Cardiac iron measurement and iron chelation therapy in patients with ß thalassaemia major: experience from Taiwan.

BACKGROUND: The aims of our study were to evaluate (i) the relationship between cardiac T2* values and cardiac complications in Asian ß-thalassaemia major (TM) patients, and (ii) the association between cardiac T2* values and other parameters currently used to predict cardiac complications as a result of transfusion iron overload. METHODS: We examined the myocardial iron loads of 88 TM patients from Taiwan with cardiac T2* magnetic resonance imaging (MRI) and assessed the correlation between cardiac T2* values and serum ferritin levels, liver iron concentration and left ventricular ejection fraction (LVEF). We also determined the predictive value of these measurements for the development of arrhythmia. RESULTS AND CONCLUSION: In our group of Taiwanese patients, the relative risk for arrhythmia was 10·36 when cardiac T2* values were less than 10 ms (compared with ≥10 ms) and 1·98 when serum ferritin levels increased >2500 ng mL(-1) (compared with ≤2500 ng mL(-1) ). Serum ferritin levels correlated with cardiac T2* values in patients with abnormal myocardial iron loads (T2* < 20 ms, r = -0·48, P = 0·004, n = 34), but LVEF (measured by echocardiography) gave no indication of excess myocardial iron deposition (r = -0·07, P = 0·52) or of the risk of developing arrhythmia.

Iron overload is associated with low anti-müllerian hormone in women with transfusion-dependent ß-thalassaemia.

OBJECTIVE: To investigate anti-müllerian hormone (AMH) as a best test of ovarian reserve in women with transfusion-dependent ß-thalassaemia, and the relationship between AMH and iron overload. DESIGN AND SETTING: A case-control study in a tertiary medical centre. POPULATION: Twenty-nine women with transfusion-dependent ß-thalassaemia and 29 healthy controls of a similar age were recruited. METHODS: Blood sampling, questionnaires and medical record reviews were used. MAIN OUTCOME MEASURES: The history of iron overload-related morbidities, haematological phenotypes, serum levels of AMH and ferritin, and hormonal profiles were analysed. RESULTS: The serum levels of AMH, luteinising hormone, and estradiol were lower in women with transfusion-dependent ß-thalassaemia than in age-matched normal controls. In women with transfusion-dependent ß-thalassaemia, the serum AMH level was significantly inversely related to the ferritin level, but not related to the presence of hypogonadotrophic hypogonadism, diabetes and haematological phenotypes. The serum ferritin level was positively associated with advanced age and the presence of hypogonadotrophic hypogonadism in the study participants. However, the inverse relationship between AMH and ferritin still exists after further adjustment for advanced age in women with transfusion-dependent ß-thalassaemia. CONCLUSIONS: The present study indicates that the serum AMH levels in women with transfusion-dependent ß-thalassaemia are lower when compared with normal healthy women of a similar age, and are significantly negatively correlated with their serum ferritin levels. This implies that ovarian function might be impaired by the chronic iron overload status in women with transfusion-dependent ß-thalassaemia.

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.

Financial burden of national health insurance for treating patients with transfusion-dependent thalassemia in Taiwan.

The thalassemias are a heterogeneous group of inherited hypochromic anemias of varying severity. The mainstay of supportive treatment is regular blood transfusion accompanied by iron-chelating therapy. Hematopoietic stem cell transplantation (HSCT) provides an alternative option when curative therapy is considered. More than 400 patients in Taiwan have beta-thalassemia major or other transfusion-dependent thalassemias, and their treatment costs account for a considerable percentage of the National Health Insurance expenditure. In this report, we estimated the treatment costs of conventional therapy (regular blood transfusion accompanied by iron-chelating agents) and HSCT. The undiscounted medical cost of 20 years of follow-up (20 years from diagnosis) and the undiscounted total lifetime cost were NT$ 4 739 888 (NT$ means New Taiwan Dollars)/US$ 149 288 and NT$ 11 529 990/US$ 363 149, respectively, for patients undergoing conventional therapy, and NT$ 2 639 982/US$ 83 149 and NT$ 3 511 172/US$ 110 588, respectively, for those undergoing successful HSCT. Comparisons of treatment costs and other parameters between these two modalities can add to the information base on which policy is made by health authorities or clinicians.

T cell lymphoproliferative disorder following bone marrow transplantation for severe aplastic anemia.

