ALBERT

Description: Background Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine is the preferred treatment for patients with severe acquired aplastic anemia (SAA) ineligible for hematopoietic stem cell transplantation. In 2007, horse ATG (hATG) was removed from most markets outside the US limiting patients to the use of rabbit ATG (rATG). Response rates for hATG range from 60-70%, with overall survival (OS) rates of 60-90% (Korean J Intern Med. 2014;29:713-726). Although, many studies have shown no differences in efficacy between ATG types, others have shown rATG to be inferior to hATG. A prospective study by the US National Institutes of Health (NIH) showed a 6-month RR of 37% for rATG compared to 68% for hATG (N Engl J Med. 2011;365:430-438). The discrepancies in efficacy could be due to many factors including dose and ethnicity. We aimed to analyze hematologic response, survival, and safety of rATG (Thymoglobulin®) as first-line therapy of SAA and very SAA (vSAA) in Asian patients of all ages. Methods We retrospectively reviewed the medical records of 97 consecutive patients who received rATG in combination with cyclosporine and/or a corticosteroid as first-line treatment of SAA or vSAA at participating centers in Malaysia, Taiwan, Hong Kong, and Thailand between 2006 and 2012. The primary endpoint was overall RR (ORR) (complete response [CR] plus partial response [PR]) at 6 and 12 months for patients receiving rATG within the recommended dose range (2.5-3.75 mg/kg/day). Response was evaluated using British Guidelines (Br J Haematol. 2009;147:43-70). Secondary endpoints included ORR in patients receiving any dose of rATG, 2-year OS, OS in responders vs non-responders, relapse rate, and safety. Response and survival with 95% confidence intervals (CI) were estimated using the Kaplan-Meier method. Results Patient median age was 31 years (range 2-81 years); 51% (n= 49) were male and 49% (n=48) female. Eighty-seven percent (n=84) were diagnosed with SAA and 13% (n=13) with vSAA. Twelve patients were excluded from the response evaluation due to the following: lack of post-baseline response data, n=6; second-line rATG within 3 months of first-line treatment, n=3; did not meet criteria for SAA, n=3. Of the 85 patients evaluable for response, only 73% (n=62) received rATG within the recommended dose range; 20% (n=17) received 〈 2.5 mg/kg/day and 7% (n=6) received 〉 3.5 mg/kg/day. For patients who received rATG within the recommended dose range, 6- and 12-month ORR were 17.4% (95% CI, 9.8-30.0) and 63.6% (95% CI, 49.4-77.7), respectively. For patients who received any dose of rATG, 6- and 12-month ORR were 24.3% (95% CI, 16.2-35.4) and 68.6% (95% CI, 56.9-80.1), respectively. The 2-year OS rate was 86.3% (95% CI, 77.0-92.0). For patients with a response to treatment (n=46), the 2-year OS was 97.7% (95% CI, 84.6-99.7) compared to 78.9% (95% CI, 59.9-89.6) for patients with no response (n=39), P =.006. The 2-year rate of relapse rate was 6.3% (95% CI 2.1-18.2). The most common serious adverse events (≥ 5%) that occurred within 30 days of last treatment were febrile neutropenia (28%), sepsis (12%), pyrexia (5%), and pneumonia (5%). Grade 4 infusion-related reactions occurred in only 1 (1%) patient. Conclusions Although the 6-month ORR for rATG was low compared to hATG in the NIH study, the 12-month ORR and 2-year OS were comparable to historical results obtained with hATG, suggesting that more time may be needed to achieve maximal response with rATG. Our results show that rATG is an effective form of IST in the Asian population with over 60% of patients achieving a CR or PR at 12 months and an overall survival rate of 86.3% at 2 years. Disclosures Wong: GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Merck Sharp & Dohme: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Rojnuckarin:Sanofi: Research Funding. Chang:Novartis: Honoraria.

