SP-052 WHEN TO CONSIDER BONE MARROW TRANSPLANT IN SCD?

Speakers Presentations – Vth International Eurasian Hematology Congress / Leukemia Research 38 S1 (2014) S1–S65

of disease is presented more clinical form [1]. Considering the aggressive clinical course of the disease and the short overall survival of these patients (between 3 and 4 years), the treatment strategy at diagnosis is still a matter of discussion [3]. Conventional chemotherapy based on monoor poly-chemotherapy did not bring satisfactory control of the disease, for example, the “CHOP” regimen. The use of fludarabine as monotherapy showed moderate efficacy, and its association with alkylating agents, demonstrated in cases of relapses relative success. The combination of antiCD20 monoclonal antibody to these chemotherapeutic regimens increased response contributed between 20 and 40% when used with scheme “CHOP” [4,5]. Recent studies of the therapy intensified chemotherapy, either with “DHAP” or “hyper-CVAD” protocols, applied as induction therapy followed by consolidation with high dose therapy followed by autologous peripheral progenitor cell transplantation. The myeloablative consolidation should be considered in first remission of the disease in young adults (up to 65 years of age) [6–9]. Allogeneic transplantation with reduced dose intensity is also a therapeutic option for patients with advanced disease after autologous transplantation, based on the perspective of the graft-versus-lymphoma effect. One of the pioneering studies of this procedure in patients with cell lymphoma and relapsed chemosensitive mantle cell lymphoma, complete remission occurred in 97% of patients and only 9% died in the first year post-treatment. The study also demonstrated in a follow-up of 56 months, estimated at six years, the progression-free survival and overall survival was 46% and 53%, respectively [10]. New drugs have been studied in several clinical trials in the treatment of Hodgkin’s mantle cell such as bortezomib, thalidomide, lenalidomide, temsirolimus and obinutuzumab (GA101) and data are still under review and development of clinical [11–13] studies. References [1] Tiemann M, Schrader C, Klapper W,et al. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol. 2005; 131:29–38. [2] Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2008 [3] Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511–518. [4] Martin P, Chadburn A, Christos P, et al. Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding seven years with standard therapies. Ann Oncol. 2008; 19:1327–1330. [5] Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009; 27:1209–1213. [6] Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol. 2002;20:1288–1294. [7] Lefrere F, Delmer A, Levy V, et al. Sequential chemotherapy regimens followed by high-dose therapy with stem cell transplantation in mantle cell lymphoma: an update of a prospective study. Haematologica. 2004;89:1275–1276. [8] de Guibert S, Jaccard A, Bernard M, et al. Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma. Haematologica. 2006;91:425- 426. [9] Delarue R, Haioun C, Ribrag V, et al. RCHOP and RDHAP followed by autologous stem cell transplantation (ASCT) in mantle cell lymphoma (MCL): final results of a phase II study from the GELA [abstract]. Blood. 2008; 112:581. [10] Khouri IF, Lee MS, Saliba RM, et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. J Clin Oncol. 2003;21:4407–4412. [11] Zinzani PL, Witzig T, Vose JM. Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle cell lymphoma: results of an international study (NHL-003). Blood 2008; 112:262. [12] Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005;23:5347–5356. [13] Morschhauser FA, Cartron G, Thieblemont C, et al. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-Cell lym-

