4(4.7%) was high, but Hasford (Euro) Score for all patients was low. The 5-year survival rate for treated patients with Imatinib, Imatinib plus HU and Imatinib plus HU plus IFN-α was 90.5%, 81.1% and 55.6%, respectively. The mean age and median age at diagnosis for the patients are around 40-50 years. Also, the results show that Imatinib therapy alone approves survival in CML patients compared to HU or IFN-α. Combination of IFN-α and/or HU with Imatinib probably reduce survival.
Mahdi Shahriari
Shiraz University of Medical Sciences, Iran
Title: Report of 20 years’ Experience on the effect of intensive intrathecal chemotherapy on prognosis of childhood lymphoblastic leukemia with central nervous system (CNS) involvement
Biography:
Mahdi Shahriari is currently working as an Associate Professor in Department of Paediatrics in Shiraz University of Medical Sciences, Iran since 1994. He has published many articles in reputed National & International Journals. His area of expertise include Medicine, Oncology, Hematology, Pediatric Hematology, Pediatric Oncology, Hemophilia, Thalassemia & Cord Blood Stem Cell Transplantation.
Abstract:
Introduction: Primary central nervous system (CNS) involvement and CNS relapse are poor prognostic events in acute lymphoblastic leukemia (ALL). With cranial radiotherapy second CNS relapse or bone marrow (BM) relapse is usual. So prevention from CNS relapse is very important way to decrease both mortality and morbidity in childhood leukemia. Method: In a Prospective study from June1995 to May 2014; thirty children with CNS involvement and 60 children with CNS relapse of Acute Lymphoblastic Leukemia (ALL) were enrolled in the study with written consent form. They randomly were divided in two groups: 30 patients in group A (as control group) received triple intrathecal (IT) injections every 2 months for three years; including A1: 15 control patients with primary CNS involvement; and A2: 15 control patients with CNS relapse. Sixty patients in group B (Case group) received further triple IT injections in the fourth and fifth years including B1: 20 cases of primary CNS involvement and 40 cases of CNS relapses. For each patient in group A, two age and sex matched patients were enrolled in group B. They had 2-15 years follow up. Results: in group A1: 5 CNS relapses, 3 BM relapses and 2 deaths were occurred. Boys had more relapses and deaths than girls (Chi square=15.63, P value <0.001); most relapses were in the third to fifth years. In group A2: 7 Second CNS relapses, 6 BM relapses and 2 deaths were occurred; most relapses were occurred in the boys and in the third to fifth years; again boys had more relapses and deaths (P <0.005). In group B1 only 2 boys had CNS relapses; no BM relapse and no death was occurred. No relapse or death in girls was occurred (Fisher exact test: P<0.001). In group B2: 8 second CNS relapses; 3 BM relapse and 2 deaths were occurred (P<0.003). Most of the relapses were occurred in the third to fifth years of maintenance therapy. Overall even boys in groups B1 and B2 had lesser mortality and morbidity (Chi square=27.6, P<0.001) and better prognosis. Conclusion: Extended intrathecal injections after discontinuation of maintenance chemotherapy is advisable for cases of primary CNS involvement and CNS relapses, however national and international studies with greater number of patients is suggested. Keywords: Childhood Leukemia, CNS involvement, CNS relapse, CNS prophylaxis, Prognosis.
Farhad Zaker
Iran University of Medical Sciences, Iran
Title: Biological and molecular effects of selective inhibitor of ‘Aurora Kinase B’ (Barasertib) on a human promyelocytic leukemia cell line
Biography:
Farhad Zaker is working as a Professor of Hematology and Assistant Head of Department of Haematology and Blood Banking at Iran University Medical Sciences. He completed PhD in Haematology in 1997 from University of Wales, College of Medicine, Cardiff-UK. His research interests include haematology, immunohematology, cell culture & molecular medicine.
