- Email: [email protected]
SP-057 RARE BLEEDING DISORDERS: UPDATE ON DIAGNOSIS AND MANAGEMENT, ROLE OF PRENATAL DIAGNOSIS AND PROPHYLAXIS
Speakers Presentations – Vth International Eurasian Hematology Congress / Leukemia Research 38 S1 (2014) S1–S65
to reduce this duration resulted in high relapse rates after therapy was stopped. Management of high-risk disease: The optimal treatment for patients with very high-risk (VHR) acute lymphoblastic leukemia (ALL) has not been determined; however, some centers recommend allogeneic hematopoietic stem cell transplantation (HSCT) soon after first remission (CR1) is achieved. For the subset of patients with BCR-ABL gene rearrangement, the addition of imatinib to intensified chemotherapy produced survival results equivalent to allogeneic HSCT. Management of Down syndrome with ALL: Patients with Down Syndrome and ALL (DS-ALL) constitute only 2–3% of all patients diagnosed with ALL, but are highly vulnerable to toxicity from the chemotherapy agents used as well as infection, so patients are usually treated on a modified ALL protocol with omission of high-dose methotrexate, leucovorin rescue after intrathecal methotrexate, and decreased exposure to dexamethasone and vincristine. Management of relapse: Relapse occurs in 20% of children with ALL, when blasts reappear after complete remission (CR) is achieved. The site of relapse in the vast majority of cases involves the bone marrow, but other sites include the CNS or testes. Patients at high risk for further relapse and poor survival are those with B-lineage ALL with early relapse in bone marrow that occurs within 36 months of initial diagnosis or within 6 months of completion of primary therapy (which may be combined with other sites, such as CNS) or all T-lineage ALL. Patients often respond to the same agents initially used for induction; the problem is in keeping them in remission. After reinduction, consolidation treatment might be HSCT. Hematopoietic stem cell transplantation (HSCT): HSCT has been used in very high risk patients in first remission (CR1) as well as in patients with ALL relapse at high risk for further relapse (eg, early BM relapse). A matched sibling donor (MSD) is preferred, but with advances in HSCT technique and supportive care, alternative donors (eg, matched unrelated donors) can also be used with equivalent survival outcomes if a MSD is not available. Molecular-targeted therapy: A drug targeted at the underlying molecular defect that is unique to certain leukemias can have potent and specific antileukemic activity while producing minimal toxicity to normal cells. The best example of molecular targeted therapy is imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, that is standard front-line treatment for Ph-positive chronic myeloid leukemia (CML). Combination regimens with imatinib and conventional chemotherapy have shown efficacy in Ph-positive acute lymphoblastic leukemia. The use of tyrosine kinase inhibitor or JAK2 inhibitor therapy for Ph-like ALL will be evaluated in future clinical trials. Cellular therapy: Although HSCT with its graft versus leukemia (GVL) effect is the most commonly used cellular therapy, several other interventions like donor leukocyte infusion (DLI), natural killer (NK) cell infusion, chimeric Ag receptor (CAR)-modified T-cells infusion are possible. Outcome: The 5-year event-free survival (EFS) varies considerably depending on risk category, from 95% (low risk) to 30–80% (very high risk), with infant leukemia having the worst outcomes: 20% for patients younger than 90 days. In low-income countries (LIC), therapeutic results for pediatric ALL have been less encouraging due to delayed diagnosis, abandonment of therapy, and death from toxicity due to suboptimal supportive care. Nevertheless, current 4-year event-free survival rates are 61% in India, and over 78% in Lebanon, demonstrating that pediatric ALL is curable in LIC. References [1] Kanwar VS, Pediatric Acute Lymphoblastic Leukemia Treatment & Management, Medscape Education, Chief Editor: Arceci RJ, Updated: Apr 25, 2014. [2] Childhood Acute Lymphoblastic Leukemia Treatment (PDQ® ), National Cancer Institute, Health Professionals Report, Last Modified: 05/02/2014. [3] Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. Mar 22 2008;371(9617):1030–43. [4] Campana D. Role of minimal residual disease monitoring in adult and pediatric acute lymphoblastic leukemia. Hematol Oncol Clin North Am. Oct 2009;23(5):1083–98, vii. [5] Ribera JM, Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am. Oct 2009;23(5):1033–42, vi. [6] Hunger SP, Lu X, Devidas M, et al. Improved Survival for Children and Adolescents With Acute Lymphoblastic Leukemia Between 1990 and 2005: A Report From the Children’s Oncology Group. J Clin Oncol. Mar 12 2012.
