Kuo-Sin Lin

Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia

The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3±1.9% in 1997–2001 to 77.4±1.7% in 2002–2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997–2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.

Severe Bacterial Infection in Transfusion-Dependent Patients with Thalassemia Major

The incidence and clinical spectrum of severe bacterial infection were studied in 89 patients with thalassemia major that was diagnosed between January 1971 and March 2002. There were 20 patients with 24 episodes of severe bacterial infection, resulting in an incidence of 1.6 infections per 100 patient-years. The clinical spectrum included liver abscess (6 cases), septicemia (6 cases), soft-tissue infection (2 cases), osteomyelitis (2 cases), corneal ulcer (1 case), enteritis (1 case), and abscesses of the lung, kidney, intra-abdominal region, retropharynx, gums, and buttocks (1 case each). The leading causal microorganisms were gram-negative bacilli, especially Klebsiella pneumoniae (10 of 20 isolates). Other responsible pathogens were Pseudomonas aeruginosa (2/20), Vibrio vulnificus (2/20), Acinetobacter baumanii (1/20), Streptococcus intermidius (1/20), Yersinia enterocolitica (1/20), Staphylococcus aureus (1/20), Escherichia coli (1/20), and Salmonella species (1/20). Splenectomy and delays in the start of iron-chelating therapy were 2 independent risk factors.

Improved treatment results for childhood acute myeloid leukemia in Taiwan

To improve treatment results for children with de novo acute myeloid leukemia (AML), we introduced a novel protocol, Taiwan Pediatric Oncology Group-AML-97A, for AML other than acute promyelocytic leukemia (APL), for which modified conventional protocols were used. From January 1, 1997, to December 31, 2002, 141 children younger than 17 years old with de novo AML were enrolled. In total, 117 patients with non-APL AML were treated with induction therapy of idarubicin and cytarabine (Ara-C), postremission therapy with high-dose Ara-C – containing regimens for four monthly courses, and moderate-dose therapy with idarubicin and Ara-C for four monthly courses. The first 19 patients with APL were treated with all-trans retinoic acid, idarubicin and Ara-C, with the remaining five patients receiving all-trans retinoic acid and idarubicin, followed by maintenance therapy for 2 years. Stem cell transplantation was performed in 29 patients in first remission with a similar outcome as chemotherapy alone. The remission rate in the AML-97A study was 90%, the 5-year survival 51±5.3% (s.e.) and the 5-year event-free survival 50±4.8%; for APL, these were 100%, 86±7.0, and 75±9.8%. For the whole group, the 5-year survival was 57±4.7% and the 5-year event-free survival 54±4.4%. The AML-97A regimen was well tolerated.

Unexpected mortality from the use of E. coli L-asparaginase during remission induction therapy for childhood acute lymphoblastic leukemia: A report from the Taiwan Pediatric Oncology Group

The relative efficacy and toxicity of E. coli L-asparaginase and epidoxorubicin used in remission induction therapy for childhood acute lymphoblastic leukemia (ALL) were assessed in a randomized trial conducted in Taiwan. All patients had standard-risk ALL, defined as a leukocyte count <10 × 109/l and were aged between 1 and 2 or 7 and 10 years, or a leukocyte count <50 × 109/l and were aged between 2 and 7 years, without evidence of a T cell or mature B cell immunophenotype, central nervous system leukemia or expression of two or more myeloid-associated antigens. Ninety-three patients were randomized to receive E. coli L-asparaginase at 10 000 IU/m2 thrice weekly for nine doses and 108 to receive epidoxorubicin at 20 mg/m2 weekly for two doses during remission induction with daily prednisolone, weekly vincristine and, on day 22, a dose of etoposide plus cytarabine. Patients treated with L-asparaginase had a significantly higher rate of fatal infection with or without hemorrhage than did those who received epidoxorubicin during remission induction (six of 93 vs none of 108, P = 0.009), resulting in a lower rate of complete remission in the former group (93.6 vs 99.1%, P = 0.05). In addition, patients treated with L-asparaginase had a higher frequency of hyperglycemia and hypoalbuminemia. The overall rate of event-free survival was lower in patients treated with L-asparaginase than in other patients (P = 0.06); estimated 3-year rates were 72% (95% confidence interval, 55–89%) and 87.2% (78–96%), respectively. We conclude that L-asparaginase (Leunase) given at 10 000 IU/m2 for nine doses was poorly tolerated and resulted in excessive toxicity, both through its effects as a single agent and possibly through potentiation of etoposide.