Post-transplant lymphoproliferative disorder (PTLD) is uncommonly of T cell origin, especially following BMT. We describe a 13-year-old boy with severe aplastic anemia (SAA) and no evidence of Fanconi's anemia who underwent BMT at 11 years of age using CY 10 mg/kg once daily i.v. on days -5, -4, antilymphocyte globulin (ALG) 30 mg/kg once daily i.v. on days -5 approximately -3 and CsA from day -1 as conditioning. The BMT failed and he received a further peripheral blood stem cell transplant (PBSCT) 240 days after BMT. Conditioning was with CY 50 mg/kg once daily i.v. on days -5 approximately -2, and ALG 15 mg/kg once daily i.v. on days -4 approximately -2. GVHD prophylaxis included CsA and MTX. Engraftment was later confirmed by cytogenetic studies. Desquamation and ulcers of the oral mucosa and mouth angle developed in the 13th month post PBSCT. A buccal mucosa biopsy on day +524 revealed only plasmacytosis. Immunosuppressants were discontinued at that point. Generalized lymphadenopathy, prolonged fever (waxing and waning) and facial swelling developed in the 18th month post PBSCT. A neck lymph node biopsy on day +601 showed T cell lymphoma of diffuse large cell type with monoclonal TCR gamma-chain gene rearrangement. A FISH study showed that the malignant T cells were of recipient origin. EBV in situ hybridization was negative. He did not receive further treatment apart from discontinuation of immunosuppressants. He was followed up in our out-patient clinic and showed good performance 1170 days post PBSCT. We speculate that a different mechanism was operating in the pathogenesis of T cell lymphoma in this case. Risk factors include SAA and two transplants, conditioned with CY and ALG, long term use of CsA and treatment with azathioprine.

Minimally differentiated acute myeloid leukemia in Taiwan: predominantly occurs in children less than 3 years and adults between 51 and 70 years.

Acute myeloid leukemia (AML) with minimal differentiation was usually referred to as acute undifferentiated leukemia in the past. With the help of immunophenotyping, this subtype of leukemia was shown to express myeloid antigens on the blasts and was designated AML-M0 by FAB Cooperative Study Group in 1991. Among the 423 consecutive newly diagnosed de novo AML at our institution, 12 (2.8%) were of M0 subtype. The proportion of M0 in AML was higher in children than in adults (8.2% vs 1.7%). Four other M0 patients referred from outside hospitals for immunophenotyping were also included in this study. There were two peaks in age distribution of these 16 patients: less than 3 years and between 51 and 70 years, respectively. Organomegaly was more common in patients with AML-M0 than in those with other subtypes (56.3% vs 29.2%, P = 0.025). The former patients had higher incidences of CD7 and CD34 expression on the leukemic cells than the latter ones (50% vs 16.9%, P = 0.003 and 69.2% vs 37.9%, P = 0.019, respectively). The patients with AML-M0 showed more frequent clonal chromosomal abnormalities in the leukemic cells than other AML patients (83.3% vs 53.9%, P = 0.039); the same is also true for complex cytogenetic aberrations (50% vs 11. 4%, P = 0.004). Adults with AML-M0 showed a lower complete remission (CR) rate and significantly poorer survival than those with non M0-AML. However there was no significant difference in outcome between the two groups of pediatric patients. In conclusion, AML-M0 is a unique subtype of leukemia that has distinct age distribution and shows different clinical and biological characteristics from other AML. Adult patients have poor prognosis. Whether pediatric patients had better outcome than adults needs to be clarified in further studies.

Development of acute lymphoblastic leukemia in a child after treatment of Langerhans cell histiocytosis: report of one case.

Langerhans cell histiocytosis (LCH) is a group of poorly understood disorders. To our knowledge, LCH is a non-malignant disorder. The association of LCH with a secondary neoplasm has not been well assessed, however, a few cases have been reported. We report a case of LCH, a localized osteolytic lesion over metaphysis of left femur, who was treated with local curettage and chemotherapy with vincristine, prednisone and 6-mercaptopurine (6-MP) for eight months from end of 1991 to August, 1992. Six years later, she had acute lymphoblastic leukemia (ALL) in 1998. In review of current literature, only 5 cases of LCH, including our case, have preceded ALL. The possible association, a reactive process or a therapy-related process, between LCH and acute leukemia is still unclear at present and needs to be explored by more studies in the future.

Longitudinal observation and outcome of nonfamilial childhood haemophagocytic syndrome receiving etoposide-containing regimens.