Description: Background: Primary prophylaxis in severe hemophilia patients has been shown to improve patient outcomes and quality of life by decreasing the number of joint bleeds, lowering the subsequent risk of developing hemophilic arthropathy (Blanchette et al.Haemophilia 2010 (Suppl. 5); Ljung R. Blood Rev 2009) and by reducing the incidence of other bleeds including intracranial hemorrhages. Currently licensed factor concentrates have a relatively short half-life, and require frequent infusions for effectiveness. The intensity of this prophylaxis is difficult for most patients (particularly young children) and contributes to reduced compliance and quality of life. Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) with a prolonged half-life (up to 111 h in adolescent and adult patients) as compared to currently available standard plasma-derived and rFIX products (18-19 h). N9-GP is therefore expected to be effective in preventing bleeds when given less frequently than currently available FIX products. It is hoped that this will improve patient compliance, clinical outcomes and quality of life. Until now only adolescents and adults have received N9-GP. Given this experience a trial (paradigm™5) was undertaken to evaluate the safety and effectiveness of N9-GP in children ≤12 years of age. Aims: The primary objective of this trial was to evaluate immunogenicity of N9-GP in previously treated pediatric (≤12 years of age) hemophilia B patients (FIX≤2%) with no history of inhibitors and at least 50 exposures days (ED) to other FIX products. Key secondary objectives were to evaluate efficacy, pharmacokinetic (PK) properties and general safety of N9-GP in this group of patients. Methods: paradigm™5 was a multicenter, single arm, open label trial investigating the safety, efficacy and PK of N9-GP in this group of patients. A total of 20 children allocated to two age cohorts ≤6 years and 7-12 years (minimum 10 patients per age cohort) were required to be dosed with a prophylactic regimen of 40 U/kg N9-GP once weekly for at least 50 exposures (as per EMA guidelines), with treatment of breakthrough bleeds with 40 U/kg N9-GP (80 U/kg N9-GP for severe bleeding episodes). Results: 25 patients were enrolled and treated in the trial: 12 in the younger (0-6 years) and 13 in the older (7-12 years) age group. No patients developed inhibitors during the trial, and no safety concerns were observed in standard safety parameters and clinical evaluation. Among patients on prophylaxis prior to inclusion (N=22), the median (range) number of bleeds in the 12 months prior to inclusion was 2.0 (0–9). The median (range) annualized bleeding rate during the trial was 1.0 (0.0–6.5); 5 of the 12 younger patients (41.7%) and 10 of the 13 older patients (76.9%) reported bleeds. 72.7% of these bleeds in the younger cohort were reported as traumatic vs. 54.8% in the older age cohort. All bleeding episodes were treated with 40 U/kg N9-GP: 92.9% were successfully treated; 85.7% were treated with a single injection. PK analysis showed 1) an incremental recovery (IR) of N9-GP of 0.016 (U/mL)/(U/kg) with no difference between the 2 age groups; 2) a geometric mean single-dose half-life of 69.6 (0-6 years) and 76.3 hours (7-12 years) and 3) a faster clearance in the younger vs. older age group (0.758 and 0.650 mL/h/kg, respectively). Geometric mean FIX trough levels after the first dose of N9-GP was 0.084 U/ml in the 0-6 year age group and 0.109 U/ml in the 7-12 year age group. Estimated mean steady state trough levels (95% CI) for the younger age group was 0.154 U/ml (0.127; 0.186), as compared to 0.190 U/ml (0.159; 0.228) in the older age group. Steady state trough levels were reached after approximately 4 weeks of treatment. Conclusion: In this trial, N9-GP appeared to have a safe and well-tolerated profile. Prophylactic protection and treatment of bleeds with N9-GP in previously treated pediatric hemophilia B patients was confirmed. The PK profile of N9-GP confirmed an extended half-life and high trough levels with 40 U/kg once weekly injections in the pediatric population. As with other FIX products younger patients show lower IR, shorter half-lives and higher clearance than what is observed in adolescents and adults. Disclosures Carcao: Baxter, Bayer, Biogen, Novo Nordisk, Pfizer, CSL Behring, Octapharma: Honoraria, Research Funding, Speakers Bureau. Off Label Use: N9-GP is not yet FDA approved. Information provided will discuss phase 3 pediatric clinical trial data.. Zak:Novo Nordisk A/S: Employment. Hanabusa:Baxter Healthcare, Novo Nordisk, Bayer, Pfizer, Biogen Idec and KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Persson:Novo Nordisk A/S: Employment. Rangarajan:Baxter, Biotest, Grifols, Pfizer: Honoraria, Research Funding, Speakers Bureau. Santagostino:Pfizer, Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, Biotest: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Introduction: β-thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect characterized by ineffective erythropoiesis and impaired RBC maturation. Luspatercept is a first-in-class erythroid maturation agent under development to treat patients with β-thalassemia. Luspatercept binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. ClinicalTrials.gov identifier: NCT02604433. Methods: Eligible patients were aged ≥ 18 years; had β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed); and required regular transfusions of 6-20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥ 35 days during that time. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for ≥ 48 weeks. Patients in both treatment arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level. The primary endpoint was a ≥ 33% reduction in transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13-24, when compared with a 12-week baseline period. Key secondary endpoints included: ≥ 33% reduction in RBC transfusion burden at weeks 37-48, ≥ 50% reduction in transfusion burden at weeks 13-24, ≥ 50% reduction in transfusion burden at weeks 37-48, and mean change in transfusion burden at weeks 13-24. Achievement of ≥ 33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated. Results: † A total of 336 patients were randomized, of whom 332 were treated. Median age was 30 years (range 18-66) and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment. 58% of patients in each arm had undergone splenectomy. B0/B0 genotype (classification according to the HbVar database) was observed in 68 of 224 (30.4%) and 35 of 112 (31.3%) patients in the luspatercept and placebo arms, respectively. 48 of 224 (21.4%) patients in the luspatercept arm achieved the primary endpoint versus 5 of 112 (4.5%) patients receiving placebo (odds ratio 5.79, P 〈 0.0001). 44 of 224 (19.6%) patients receiving luspatercept achieved a ≥ 33% reduction in RBC transfusion burden at weeks 37-48 compared with 4 of 112 (3.6%) patients receiving placebo (P 〈 0.0001). Of 224 patients receiving luspatercept, 17 (7.6%) and 23 (10.3%) achieved a ≥ 50% reduction in RBC transfusion burden at weeks 13-24 and 37-48, respectively, compared with 2 (1.8%) and 1 of 112 (0.9%) patients receiving placebo (P = 0.0303 and P = 0.0017, respectively). The difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P 〈 0.0001). 158 of 224 (70.5%) patients receiving luspatercept achieved a ≥ 33% RBC transfusion reduction over any consecutive 12 weeks compared with 33 of 112 (29.5%) patients receiving placebo (P 〈 0.0001); statistically significant differences were also noted for all other transfusion burden reduction endpoints. Adverse events (AEs) observed in the study were generally consistent with previously reported phase 2 data. Treatment-emergent AEs leading to dose delay or dose reduction were similar between treatment arms. No patient deaths were reported for those treated with luspatercept. Conclusions: Treatment with luspatercept resulted in significant reductions in RBC transfusion burden in adults with transfusion-dependent β-thalassemia. Luspatercept was generally well tolerated in this patient population. † As of May 11, 2018, cutoff date. Disclosures Cappellini: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Taher:Protagonist Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy; La Jolla Pharmaceutical: Research Funding; Celgene Corp.: Research Funding. Georgiev:Alnylam: Consultancy. Coates:Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Forni:Novartis: Research Funding; Roche: Research Funding; Celgene: Research Funding. Perrotta:Acceleron Pharma: Research Funding; Novartis: Research Funding. Lal:Celgene Corporation: Research Funding; Bluebird Bio: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Insight Magnetics: Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding. Kattamis:ApoPharma: Honoraria; Vifor Pharma: Consultancy; CELGENE: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Vlachaki:Novartis: Honoraria. Origa:Cerus Corporation: Research Funding; Bluebird Bio: Consultancy; Novartis: Honoraria; Apopharma: Honoraria. Aydinok:TERUMO: Research Funding; Protagonist: Other: SSC; CRISPR Tech: Other: DMC; Cerus: Honoraria, Research Funding; La Jolla Pharmaceuticals: Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding. Ho:Takeda: Honoraria, Other: travel to meeting; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Other: Travel to meeting. Chew:Celgene: Research Funding. Tantiworawit:Celgene: Honoraria, Research Funding, Speakers Bureau. Shah:Novartis: Honoraria, Speakers Bureau; Sobi/Apotex: Honoraria; Celgene Corp: Other: Steering committee; Roche: Other: Advisory board meeting. Neufeld:Celgene Corp.: Consultancy, Other: Steering committee; Acceleron Pharma: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Shetty:Celgene: Employment, Equity Ownership. Zou:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zinger:Celgene Corporation: Employment. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Erythec: Research Funding; Novartis: Research Funding. Porter:Cerus: Honoraria; Agios: Honoraria; Novartis: Consultancy. Piga:La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acceleron: Research Funding.