S23
[7] Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?. Blood. Aug 9 2012;120(6):1165–74. [8] Magrath I, Shanta V, Advani S, Adde M, Arya LS, Banavali S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected]. Eur J Cancer. Jul 2005;41(11):1570–83. [9] Yamaji K, Okamoto T, Yokota S, et al.: Minimal residual disease-based augmented therapy in childhood acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. Pediatr Blood Cancer 55 (7): 1287–95, 2010. [10] Marshall GM, Dalla Pozza L, Sutton R, et al.: High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation. Leukemia 27 (7): 1497–503, 2013. [11] Gaynon PS. Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol. Dec 2005;131(5):579–87. [12] Pulsipher MA, Peters C, Pui CH. High-risk pediatric acute lymphoblastic leukemia: to transplant or not to transplant?. Biol Blood Marrow Transplant. Jan 2011;17(1 Suppl):S137–48. [13] Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. Nov 1 2009;27(31):5175–81. [14] Biondi A, Schrappe M, De Lorenzo P, et al.: Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosomepositive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol 13 (9): 936–45, 2012. [15] Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol 27 (31): 5175–81, 2009. [16] Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. Jan 2 2014;123(1):70–7. [17] Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. May 2013;14(6):e205–17. [18] Campana D, Leung W. Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. Br J Haematol. Jul 2013;162(2):147–61. [19] Henze G, v Stackelberg A, Eckert C. ALL-REZ BFM-the consecutive trials for children with relapsed acute lymphoblastic leukemia. Klin Padiatr. May 2013;225 Suppl 1:S73–8. [20] Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term outcomes in survivors of childhood acute lymphoblastic leukemia. Hematol Oncol Clin North Am. Oct 2009;23(5):1065–82, vi-vii. [21] Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. Feb 10 2011;29(5):551–65. [22] Hunger SP, Raetz EA, Loh ML, et al.: Improving outcomes for highrisk ALL: translating new discoveries into clinical care. Pediatr Blood Cancer 56 (6): 984–93, 2011. [23] Teachey DT, Hunger SP. Predicting relapse risk in childhood acute lymphoblastic leukaemia. Br J Haematol. Sep 2013;162(5):606–20. SP-057 RARE BLEEDING DISORDERS: UPDATE ON DIAGNOSIS AND MANAGEMENT, ROLE OF PRENATAL DIAGNOSIS AND PROPHYLAXIS Roula Farah. Department of Pediatrics, Division of Hematology/Oncology, St George Hospital University Medical Center, Beirut, Lebanon Rare bleeding disorders include deficiencies in coagulation factors I, II, V, VII, X, XI and XIII in addition to Bernard Soulier syndrome and Glanzman Thrombasthenia. We will focus on Factor VII and Factor XIII deficiencies. Factor XIII deficiency is a rare bleeding disorder (1:2.000.000) transmitted with an autosomal recessive pattern, with a higher frequency in countries where consanguineous marriages are practiced. It is classified as Type I, II or III depending on which subunit (A or B) is deficient. Intracranial bleeding is
S24
Speakers Presentations – Vth International Eurasian Hematology Congress / Leukemia Research 38 S1 (2014) S1–S65
prevalent and poses a major threat to life. Due to the long half-life of factor XIII, and the fact that levels need only be raised by a small percent of average to control bleeding episodes, primary prophylaxis should be considered in severe FXIII deficiency because of the high risk of spontaneous inracranial hemorrhage (10/20 U/kg every 4–6 weeks). Over 15 causative mutations have been identified. Congenital deficiency of factor VII is also rare but is the most common autosomal recessive hemorrhagic disorder. The clinical phenotype varies from asymptomatic forms to lethal hemorrhagic diathesis characterized by central nervous system (CNS) and gastro-intestinal (GI) hemorrhages which tend to occur more commonly during the