The long-term outcome of 22 children treated with etoposide-containing regimens for haemophagocytic syndrome (HS) were longitudinally studied; none of them had a family history of the disease. All patients received etoposide-containing (150 mg/m2/d) regimens, combined, in 16 cases, with intravenous immunoglobulin (IVIG) and prednisolone. Complete remission (CR) was achieved in 12 patients, partial remission in seven, and early mortality occurred in three. Of the 12 CR patients, only four remain alive and disease-free, with a median follow-up of 47.4 months; one CR patient died due to infection and the remaining seven had relapsed diseases. Three patients with a partial response or with relapsed disease progressed to T-cell lymphoma, characterized, in the two cases tested, by clonal chromosomal abnormalities. Epstein-Barr virus (EBV) infection was implicated in disease pathogenesis in 15/22 patients. The overall survival was 45.5%, 40.9% and 40.9% at 1, 3 and 5 years, respectively, and disease-free survival for CR patients at these same times was 45.5%, 36.4% and 36.4%. The etoposide-containing regimen would appear to be an effective initial therapeutic option for childhood HS. However, in view of the frequency of partial remissions and relapsed disease, a more intensive chemotherapy or bone marrow transplantation should be applied. The progression to EBV-containing T-cell lymphoma in three patients is consistent with the previous observation that EBV-associated HS is a potentially malignant disease.

Ki-1 lymphoma in two children.

Childhood Ki-1 lymphoma is rarely reported in Taiwan. We present two 8-year-old girls with Ki-1 lymphoma diagnosed and treated at the National Taiwan University Hospital. The first patient presented with a neck mass with hepatosplenomegaly. The second patient initially presented with joint pain and pathologic fracture; she was later found to have bone marrow involvement. Histologic studies of both tumors revealed bizarre large cells with pleomorphic nuclei and prominent nucleoli. All these cells were immunolabeled with monoclonal antibody Ki-1. The two patients received different polyregime chemotherapy protocols followed by bone marrow transplantation (BMT); patient 1 had autologous BMT and patient 2 had allogeneic BMT. In addition, local radiotherapy and retinoic acid were tried for patient 1 but she responded poorly and died 2 years after presentation. In patient 2, although bone marrow was initially involved, allogeneic BMT was performed smoothly after tumor loading was reduced and the patient was in remission at last follow-up, 26 months after presentation. Ki-1 lymphoma in children is characterized by clinical presentations, and histologic and immunologic findings. Aggressive polyregime chemotherapy and bone marrow transplantation are treatments for this disease.

Allogeneic bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in childhood.

Allogeneic bone marrow transplantation (BMT) offers the only potential for long-term control of chronic myelogenous leukemia. From November 1992 to August 1994, we prospectively studied five pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia, a unique finding in Taiwan, who were treated with allogeneic BMT at different stages of the disease. Their ages at diagnosis ranged from 2 to 10 years. Four donors were HLA-matched siblings and the other was an HLA-matched unrelated donor. All patients received busulfan (4 mg/kg/day for 4 days) followed by cyclophosphamide (60 mg/kg/day for 2 successive days) as the conditioning regimen. Engraftment was documented within 22 days after transplantation in all five patients. Two out of the four patients in the sibling donor group, both of whom had BMT in the first chronic phase, achieved event-free survival after follow-up for 41 months and 17 months. The other two patients, who had BMT in the second lymphoblastic crisis and the second chronic phase, died within 6 months after transplantation due to lymphoid blastic crisis and complication of cytomegaloviral pneumonitis, respectively. The patient who received marrow from the unrelated donor underwent BMT in the accelerated phase and died within 6 months after transplantation due to myeloid blastic crisis. In conclusion, allogeneic BMT performed in the first chronic phase of childhood Philadelphia chromosome-positive chronic myelogenous leukemia seems to have better results than BMT after the first chronic phase.

Cord blood transplantation for acute lymphoblastic leukemia in a pediatric patient.

The prognosis of Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is poor. While umbilical cord blood transplantation has been used successfully for hematopoietic reconstitution, patients' size may be a limiting factor. We report an 11-year-old, 55-kg patient with Ph+ ALL, who received human leukocyte antigen-identical sibling donor cord blood transplantation (5.94 x 10(6) CD34+ cells) during the second ALL relapse. On days 25, 41, 75 and 103, successful engraftment was confirmed by cytogenetic studies. However, the leukemia relapsed on day 117 and the patient died on day 146 due to refractory ALL. In conclusion, based on the documented engraftment in our patient, we believe cord blood transplantation may be successfully employed in adolescent or possibly even adult patients.

Successful bone marrow transplantation in a Chinese boy with Wiskott-Aldrich syndrome.