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phoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol 2013;31:2912–2919. SP-047 HOW I MANAGE DLBL Khalid Halahleh. Palestine Non-Hodgkin’s lymphoma is a heterogeneous disease with common morphological variants and different anatomical sites on presentation. Roughly 70,000 patients/year diagnosed in US. The incidence has tripled since 1980; Prevalence over 300,000/year in US. It is the most common hematologic cancer and the 5th overall. Survival of Non-Hodgkin’s lymphoma has significantly improved over last 5–10 years, but there are still major challenges exist in trying to improve further. Aggressive lymphoma including DLBL is one of the clinical paradigms. The practical objective of treatment is cure. Though, we have good clinical prognostic parameters for treatment selection, most of our patients still being treated with R-CHOP, which can cure only 60–70% of patient and 1/3 of patients are not cured, so we still have unmet need to improve on therapy and to reduce of toxicity of treatment. DLBL underlying genetic heterogeneity, including GC and ABC lymphomas based on immunohistochemical, GEP profiling and somewhat distinct molecular pathways, that could serve for studying new molecular targetsBCL-2, C-MYC, NF-KB, that could improve on treatment response of DLBL patients by having new approaches that potentially could target DLBL subsets-including- velcade, Ibrutinib, linaledomide, azacitidine. Lots of challenges still face lymphoma experts, so we must move faster in developing new treatments in diffuse large B cell lymphoma, earlier evaluation of novel drugs in front-line therapy and if we should continue to “lump” or are we ready to “split” patient subsets in DLBCL. In my presentation, i will update you about the management of DLBL, the improved survival over the years and the new molecular definitions, targets and targeted therapies. Also, will touch little bit about DLBL management in Palestine. SP-052 WHEN TO CONSIDER BONE MARROW TRANSPLANT IN SCD? Salam Alkindi. Department of Haematology, Sultan Qaboos University, Muscat, Oman Sickle cell disease is one of the commonest hereditary blood disorders worldwide with WHO estimate of over 300,000 affected births/year. It’s the result of glutamic acid replaced by Valine in the position 6 of βchain of the haemoglobin. It’s characterized by recurrent painful episodes, predilection to infections and recurrent anemia (haemolytic and non-haemolytic). The disease unfortunately is very heterogonous even among members of the same family, leading to significant morbidity and morality. The only curative therapeutic option is bone marrow transplantation. However In view of the small but significant transplant related mortality, BMT was reserved only for patients exhibiting severe disease who could tolerate the procedure. In recent years however, significant progress has been made in the science of HSCT, specifically, with the use of non-myeloablative conditioning regimens and better supportive care, transplant indications have become less restrictive. Currently older patients and those previously considered unfit for transplant can now benefit from HSCT. Among the suggested indications include stroke & impaired neuropsychological function, acute chest syndrome, recurrent severe painful episodes, osteonecrosis and red cell alloimmunization. Outcomes are excellent with overall survival close to 90% and disease free survival exceeding 70%. Finding a compatible family donor has remained an issue, but this limitation of donor availably has been overcome by using compatible unrelated donors of BM & well as CB. More recently the use of haploidentical is being explored and could lead to many more patients being offered transplant in the years to come. The incidence of graft versus host disease and graft rejection have remained high particularly in the latter options, demanding prospective clinical trials to evaluate strategies to overcome some of these issues. In summary pa-

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Speakers Presentations – Vth International Eurasian Hematology Congress / Leukemia Research 38 S1 (2014) S1–S65

tients with sickle cell disease should be transplanted as early as possible before major irreversible complications; however it is becoming evident that even older patients and those with co-morbidities can also benefit from HSCT. References [1] Angelucci E, et al, Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel, Haematologica. 2014 May; 99(5):811–20. SP-054 ACUTE MYELOGENOUS LEUKEMIA Burak Gumuscu. Pediatric Hematology/Oncology, Bon Secours Virginia Health System, St. Mary’s Hospital, Richmond, VA, USA Acute myeloid leukemia (AML) is a clonal disorder caused by malignant transformation of a bone marrow-derived, self-renewing stem cell or progenitor, which demonstrates an unlimited self-renewal capacity as well as aberrant differentiation. Recent high-resolution genetic profiling has demonstrated even more complexity of AML than its long known morphological and cytogenetic heterogeneity. The genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and a vast majority of AML cases can be classified according to specific genetic abnormalities. Diversity of genetic alterations, epigenetic modifications and characteristics of leukemic stem cells are some examples of this complexity. AML comprises up to 20% of all childhood leukemias. It is now considered a curable disease over the past few decades (long term survival of>60%) due to important progress in the use of chemotherapy. However, treatment related side effects are significant, and late effects can be life-threatening. Fortunately, translational research developments provide novel treatment targets and targeted therapies, which will enable minimal residual diseasedriven tailored therapy. Moreover, the development of new formulations of existing drugs and immunotherapies promise to further advance the cure rates and improve the quality of life of patients; therefore, the treatment of pediatric AML will continue to improve. SP-055 PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) S. Sema Anak. Medipol University, Medical Faculty, Dept. of Pediatric Hematology/Oncology, BMT Unit, Istanbul, Turkey Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy with an annual incidence of 3.5–4 cases per 100,000 children aged 0–14 years (USA), with a peak incidence during 2–5 years of age. The etiology is still obscure except for some inherited genetic syndromes (eg, Down syndrome) or congenital immunodeficiencies (e.g., Wiskott-Aldrich syndrome, ataxia-telangiectasia). Overall cure rates for children with acute lymphoblastic leukemia have reached 90% with improvements in diagnosis and treatment. Despite the treatment advances in childhood ALL, numerous important biologic and therapeutic questions remain to be answered before the goal of curing every child with ALL with the least associated toxicity. The systematic investigation of these issues requires large clinical trials. Risk groups & treatment strategies: Children with acute lymphoblastic leukemia (ALL) are usually treated according to risk groups defined by both clinical and laboratory features. The intensity of treatment required for favorable outcome varies substantially among subsets of children with ALL. Risk-based treatment assignment is utilized in children with ALL so that patients with favorable clinical and biological features who are likely to have a very good outcome with modest therapy can be spared more intensive and toxic treatment, while a more aggressive, and potentially more toxic, therapeutic approach can be provided for patients who have a lower probability of long-term survival. Certain ALL study groups, such as the Children’s Oncology Group (COG), use a more or less intensive induction regimen based on a subset of