neonatal period. Severe phenotypes account for about 10–15% of the whole cohort of symptomatic FVII deficient patients. Some mutations were found to be consistently associated to the severe clinical phenotype, most commonly specific missense and invariant AG or GT splice site mutations. We will discuss a case series of several Lebanese offsprings of consanguineous marriages homozygous for the same F7:c.291+1G>C splice site mutation known to be associated with life-threatening bleeding phenotype. In our series, 5 children presented as a first symptom with GI bleeds (n=4) or CNS bleed (n=1) within the first two months of life (range Day 1 to Day 40 of life). Among them, three could not receive the assigned rFVIIa prophylactic regimen and CNS bleeds recurred in all of them leading either to death (n=2) or sequelae (n=1). Three children from affected families were diagnosed prenatally via amniocentesis analysis at 16 weeks of maternal gestation, and in homozygous patients prophylaxis with rFVIIa was started at the dose of 30 μg/kg 2–3 times a week right after birth with excellent outcome in terms of bleeding prevention. When continued, this regimen which was very well tolerated, was shown to avoid any life-threatening bleed allowing the patient to lead a normal life. Early diagnosis and, if possible, prenatal diagnosis is of paramount importance in these severe variants and prophylaxis should be considered the management of choice in this clinical setting, at least till gene therapy will be available. Therefore, for this life-threatening clinical setting, in order to avoid bleeding, prevent disability and decrease mortality we propose a strategy based on prenatal diagnosis and primary prophylaxis starting at birth. SP-058 THE FUTURE TREATMENT LANDSCAPE FOR HEMOPHILIA Prasad Mathew. GMA Hematology, BHC and Professor of Pediatrics, UNM Over the past few decades, we have seen enormous advances in our understanding of coagulation, and prevention and treatment of bleeding disorders has progressed at a dramatic pace. We have seen treatment progress from Fresh Frozen Plasma and cryoprecipitate to advanced plasma-derived and recombinant clotting factor concentrates. The development of FVIII and FIX concentrates that can stop or prevent bleeding episodes has reduced the associated morbidity, as well as improved the quality of life and normalized life expectancy persons with hemophilia. Regular, long-term prophylactic therapy with factor concentrates prevents recurrent hemarthroses and reduces or prevents the development of hemophilic arthropathy. This is now the standard of care for the management of children with hemophilia. Comprehensive hemophilia centers, the adoption of home therapy, and worldwide advocacy efforts are improving health and quality of life throughout the world. The broad adoption of recombinant therapy throughout the developed world has significantly increased the supply of clotting factor concentrates and helped advance aggressive therapeutic interventions such as prophylaxis. Despite several improvements since the first recombinant FVIII in the early 90s, significant unmet needs remain for hemophilia patients; these include: use of prophylaxis in adult patients, reduced dosing frequency for prophylaxis, reduction of inhibitor formation, heat stable formulation of products, non-invasive administration routes and cure. The development of gene therapy and more efficacious products with longer half-lives would provide significant therapeutic advances, which both simplify the patient’s life and ease the burden of treatment. Additional studies about the role of adult prophylaxis would also significantly improve the lives of young patients who are now surviving into adulthood. The WFH vision of “Treatment for All” includes not only access to treatment products, but also management by a team of healthcare specialists trained in bleeding disorders.