We describe the successful use of HLA-compatible sibling bone marrow transplantation (BMT) in a 17-month-old Chinese boy in whom Wiskott-Aldrich syndrome (WAS) was diagnosed on the basis of eczema, thrombocytopenia, recurrent otitis media and abnormal immunological tests. The conditioning chemotherapy included 2 days' oral busulfan, 40 mg/m2/6 hours, and 2 days' intravenous cyclophosphamide, 60 mg/kg/day (BU2CY2). Complete hematological chimerism was achieved 3 weeks after transplantation. Eight months after his BMT the eczema has resolved, platelet count is normal, and he no longer has frequent infections. BU2CY2 as a preconditioning regimen gave complete lymphohematopoietic engraftment in this WAS patient with no evidence of graft-versus-host disease. The excellent clinical response of this patient and the inevitable fatal outcome of WAS support the opinion that where a histocompatible donor is available, BMT at the earliest opportunity is the best option. We believe this is the first case of successful BMT in a Chinese patient with WAS.

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in second remission or relapse.

Most children with acute lymphoblastic leukemia (ALL) are successfully treated by chemotherapy. For those patients, who relapse on therapy, bone marrow transplantation (BMT) is considered most appropriate after a subsequent remission is achieved. Three boys with ALL aged from 9 to 13 years met these criteria and received BMT from their HLA-compatible sisters after marrow ablation with total body irradiation 12 Gy plus high dose cytosine arabinoside 3 gm/m2/12h x 12 doses and graft-versus-host disease (GVHD) prophylaxis with cyclosporine plus short course methotrexate from March 10, 1989 to May 23, 1992. Filgrastim (rhG-CSF) was used to hasten the recovery of granulocyte in one patient. All three patients got full engraftment and two had grade 1 acute GVHD. None of them developed chronic GVHD. Two patients have disease-free survival over 51 and 12 months respectively post BMT without further chemotherapy. One patient died of recurrent refractory leukemia 5 months after BMT. The toxicity of this conditioning regimen included photophobia, conjunctivitis and erythematous skin rashes. One patient who received filgrastim from day 1 to 21 developed severe bone pain. However, this patient had faster recovery of granulocyte count than the other two patients. The preliminary results of this work favors BMT for children with recurrent ALL whose ultimate survival is usually poor when treated with chemotherapy. Further efforts are necessary to investigate new methods for reducing leukemic relapse in ALL patients undergoing BMT.

Bone marrow transplantation for childhood acute myelogenous leukemia.

Six consecutive patients with acute myelogenous leukemia (AML) underwent 7 allogeneic bone marrow transplants at National Taiwan University Hospital. Marrow ablation for 4 patients consisted of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg (BUCY 2). Two patients had busulfan 16 mg/kg and cyclophosphamide 200 mg/kg (BUCY 4) as marrow ablation. One had a second transplant following cytosine arabinoside 3 gm/m2/dose x 10 doses plus total body irradiation 12 Gy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short course methotrexate. Four patients received marrow from their HLA compatible siblings and two from their HLA-haplotype-matched fathers. Four transplants were performed during first remission and the other three during subsequent remission or relapse. All patients except one engrafted and achieved a complete remission (CR). Three of 4 patients transplanted in first CR are alive for over 10, 20 and 59 months respectively after transplant. One of the two patients who each received marrow from their fathers during 2nd CR and relapse, developed relapse 5 months later and the other developed aplasia 3 months later. Acute GVHD occurred in two of six patients. Localized chronic GVHD occurred in one of these two patients. Toxicities of BUCY 2 were minimal except veno-occlusive disease. One patient who received BUCY 4 developed hemorrhagic cystitis. There were no treatment related deaths except one patient who received 2nd transplant. These results demonstrate that BUCY 2 should be considered as a preparative regimen for allogeneic bone marrow transplantation for patients with AML in first remission.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic recurrent multifocal osteomyelitis: report of a case.

We report on a Chinese boy with chronic recurrent multifocal osteomyelitis (CRMO). The eight-year-old boy presented with intermittent exacerbation and spontaneous remission of bone pain at two bone sites, associated with local erythema, swelling and tenderness. The white blood cell count, erythrocyte sedimentation rate, alkaline phosphatase, lactate dehydrogenase, calcium and phosphate were normal or mildly elevated. The roentgenogram and scintigram were consistent with osteomyelitis. The pathologic feature of the bone biopsy specimens was compatible with osteomyelitis. However, no organisms were consistently isolated from culture, and the disease was unaffected by antimicrobial therapy. CRMO is an uncommon childhood disease of still unknown etiology. It is the purpose of this paper to present our experience with the first case in a Chinese person and to review the literature with a discussion of what is currently known about CRMO.