Description: Introduction: Previous studies have examined the total healthcare resource utilization (HCRU) of patients with beta-thalassemia in relation to the general population. However, limited studies have examined the impact of red blood cell transfusion (RBCT) burden on broad aspects of HCRU beyond transfusion costs among patients with beta-thalassemia. Methods: Patients with beta-thalassemia in Taiwan's National Health Insurance Research Database (NHIRD) in 2016 were identified (International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] of D56.1). The index date was the first medical claim in the database after 2001. Identified patients were followed from the index date until the end of the study period (December 31, 2016). During the follow-up period, RBCT units and HCRU (all-cause and thalassemia-related) were measured. Thalassemia-related HCRU was defined as any HCRU claim accompanied by a thalassemia or beta-thalassemia diagnosis code. To control for the different lengths of follow-up between patients, both RBCT units and HCRU were reported as the average per 12 weeks over the entire follow-up period. Patients were categorized into 4 cohorts based on the average number of RBCT units received per 12 weeks during follow-up: 0 RBCT units; 〉 0 to 〈 6 RBCT units; ≥ 6 to 〈 12 RBCT units; or ≥ 12 RBCT units. HCRU outcomes of interest were hospital admissions, hospitalized days, outpatient visits, and emergency room (ER) visits. Descriptive statistics were computed to describe HCRU observed in each cohort. Results: A total of 2,984 patients with beta-thalassemia were included in the analysis, with a mean follow-up of 6.87 years. Mean age at index was 37.8 (standard deviation 23.7) years, and 1,903 (63.8%) patients were female. A total of 1,616 (54.2%) patients did not receive RBCT units during the follow-up period. Of the remaining 1,368 patients, 1,112 (81.3%) received 〉 0 to 〈 6 RBCT units, 112 (8.2%) received ≥ 6 to 〈 12 RBCT units, and 144 (10.5%) received ≥ 12 RBCT units per 12 weeks during follow-up. Mean all-cause and thalassemia-related HCRU was higher for transfused patients than for non-transfused patients across all HCRU categories. Thalassemia-related hospital admissions, hospitalized days, and outpatient days all increased as the transfusion burden increased. Patients in the cohort with the highest average transfusion burden (≥ 12 RBCT units per 12 weeks) had numerically greater mean thalassemia-related hospital admissions (0.5; standard error [SE] = 0.04), hospitalized days (2.5; SE = 0.21), and outpatient visits (4.9; SE = 0.41) than the other cohorts (Figure). Conclusions: Patients with beta-thalassemia and higher average transfusion burden during the follow-up period had additional HCRU compared with patients who required fewer RBCT units. These data may support physician and payer understanding of the downstream economic impact of RBCT burden in beta-thalassemia. Disclosures Tang: GSK: Consultancy; Roche: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Furnback:Sanofi: Consultancy; Regeneron: Consultancy; Celgene Corporation: Consultancy; Abbott: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Eli Lilly: Consultancy; Janssen: Consultancy; Johnson & Johnson: Consultancy; Gilead: Consultancy; Novocure: Consultancy; Progentec Diagnostics: Consultancy; Becton Dickinson: Consultancy; AstraZeneca: Consultancy; Bristol-Myers Squibb: Consultancy. Wang:Gilead Sciences: Consultancy, Equity Ownership; Celgene Corporation: Consultancy, Equity Ownership; Regeneron Pharmaceuticals: Consultancy, Equity Ownership; Novocure: Consultancy; Pfizer: Consultancy; Eli Lilly: Consultancy; Johnson & Johnson: Consultancy; Astellas: Consultancy; Amgen, Vertex Pharma, Illumina, Biogen, Alexion Pharma, Incyte, Biomarin Pharma, Seattle Genetics, Sarepta Therapeutics, Array Biopharma, Ionis Pharma, Sage Therapeutics, Mylan NV, Neurocrine Biosciences, Bio Techne Corp, Jazz Pharma, Alnylam Pharma, Blue: Equity Ownership. Tang:Asclepius Analytics: Employment. Huang:Celgene Corporation: Employment. Tang:Celgene Corporation: Employment, Equity Ownership. Musallam:Celgene Corporation: Consultancy.