Abstract:
Introduction: The Aurora (Aur) family of serine/threonine kinases has been implicated in the survival and proliferation of both hematologic and solid malignancies. Overexpression of Aurora kinase B has been shown in a variety of human cancers including leukemia and lymphoma. In the quest for novel anti-cancer agents, several inhibitors of aurora kinases such as AZD1152 (Barasertib) have been introduced. Barasertib has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic and metabolic profiles of Barasertib were characterized in Phase I/II study. The objective of this study was to evaluate the molecular and biological effects of AZD1152 on NB-4 Cell line as an acute promyelocytic leukaemia (APL). Methods: NB4 Cells treated with various concentrations of AZD1152 and incubated in culture for several days. Transcriptional alteration of genes involved in apoptosis, viability, metabolic activity, morphological changes, nuclear shape variations, cell cycle distribution and apoptosis of inhibitor-treated NB4 cells were assessed using Real Time PCR, trypan blue dye exclusion, MTT, wright-giemsa staining, DAPI staining and flowcytometry assays, respectively. Results: It was shown that metabolic activity and viability of NB4 cells reduced and in contrast, cell size, G2/M arrest, polyploidy giant cells formation and apoptotic population increased in a concentration and/or time-dependent manner after exposure to AZD1152. In addition, it was observed an expressive enhancement in mRNA levels of p73, Bax, Puma and Bcl-2 coupled with a significant increase in Bax/Bcl-2 molecular ratio. Conclusion: Our data indicate that AZD1152 induces p73, which in turn up-regulates p53 target genes and orchestrates apoptosis in a p53-independent manner. This inhibitor may be beneficial to refractory APL or resistance to chemotherapy and also further investigation is required to prove this effect.
Biography:
Ahmad Ali Basha is currently working as Specialist Haematologist / Oncologist in Saudi German Hospital,Dubai,UAE. He is the Head of Hematology & Oncology Department in Aleppo University. He is also working as a Medical Director in Al-Kindi University Hospital, Aleppo Unversity in Syria.Ahmad Ali Basha is also Member of the American Society of Clinical Oncology - ASCO since 2010 .
Abstract:
Myelodysplastic syndromes (MDS) are a spectrum of clonal myeloid disorders characterized by ineffective haematopoiesis, cytopenias, qualitative disorders of blood cells, clonal chromosomal abnormalities,and the potential for clonal evolution to acute myeloid leukemia (AML).1 In this review, we discuss the various pathogenic conditions included in the spectrum of MDS and the associated risk stratification for these conditions. We further discuss the treatment recommendations based on the risk status and the expected prognosis. Epidemiology, Etiology, and Pathogenesis In the western population, the onset of MDS usually occurs after age 50 years, except in cases where the individual has undergone radiation therapy or chemotherapy for a prior malignancy.2,3 The annual incidence of MDS increases in a logarithmic fashion after the age of 40 years. According to National Cancer Institute data, the annual incidence of MDS increases from 2 per 1 million persons at age 40 years to more than 40 per 100,000 persons in the septuagenarian population. Males are affected 1.5 times as often as females.
Amer Zeidan
Yale University,USA
Title: The utility of risk models in predicting outcomes of patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) treated with hypomethylating agents (HMA)
Biography:
Amer Zeidan MBBS, MHS, is an Assistant Professor of Medicine (Hematology) at Yale University. Dr. Zeidan has completed a hematology/oncology fellowship and a clinical research fellowship in myelodysplastic syndromes at Johns Hopkins University where he also earned a Master of Health Science (MHS) degree in Clinical Investigation. Dr. Zeidan received his MBBS degree from the Faculty of Medicine, University of Jordan, Amman, Jordan before completing his internal medicine residency at Rochester General Hospital, Rochester, NY. Dr. Zeidan's clinical interest is in the management of hematologic malignancies. The focus of his clinical/translational research is the development of novel therapies for myelodysplastic syndromes, acute myeloid leukemia and other myeloid malignancies. Dr. Zeidan has been working on designing and conducting early phase clinical trials in refractory myeloid malignancies especially focusing on immunotherapeutic and epigenetic approaches. In addition, Dr. Zeidan also has an interest in effectiveness and outcomes research in myeloid malignancies. Dr Zeidan has authored more than 70 peer-reviewed publications including more than 25 original research papers and several book chapters. Dr Zeidan has also presented many abstracts in national and international hematology meetings and delivered invited presentations in several prestigious institutions in USA and Mexico.