pretreatment factors, while other groups give a similar induction regimen to all patients. NCI risk group classification stratifies risk according to age and white blood cell (WBC) count: • Standard risk – WBC count less than 50,000/μL and age 1 to younger than 10 years. • High risk – WBC count 50,000/μL or greater and/or age 10 years or older. Risk-based treatment assignment requires the availability of prognostic factors that reliably predict outcome. Patient characteristics affecting prognosis include age at diagnosis (Infants, young children (aged 1 to <10 years), adolescents and young adults (≥10 years)), WBC count at diagnosis (A WBC count of 50,000/μL is generally used as an operational cut point between better and poorer prognosis), central nervous system (CNS) involvement at diagnosis, testicular involvement at diagnosis, Down syndrome (trisomy 21), gender (the prognosis for girls with ALL is slightly better than it is for boys with ALL) and race (survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL). Leukemic cell characteristics affecting prognosis include morphology, immunophenotype and cytogenetics/genomic alterations. Response to initial treatment affecting prognosis include MRD determination, day 7 and day 14 bone marrow responses, peripheral blood response to steroid prophase, peripheral blood response to multiagent induction therapy, peripheral blood MRD before end of induction (day 8, day 15) and induction failure. In COG protocols, children with ALL are initially stratified into treatment groups (with varying degrees of risk of treatment failure) based on a subset of prognostic factors, including age, WBC count at diagnosis, immunophenotype, cytogenetics/genomic alterations, presence of extramedullary disease, Down syndrome, steroid pretreatment. Patients who are at very high risk of treatment failure include infants with MLL translocations, patients with hypodiploidy (<44 chromosomes), patients with initial induction failure. Since 2000, risk stratification on BFM protocols has been based almost solely on treatment response criteria. In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two time points, end induction (week 5) and end consolidation (week 12). The BFM risk groups include the following: • Standard risk: Patients who are MRD-negative (i.e., <10–4 ) at both time points are classified as standard risk. • Intermediate risk: Patients who have positive MRD at week 5 and low MRD (<10–3 ) at week 12 are considered intermediate risk. • High risk: Patients with high MRD (≥10–3 ) at week 12 are high risk. Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD. Phenotype, leukemic cell mass estimate, also known as BFM risk factor, and CNS status at diagnosis do not factor into the current risk classification schema. However, patients with either the t(9;22) or the t(4;11) are considered high risk, regardless of early response measures. The use of risk-adapted treatment protocols has improved cure rates while limiting the toxicity of therapy. Different forms of ALL require different approaches for optimal results, nevertheless ALL treatment typically consists of a remission-induction phase, intensification (consolidation) phase, and continuation therapy targeted at eliminating residual disease. Central Nervous system (CNS) directed therapy is critical for improved survival rates. The addition of cyclophosphamide and asparaginase is also beneficial in the treatment of T-cell ALL. Mature B-cell ALL needs to be treated like disseminated Burkitt lymphoma, with short-term intensive chemotherapy, including high-dose methotrexate (MTX), cytarabine, and cyclophosphamide over a 6-month period. Because of the use of MTX, avoid folate supplementation. Initially children must be transferred to a facility in which they can be in the care of a pediatric oncologist; any patient who is neutropenic and who develops chills or fever must immediately be admitted to administer intravenous (IV) broad-spectrum antibiotics; the need for blood transfusions must also be evaluated. Phases of therapy: The treatment of childhood ALL, with the exception of mature B-cell ALL, commonly has several components: induction, consolidation, interim maintenance, delayed intensification, and maintenance. Prophylactic or therapeutic approach to sanctuary sites (CNS, testis) must also be considered. Duration of therapy: Whereas mature B-cell acute lymphoblastic leukemia (ALL) is treated with a 6-month to 8-month course of intensive therapy, achieving acceptable cure rates for patients with B-lineage and T-lineage ALL requires approximately 2–2.5 years of continuation therapy. Attempts