Description: Abstract 3018 Background and Purposes Epstein-Barr virus (EBV)-associated PTLD is a life-threatening complication following hematopoietic stem cell transplantation (HSCT). Independent risk factors include use of ATG, acute GVHD, CMV antigenemia, T-depleted graft, and unrelated donor in our previous study. Quantitative real-time polymerase chain reaction (Q-PCR) was developed for early detection and intervention of EBV reactivation to prevent PTLD-related mortality. Patients and Methods Between Apr 2004 and Oct 2010, EBV viral load in plasma was monitored by Q-PCR in 222 HSCT patients (total 2945 samples) in NTUH. EBV reactivation was defined as 〉 500 copies/mL in two consecutive assays or 〉 10-fold elevation than baseline level. Results EBV reactivation occurred in 50 (22%) patients. The cumulated incidence of EBV reactivation was 28% at 1-year and 32% at 2-year. Median time to EBV reactivation was 40 days (ranges, 26–406) after SCT and median peak EBV-viral load, 10888 copies/ml (ranges, 948–3×107). The risk of EBV reactivation was significantly higher in patients receiving ATG (52% vs. 13%, p〈 0.001), use of TBI (58% vs. 26%, p

Description: Introduction Patients with non-transfusion-dependent thalassemia experience a wide array of clinical complications despite their independence from frequent, regular red blood cell transfusions. They have the higher incidence of osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, cholelithiasis, thromboembolic disease, pulmonary hypertension, silent cerebral ischemia, and leg ulcers. Thalassemia is highly prevalent in Taiwan and Hb H disease is predominant. But limited data are available about clinical features and morbidities. Here, we studied clinical features and morbidities in Taiwanese patients with Hb H disease. Methods & Results We collected 90 patients with Hb H disease in three hospitals since 2014 Nov till 2016 July. Male to female were 43/59. The mean age was 33.1 years ( from 0.5 to 92.3 years). Two cases died of pulmonary hypertension and old age at 31 years old and 87 years old. Alfa-globin gene genotype studies were done in 44 cases. The (- -(SEA)) type of α(0)-thalassemia mutation was detected in all patients. Twenty- four (57.1%) cases were deletional (α(3.7)/ α(4.2)/unknown 19/4/1) and 20 (42.9%) were nondeletional (CS/RS 18/2) type. The mean of Hemoglobin (Hb) and serum ferritin level were 8.7 g/dL and 730 ng/mL. We also revealed the positive correlation between age and serum ferritin level. The liver iron concentration (LIC) were 6.694 mg Fe/g dw (n=35). The Hb, ferritin and LIC level were not different between deletional and non- deletional groups. They received the transfusion management : 1 with regular transfusion ≦ 6 weeks interval, 5 with irregular transfusion ≧ 6 weeks interval, 27 with occasional transfusion and 57 without transfusion. Fifteen cases received splenectomy. There were significantly higher prevalence for transfusion frequency and splenectomy in non-deletional group. The prevalence of morbidities were 16/79 for cholelithiasis, 12/90 for thromboembolic event, 4/90 for heart failure symptoms ( 2 for pulmonary hypertension), 5/90 for arrhythmia, 3/90 for bone fracture, 5/20 for osteoporosis and 0 for renal stone. There were non-significantly higher prevalence for morbidities in non-deletional group. Discussion & Conclusion The study provides the clinical features and the prevalence of morbidities in Hb H disease in Taiwan. Surprisingly, the prevalence of thromboembolic event and pulmonary hypertension are overlooked in our routine Hb H disease care. We need to schedule close and careful clinical follow up of Hb H patients as they get older, they get some morbidities or they are non-deletional genotype. Disclosures No relevant conflicts of interest to declare.