Long-acting biological therapeutics are an incremental advance toward overcoming some of these barriers. Strategies that are being applied to FVIII and FIX include modifications such as the addition of polyethylene glycol (PEG) polymers and polysialic acids, and bioengineered fusion proteins. Some of these therapies may open up alternative delivery routes such as subcutaneous administration. A recently published gene therapy trial in a small group of FIX patients has shown that a potential for a cure using gene therapy may very soon be achievable, Gene therapy trials in FVIII patients are still in the early development phases. Following the randomized joint outcome (JOS) study, which showed the benefits of prophylaxis in children, a randomized study about use of prophylaxis in adults (SPINART) has just been completed. In addition, an emerging pipeline of differentiated products to help the hemophilia community (e.g. BAY 94-9027) will soon be available from different manufacturers, as we move from replacement therapy to a comprehensive care era. All in all, persons with hemophilia are living today in exciting times where their future looks bright and a potential for a cure may be on the horizon. References [1] Skinner MW. Haemophilia: provision of factors and novel therapies: World Federation of Hemophilia goals and achievements. Br J Haematol 2011; 154: 704–14. [2] Skinner MW: Haemophilia care – past, present and future from a patient perspective Haemophilia 2012; 18: 3–5. [3] Pipe SW. The hope and reality of long acting products. THSNA meeting proceedings. Am. J. Hematol. 2012; 87:S33–S39. [4] Dolan G et al. Advance in hemophilia care: report of two symposia at the Hemophilia 2010 world congress. Adv Ther (2012) 29(Suppl.1): DOI 10.1007/s12325-012-0010-3. [5] Manco-Johnson MJ, et al. J Thromb Haemost. 2013;11:1119–1127 [published correction appears in J Thromb Haemost. 2014;12:119–122. [6] Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011 Dec 22;365(25):2357–65. [7] Mei B, et al. Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood. 2010; 116:270–279. [8] Ivens IA, Baumann A, McDonald T, Humphries T, Michaels LA, Mathew P. PEGylated Therapeutic Proteins for Hemophilia Treatment: A Review for Hemophilia Caregivers. Haemophilia 2013, 19: 11–20. SP-060 PNH: A MULTISYSTEMIC AND MULTIDISCIPLINARY DISEASE Fahri Sahin. Ege University School of Medicine, Izmir, Turkey PNH (Paroxysmal Nocturnal Hemoglobinuria), is a clonal disease of the stem cell that manifests with acquired, non-immune findings of intravascular hemolysis, bone marrow failure and thrombosis. As PNH is caused by the somatic mutation of the hematopoietic stem cell, it affects all 3 cell lines of the hematopoietic system. PNH is a rare disease. Because PNH is rare and its clinical features may easily be confused with that of other disorders, its real incidence is yet to be known. Although its name implies a benign disorder, a 5-year mortality rate of 35% suggests that the disease should in fact, be considered a malignant condition. In addition to its high rate of mortality, the disease also has a quite high morbidity rate. The clinical course of PNH largely based on this picture. For this reason, the presence of hemolysis, whether small or extensive, indicates that the underlying destruction is continuing even in patients with no clinical findings, and that it may lead to morbidity or mortality of the patient at a point in the future. Clinical findings caused by intravascular hemolysis are extremely variable and include: general findings pertaining to iron deficiency and anemia, muscular weakness, asthenia, fatigue, decline in quality of life, clinical findings that vary according to thrombosis and the location of thrombosis, renal failure, smooth muscle contractions and dysphagia due to NO depletion, abdominal pain, erectile dysfunction, bone marrow deficiency and clinical findings caused by cytopenia. Studies indicate that the mean time between the PNH diagnosis and the occurrence of a thromboembolic event is 2.1–2.3 years. The first item in the diagnostic algorithm of PNH is for the physician to consider the possibility of PNH. Presence or history of hemolysis, cytopenia or thrombosis should all be a sign of warning for the physician.