Hypogonadotropic hypogonadism and hematologic phenotype in patients with transfusion-dependent beta-thalassemia

Objective To determine the prevalence and risk factors of hypogonadotropic hypogonadism in transfusion-dependent patients with thalassemia. Patients and Methods The authors examined 29 patients with thalassemia major aged 15 years or older. Luteinizing hormone-releasing hormone tests were performed and &bgr;-thalassemia mutations were analyzed by direct sequencing. Results The prevalence of hypogonadotropic hypogonadism was 72%. Failure of puberty was observed in 5 of 11 (45%) boys and 7 of 18 (39%) girls. Arrested puberty was noted in two boys (18%) and five girls (28%). Ten girls (56%) did not menstruate, two (11%) had regular menstrual cycles, one (6%) had irregular menstrual cycles, and five (28%) developed secondary amenorrhea. Twenty-one and eight patients had the &bgr;0/&bgr;0 and &bgr;0/&bgr;+ hematologic phenotypes, respectively. &bgr;0-thalassemia mutation alleles involved IVS II-654 (C-T), codons 41/42 (-TCTT), codons 27/28 (+C), and codons 17 (A-T). &bgr;+-thalassemia mutations alleles were -28 (A-G) and HbE (codons 26(GAG-AAG)). Hematologic phenotype (odds ratio, 28.50; P = 0.002) was the only risk factor identified in the logistic regression analysis. Conclusions In patients with thalassemia major, genetic differences may influence their susceptibility to hypogonadotropic hypogonadism, possibly as a result of differences in the amounts of blood transfused and/or their vulnerability to free radical damage. The hematologic phenotype is a main determinant of the severity of thalassemia major; hence, it may influence the need for and frequency of blood transfusion and the patients iron-overload status.

Survival, mortality, and complications in patients with β‐Thalassemia major in northern Taiwan

Advances in treatment have improved the prognosis in β‐thalassemia major. We present the survival and complications pattern of those patients in northern Taiwan born after 1970.

Epitope‐based matching for HLA‐alloimmunized platelet refractoriness in patients with hematologic diseases

BACKGROUND: For HLA‐alloimmunized patients, platelet (PLT) concentrations are provided either at matched HLA‐A and HLA‐B loci or by serologic cross‐reactivity groups (CREG) matching strategy. However, this method has some limitations.

Impact of a national β-thalassemia carrier screening program on the birth rate of thalassemia major

In Taiwan, the prevalence of β‐thalassemia trait is at least 1.1%. The Taiwan government initiated a National Screening Program in 1993. Herein we examine the differences before and after the initiation of this program.

Post‐hepatitic aplastic anaemia in children in Taiwan, a hepatitis prevalent area

Aplastic anaemia is a rare but serious complication of hepatitis, and hepatitis is an unusual cause of aplastic anaemia in children in the West. However, the relative frequencies of acquired aplastic anaemia in children in Taiwan, a hepatitis prevalent area, differ from those in the West, in the very high frequency of post‐hepatitic aplastic anaemia (23.9% of all cases of aplastic anaemia). This may account for the higher incidence of aplastic anaemia in children in Taiwan. Although the prognosis of post‐hepatitic severe aplastic anaemia was very poor, the present study using bone marrow transplantation, antithymocyte (or antilymphocyte) globulin, high‐dose methylprednisolone and cyclosporin, etc., has improved the response rate and the survival.

Increased Risk of Parvovirus B19 Infection in Young Adult Cancer Patients Receiving Multiple Courses of Chemotherapy

ABSTRACT An increased human parvovirus B19 infection rate has been observed in immunocompromised hosts. In this study, we sought to determine the prevalence of parvovirus B19 infection in adult cancer patients receiving multiple courses of systemic chemotherapy. From March 1999 through April 2000, 59 men and 68 women, with a median age of 49 (18 to 79) years, were enrolled in this study. They had received an average of 7.1 (4 to 32) courses of systemic chemotherapy. The median duration from the date of starting chemotherapy to the date of blood sampling was 11 (4 to 88) months. Serum B19 immunoglobulin G (IgG) and IgM levels were examined by an enzyme-linked immunosorbent assay, and B19 DNA was examined by a nested PCR. A group of 400 healthy blood donors served as the control group. The overall prevalences of anti-B19 IgG in adult cancer patients and healthy blood donors were 61.4 and 25.0%, respectively (P < 0.01). Anti-B19 IgM and B19 DNA were not detectable in these anti-B19 IgG-seropositive individuals. A further age-stratified comparison revealed that only patients younger than 40 years had a significantly higher anti-B19 IgG seropositivity rate than the controls (19 of 39 versus 53 of 310; P < 0.001). The increased prevalence of B19 infection in these 39 adult patients younger than 40 years might be clinically significant, since unexplained anemia, a common sequela of B19 infection, was detected in 3 of 20 seronegative patients (15.0%) and in 12 of 19 seropositive patients (63.2%) (P < 0.005). The results of this study suggest that adult patients younger than 40 years and receiving multiple courses of systemic chemotherapy may have a significantly increased risk of B19 infection. Prospective studies to define the time course and clinical consequence of B19 infection in this group of patients are needed.