Description: In adaptation of risk-directed combined chemotherapies, the initial remission rate in treatment of childhood acute lymphoblastic leukemia (ALL) has exceeded 95%. Hematological relapse during maintenance therapy, in which methotrexate (MTX) and thiopurine are applied, is the major cause of treatment failure. A retrospective study was performed to evaluate the role of pharmacogenomic effects in the treatment of children with ALL in the southern Chinese population. A total of 105 Taiwanese children with ALL, who received combined chemotherapy of different intensities based on risk-directed Taiwan Pediatric Oncology Group (TPOG)-ALL-93 protocols between Oct. 1993 to Dec. 2001, were recorded in long-term follow-up (6.5 to 13.7 years) for events (hematological relapse or death) occurrence (Figure 1). Seventeen genetic polymorphisms in 13 pharmacogenomic targets that implicated in MTX/thiopurine metabolism were analyzed by PCR-based restriction length polymorphism (RFLP) or sequence-specific oligonucleotide (SSO) probe hybridization. Pharmacogenomic polymorphisms were correlated with long-term event-free survival (EFS) of patients, with confounding effects adjusted by multivariate regression. Homozygosity of the 2677–3435 G-C allele in the multi-drug resistance gene (MDR-1, ABCB1) was highly associated with a significant reduction in long-term EFS in those patients treated with the standard risk protocol (TPOG-ALL-93-SR) (Figure 2). In the 36 patients receiving TPOG-ALL-93-SR treatment protocol, 6 out of 12 (50%) subjects carried homozygotic MDR1 2677–3435 G-C/G-C genotype suffered hematological relapse in 2 years, compared to 21 of 24 (88%) the non-homozygotic subjects remained event-free after 5 years (hazard ratio: 6.8, p=0.01). Among patients treated with the a high risk protocol (TPOG-ALL-93-HR) due to the presence of myeloid markers on the leukemic cells or manifested central nervous system leukemia, the thymidylate synthase (TYMS) enhancer 28-bp repeats 3R3R, and the glutathione-S-transferase M1 (GSTM1) null genotypes were associated with inferior clinical outcomes (p=0.029 and 0.058, respectively). Moreover, for patients with T-cell ALL that received the very high risk protocol (TPOG-ALL-97-VHR), the methionine synthase reductase (MTRR) 66AA genotype correlated with a superior prognosis compared to the AG or GG genotypes. These findings indicated independent pharmacogenomic determinants could be identified in subsets of Taiwanese children with ALL and correlated to the treatment outcome. In conclusion, we propose the pharmacogenomic determinants disclosed in the context of TPOG-ALL-93 protocols could be used to refine protocols for the treatment of pediatric ALL patients. Fig. 1 Kaplan-Meier plot depicting event-free survival of the ALL patients. The estimate of five-year event-free-survival (and the standard error) is illustrated for 105 patients received TPOG-ALL-93 protocols. Fig. 1. Kaplan-Meier plot depicting event-free survival of the ALL patients. The estimate of five-year event-free-survival (and the standard error) is illustrated for 105 patients received TPOG-ALL-93 protocols. Fig. 2 MDR1 2677–3435 G-C/G-C genotype identified a subset with poor prognosis in the 36 ALL patients received TPOG-ALL-93-SR treatment protocol. Fig. 2. MDR1 2677–3435 G-C/G-C genotype identified a subset with poor prognosis in the 36 ALL patients received TPOG-ALL-93-SR treatment protocol.

Description: MicroRNAs (miRNAs) are small RNAs of 19 to 25 nucleotides that are regulators of gene expression. A role for microRNAs in leukemia, such as chronic lymphoblastic leukemia, acute myelogeneous leukemia has recently been recognized. However, little is known about the role of microRNAs in childhood acute lymphoblastic leukemia (ALL). To determine whether miRNAs are associated with the clinical features of childhood ALL and its association with cytogenetic abnormalities, we analyzed 60 untreated childhood ALL cases for their miRNA expression using a microarray platform. Leukemic samples were collected from the ALL children between 1–18 years of age. Of the 365 miRNA analyzed with a training group of 40 patients, a miRNA signature was derived that was associated with event-free survival. The signature was tested in a validation group of 20 patients. For the latter, a miRNA compound covariate predictor (i.e., a miRNA risk score) was computed on the basis of weighted levels of the miRNAs forming the outcome signature. The signature identified from the training group contained 5 miRNA highly associated with event-free survival (P