to reduce this duration resulted in high relapse rates after therapy was stopped. Management of high-risk disease: The optimal treatment for patients with very high-risk (VHR) acute lymphoblastic leukemia (ALL) has not been determined; however, some centers recommend allogeneic hematopoietic stem cell transplantation (HSCT) soon after first remission (CR1) is achieved. For the subset of patients with BCR-ABL gene rearrangement, the addition of imatinib to intensified chemotherapy produced survival results equivalent to allogeneic HSCT. Management of Down syndrome with ALL: Patients with Down Syndrome and ALL (DS-ALL) constitute only 2–3% of all patients diagnosed with ALL, but are highly vulnerable to toxicity from the chemotherapy agents used as well as infection, so patients are usually treated on a modified ALL protocol with omission of high-dose methotrexate, leucovorin rescue after intrathecal methotrexate, and decreased exposure to dexamethasone and vincristine. Management of relapse: Relapse occurs in 20% of children with ALL, when blasts reappear after complete remission (CR) is achieved. The site of relapse in the vast majority of cases involves the bone marrow, but other sites include the CNS or testes. Patients at high risk for further relapse and poor survival are those with B-lineage ALL with early relapse in bone marrow that occurs within 36 months of initial diagnosis or within 6 months of completion of primary therapy (which may be combined with other sites, such as CNS) or all T-lineage ALL. Patients often respond to the same agents initially used for induction; the problem is in keeping them in remission. After reinduction, consolidation treatment might be HSCT. Hematopoietic stem cell transplantation (HSCT): HSCT has been used in very high risk patients in first remission (CR1) as well as in patients with ALL relapse at high risk for further relapse (eg, early BM relapse). A matched sibling donor (MSD) is preferred, but with advances in HSCT technique and supportive care, alternative donors (eg, matched unrelated donors) can also be used with equivalent survival outcomes if a MSD is not available. Molecular-targeted therapy: A drug targeted at the underlying molecular defect that is unique to certain leukemias can have potent and specific antileukemic activity while producing minimal toxicity to normal cells. The best example of molecular targeted therapy is imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, that is standard front-line treatment for Ph-positive chronic myeloid leukemia (CML). Combination regimens with imatinib and conventional chemotherapy have shown efficacy in Ph-positive acute lymphoblastic leukemia. The use of tyrosine kinase inhibitor or JAK2 inhibitor therapy for Ph-like ALL will be evaluated in future clinical trials. Cellular therapy: Although HSCT with its graft versus leukemia (GVL) effect is the most commonly used cellular therapy, several other interventions like donor leukocyte infusion (DLI), natural killer (NK) cell infusion, chimeric Ag receptor (CAR)-modified T-cells infusion are possible. Outcome: The 5-year event-free survival (EFS) varies considerably depending on risk category, from 95% (low risk) to 30–80% (very high risk), with infant leukemia having the worst outcomes: 20% for patients younger than 90 days. In low-income countries (LIC), therapeutic results for pediatric ALL have been less encouraging due to delayed diagnosis, abandonment of therapy, and death from toxicity due to suboptimal supportive care. Nevertheless, current 4-year event-free survival rates are 61% in India, and over 78% in Lebanon, demonstrating that pediatric ALL is curable in LIC. References [1] Kanwar VS, Pediatric Acute Lymphoblastic Leukemia Treatment & Management, Medscape Education, Chief Editor: Arceci RJ, Updated: Apr 25, 2014. [2] Childhood Acute Lymphoblastic Leukemia Treatment (PDQ® ), National Cancer Institute, Health Professionals Report, Last Modified: 05/02/2014. [3] Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet. Mar 22 2008;371(9617):1030–43. [4] Campana D. Role of minimal residual disease monitoring in adult and pediatric acute lymphoblastic leukemia. Hematol Oncol Clin North Am. Oct 2009;23(5):1083–98, vii. [5] Ribera JM, Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am. Oct 2009;23(5):1033–42, vi. [6] Hunger SP, Lu X, Devidas M, et al. Improved Survival for Children and Adolescents With Acute Lymphoblastic Leukemia Between 1990 and 2005: A Report From the Children’s Oncology Group. J Clin Oncol. Mar 12 2012.