Abstract:
Background: Although HMA (azacitidine [aza] or decitabine [dac]) are standard of care therapies for pts with HR-MDS, responses may not be seen for 4-6 months and occur in <50% of treated pts. Moreover, curative hematopoietic cell transplantation (HCT), which is recommended as up-front therapy for HR-MDS, is used USA in <5% of pts. The ability to identify pts with a low likelihood of benefiting from HMA who instead should receive immediate HCT or experimental treatment approaches is a clinical and research priority. Established MDS prognostic systems include the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R) which were derived from untreated pt cohorts and the MD Anderson Prognostic Scoring System (MDAPSS) which was derived from a cohort composed of treated and untreated pts. A French Prognostic Scoring System (FPSS) was developed specifically to predict survival benefit among aza-treated HR-MDS pts. We sought to compare the relative prognostic discriminatory power of these models in a large cohort of HMA-treated pts with HR-MDS. Methods: The combined MDS database obtained from six institutions in the MDS Clinical Research Consortium (H. Lee Moffitt Cancer Center and Research Institute, Cleveland Clinic, MD Anderson Cancer Center, Dana Farber Cancer Institute, Weill Medical College of Cornell University, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins) was used to identify patients with HR-MDS (IPSS intermediate-2 [INT-2] and high) who received HMA therapy (aza or dac). The prognostic scores were calculated as previously described. Responses were defined per International Working Group 2006 criteria. According to best response, pts were categorized into responders (complete response [CR], partial response [PR], hematologic improvement [HI], and marrow CR) and non-responders (stable disease [SD] and progressive disease [PD]). Multiple imputation using the chained equation approach was used to impute all missing data. 100 imputations were generated from a model with 82 variables using random forest imputation for missing continuous data and logistic/polytomous imputation for missing categorical data. All statistical analyses were performed on the 100 completed datasets, then combined using the standard multiple imputation combining rules. Fraction of missing information (FMI), which gives the fraction of information that was lost for a quantity of interest due to missing data under a given imputation model, was estimated for every analysis from the 100 imputations. Logistic regression models were fitted and tested for association of response with prognostic risk categories. Overall survival (OS) was calculated from the time of diagnosis to time of death or last follow-up. Kaplan-Meier (KM) curves were generated for OS and the stratified (by institution) log-rank test was used to compare median OS. Stratified (by institution) Cox proportional hazards models were fit to assess association of prognostic systems with OS. Corrected Akaike information criteria (AICc) were used to assess the relative goodness of fit of these fitted models. Results: We identified 626 pts with HR-MDS (69.9% with INT-2 and 30.1% with high IPSS) who received HMA as upfront therapy (67.8% aza, 32.2% decitabine). Median duration of follow-up from diagnosis was 15.5 months (M) (95% confidence interval [CI], 14.5-16.7 M): 66.4% of pts were male, 86.6% white, 85.0% were > 60 years, and 8.9% had therapy-related MDS. Median number of HMA cycles was 4.4 (1st-3rd Quartiles, 3.0-7.6), with 70.8% of pts receiving ≥4 cycles of therapy. Median time from diagnosis to start of HMA was 0.94 M (1-3 Q, 0.40-2.1 M). In total, 43.0% responded (CR 20.7%, PR 9.5%, HI-E 6.4%, HI-N 3.6%, HI-P 2.7%) while 57.0% were non-responders (SD 37.9% and PD 19.1%). Consistent with literature, none of the prognostic systems predicted best response to HMA: IPSS (P=0.55), IPSS-R (P=0.14), FPSS (P=0.21), MDAPSS (P=0.39), WPSS (P=0.88). Median OS for the entire cohort was 16.9 M (95%CI, 15.6-18.2 M, FMI=3.3%). Figure 1 shows the KM curves by the 5 prognostic models for a representative completed dataset. All prognostic models showed association with OS: IPSS (P=0.036), IPSS-R (P=1.6e-10), WPSS (P=0.00020), FPSS (P=4.0e-9), MDAPSS (5.7e-13). Scores generated using the AICc to assess the relative goodness of fit (lower is better) were 4146 (MDAPSS), 4149 (FPSS), 4157 (IPSS-R), 4189 (WPSS) and 4207 (IPSS). Conclusions: This is the largest reported direct comparison of the commonly used prognostic models for MDS among HMA-treated MDS patients. None of the prognostic models predicted best response to HMA therapy. Nonetheless, the IPSS-R, MDAPSS, and the FPSS all functioned well to separate HMA-treated pts with HR-MDS into prognostic groups with different survivals. The MDAPSS and FPSS appear superior to the IPSS-R, WPSS and the IPSS for survival prediction among HMA-treated pts. HR-MDS patients with poor projected survival with HMA therapy should be considered for up-front HCT or for experimental approaches.