S23
[7] Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?. Blood. Aug 9 2012;120(6):1165–74. [8] Magrath I, Shanta V, Advani S, Adde M, Arya LS, Banavali S, et al. Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected]. Eur J Cancer. Jul 2005;41(11):1570–83. [9] Yamaji K, Okamoto T, Yokota S, et al.: Minimal residual disease-based augmented therapy in childhood acute lymphoblastic leukemia: a report from the Japanese Childhood Cancer and Leukemia Study Group. Pediatr Blood Cancer 55 (7): 1287–95, 2010. [10] Marshall GM, Dalla Pozza L, Sutton R, et al.: High-risk childhood acute lymphoblastic leukemia in first remission treated with novel intensive chemotherapy and allogeneic transplantation. Leukemia 27 (7): 1497–503, 2013. [11] Gaynon PS. Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol. Dec 2005;131(5):579–87. [12] Pulsipher MA, Peters C, Pui CH. High-risk pediatric acute lymphoblastic leukemia: to transplant or not to transplant?. Biol Blood Marrow Transplant. Jan 2011;17(1 Suppl):S137–48. [13] Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. Nov 1 2009;27(31):5175–81. [14] Biondi A, Schrappe M, De Lorenzo P, et al.: Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosomepositive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol 13 (9): 936–45, 2012. [15] Schultz KR, Bowman WP, Aledo A, et al.: Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol 27 (31): 5175–81, 2009. [16] Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood. Jan 2 2014;123(1):70–7. [17] Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. May 2013;14(6):e205–17. [18] Campana D, Leung W. Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. Br J Haematol. Jul 2013;162(2):147–61. [19] Henze G, v Stackelberg A, Eckert C. ALL-REZ BFM-the consecutive trials for children with relapsed acute lymphoblastic leukemia. Klin Padiatr. May 2013;225 Suppl 1:S73–8. [20] Nathan PC, Wasilewski-Masker K, Janzen LA. Long-term outcomes in survivors of childhood acute lymphoblastic leukemia. Hematol Oncol Clin North Am. Oct 2009;23(5):1065–82, vi-vii. [21] Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. Feb 10 2011;29(5):551–65. [22] Hunger SP, Raetz EA, Loh ML, et al.: Improving outcomes for highrisk ALL: translating new discoveries into clinical care. Pediatr Blood Cancer 56 (6): 984–93, 2011. [23] Teachey DT, Hunger SP. Predicting relapse risk in childhood acute lymphoblastic leukaemia. Br J Haematol. Sep 2013;162(5):606–20. SP-057 RARE BLEEDING DISORDERS: UPDATE ON DIAGNOSIS AND MANAGEMENT, ROLE OF PRENATAL DIAGNOSIS AND PROPHYLAXIS Roula Farah. Department of Pediatrics, Division of Hematology/Oncology, St George Hospital University Medical Center, Beirut, Lebanon Rare bleeding disorders include deficiencies in coagulation factors I, II, V, VII, X, XI and XIII in addition to Bernard Soulier syndrome and Glanzman Thrombasthenia. We will focus on Factor VII and Factor XIII deficiencies. Factor XIII deficiency is a rare bleeding disorder (1:2.000.000) transmitted with an autosomal recessive pattern, with a higher frequency in countries where consanguineous marriages are practiced. It is classified as Type I, II or III depending on which subunit (A or B) is deficient. Intracranial bleeding is
S24
Speakers Presentations – Vth International Eurasian Hematology Congress / Leukemia Research 38 S1 (2014) S1–S65
prevalent and poses a major threat to life. Due to the long half-life of factor XIII, and the fact that levels need only be raised by a small percent of average to control bleeding episodes, primary prophylaxis should be considered in severe FXIII deficiency because of the high risk of spontaneous inracranial hemorrhage (10/20 U/kg every 4–6 weeks). Over 15 causative mutations have been identified. Congenital deficiency of factor VII is also rare but is the most common autosomal recessive hemorrhagic disorder. The clinical phenotype varies from asymptomatic forms to lethal hemorrhagic diathesis characterized by central nervous system (CNS) and gastro-intestinal (GI) hemorrhages which tend to occur more commonly during the neonatal period. Severe phenotypes account for about 10–15% of the whole cohort of symptomatic FVII deficient patients. Some mutations were found to be consistently associated to the severe clinical phenotype, most commonly specific missense and invariant AG or GT splice site mutations. We will discuss a case series of several Lebanese offsprings of consanguineous marriages homozygous for the same F7:c.291+1G>C splice site mutation known to be associated with life-threatening bleeding phenotype. In our series, 5 children presented as a first symptom with GI bleeds (n=4) or CNS bleed (n=1) within the first two months of life (range Day 1 to Day 40 of life). Among them, three could not receive the assigned rFVIIa prophylactic regimen and CNS bleeds recurred in all of them leading either to death (n=2) or sequelae (n=1). Three children from affected families were diagnosed prenatally via amniocentesis analysis at 16 weeks of maternal gestation, and in homozygous patients prophylaxis with rFVIIa was started at the dose of 30 μg/kg 2–3 times a week right after birth with excellent outcome in terms of bleeding prevention. When continued, this regimen which was very well tolerated, was shown to avoid any life-threatening bleed allowing the patient to lead a normal life. Early diagnosis and, if possible, prenatal diagnosis is of paramount importance in these severe variants and prophylaxis should be considered the management of choice in this clinical setting, at least till gene therapy will be available. Therefore, for this life-threatening clinical setting, in order to avoid bleeding, prevent disability and decrease mortality we propose a strategy based on prenatal diagnosis and primary prophylaxis starting at birth. SP-058 THE FUTURE TREATMENT LANDSCAPE FOR HEMOPHILIA Prasad Mathew. GMA Hematology, BHC and Professor of Pediatrics, UNM Over the past few decades, we have seen enormous advances in our understanding of coagulation, and prevention and treatment of bleeding disorders has progressed at a dramatic pace. We have seen treatment progress from Fresh Frozen Plasma and cryoprecipitate to advanced plasma-derived and recombinant clotting factor concentrates. The development of FVIII and FIX concentrates that can stop or prevent bleeding episodes has reduced the associated morbidity, as well as improved the quality of life and normalized life expectancy persons with hemophilia. Regular, long-term prophylactic therapy with factor concentrates prevents recurrent hemarthroses and reduces or prevents the development of hemophilic arthropathy. This is now the standard of care for the management of children with hemophilia. Comprehensive hemophilia centers, the adoption of home therapy, and worldwide advocacy efforts are improving health and quality of life throughout the world. The broad adoption of recombinant therapy throughout the developed world has significantly increased the supply of clotting factor concentrates and helped advance aggressive therapeutic interventions such as prophylaxis. Despite several improvements since the first recombinant FVIII in the early 90s, significant unmet needs remain for hemophilia patients; these include: use of prophylaxis in adult patients, reduced dosing frequency for prophylaxis, reduction of inhibitor formation, heat stable formulation of products, non-invasive administration routes and cure. The development of gene therapy and more efficacious products with longer half-lives would provide significant therapeutic advances, which both simplify the patient’s life and ease the burden of treatment. Additional studies about the role of adult prophylaxis would also significantly improve the lives of young patients who are now surviving into adulthood. The WFH vision of “Treatment for All” includes not only access to treatment products, but also management by a team of healthcare specialists trained in bleeding disorders.
Long-acting biological therapeutics are an incremental advance toward overcoming some of these barriers. Strategies that are being applied to FVIII and FIX include modifications such as the addition of polyethylene glycol (PEG) polymers and polysialic acids, and bioengineered fusion proteins. Some of these therapies may open up alternative delivery routes such as subcutaneous administration. A recently published gene therapy trial in a small group of FIX patients has shown that a potential for a cure using gene therapy may very soon be achievable, Gene therapy trials in FVIII patients are still in the early development phases. Following the randomized joint outcome (JOS) study, which showed the benefits of prophylaxis in children, a randomized study about use of prophylaxis in adults (SPINART) has just been completed. In addition, an emerging pipeline of differentiated products to help the hemophilia community (e.g. BAY 94-9027) will soon be available from different manufacturers, as we move from replacement therapy to a comprehensive care era. All in all, persons with hemophilia are living today in exciting times where their future looks bright and a potential for a cure may be on the horizon. References [1] Skinner MW. Haemophilia: provision of factors and novel therapies: World Federation of Hemophilia goals and achievements. Br J Haematol 2011; 154: 704–14. [2] Skinner MW: Haemophilia care – past, present and future from a patient perspective Haemophilia 2012; 18: 3–5. [3] Pipe SW. The hope and reality of long acting products. THSNA meeting proceedings. Am. J. Hematol. 2012; 87:S33–S39. [4] Dolan G et al. Advance in hemophilia care: report of two symposia at the Hemophilia 2010 world congress. Adv Ther (2012) 29(Suppl.1): DOI 10.1007/s12325-012-0010-3. [5] Manco-Johnson MJ, et al. J Thromb Haemost. 2013;11:1119–1127 [published correction appears in J Thromb Haemost. 2014;12:119–122. [6] Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011 Dec 22;365(25):2357–65. [7] Mei B, et al. Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood. 2010; 116:270–279. [8] Ivens IA, Baumann A, McDonald T, Humphries T, Michaels LA, Mathew P. PEGylated Therapeutic Proteins for Hemophilia Treatment: A Review for Hemophilia Caregivers. Haemophilia 2013, 19: 11–20. SP-060 PNH: A MULTISYSTEMIC AND MULTIDISCIPLINARY DISEASE Fahri Sahin. Ege University School of Medicine, Izmir, Turkey PNH (Paroxysmal Nocturnal Hemoglobinuria), is a clonal disease of the stem cell that manifests with acquired, non-immune findings of intravascular hemolysis, bone marrow failure and thrombosis. As PNH is caused by the somatic mutation of the hematopoietic stem cell, it affects all 3 cell lines of the hematopoietic system. PNH is a rare disease. Because PNH is rare and its clinical features may easily be confused with that of other disorders, its real incidence is yet to be known. Although its name implies a benign disorder, a 5-year mortality rate of 35% suggests that the disease should in fact, be considered a malignant condition. In addition to its high rate of mortality, the disease also has a quite high morbidity rate. The clinical course of PNH largely based on this picture. For this reason, the presence of hemolysis, whether small or extensive, indicates that the underlying destruction is continuing even in patients with no clinical findings, and that it may lead to morbidity or mortality of the patient at a point in the future. Clinical findings caused by intravascular hemolysis are extremely variable and include: general findings pertaining to iron deficiency and anemia, muscular weakness, asthenia, fatigue, decline in quality of life, clinical findings that vary according to thrombosis and the location of thrombosis, renal failure, smooth muscle contractions and dysphagia due to NO depletion, abdominal pain, erectile dysfunction, bone marrow deficiency and clinical findings caused by cytopenia. Studies indicate that the mean time between the PNH diagnosis and the occurrence of a thromboembolic event is 2.1–2.3 years. The first item in the diagnostic algorithm of PNH is for the physician to consider the possibility of PNH. Presence or history of hemolysis, cytopenia or thrombosis should all be a sign of warning for the physician.