Oral arsenic trioxide-based regimen as salvage treatment for relapsed or refractory mantle cell lymphoma.

BACKGROUND: Mantle cell lymphoma (MCL) is aggressive, and relapsed/refractory disease has poor outcomes. PATIENTS AND METHODS: Thirty-nine patients (men = 34, women = 5) at 64 (41-82) years of age with relapsed/refractory MCL, ineligible for high-dose chemotherapy and had received 2 (1-5) prior regimens, were treated with a continuous oral regimen, comprising oral arsenic trioxide (oral-As2O3), chlorambucil and ascorbic acid. RESULTS: Overall response rate was 49% (complete response, CR = 28%; partial response, PR = 21%). Only grade 1/2 toxicities were observed (hematologic: 56%, hepatic: 8%). Response was maintained in 11 patients (CR = 8; PR = 3), after a median of 24 (2-108) months. Independent prognostic factors for response were increased lactate dehydrogenase (P = 0.04) and unfavorable MCL international prognostic index (P = 0.04). At a median follow-up of 21 (1-118) months, the median progression-free survival (PFS) was 16 months, and overall survival (OS) 38 months. Independent prognostic factors for PFS were female gender (P = 0.002), and Eastern Cooperative Oncology Group (ECOG) performance score of 2 (P = 0.009). Independent prognostic factors for OS were female gender (P < 0.001), ECOG performance score of 2 (P = 0.03), non-response (P < 0.001), and disease progression after initial response (P = 0.05). CONCLUSION: An oral regimen of oral-As2O3, chlorambucil and ascorbic acid was active with minimal toxicity in relapsed/refractory MCL, achieving durable responses in ∼30% of cases.

Cough mixture abuse and rhabdomyolysis.

Cough mixture abuse is an emerging problem among young men in Oriental countries. Its metabolic consequences have been recognised only recently. Such abusers can develop severe folate deficiency, which may be related to peripheral and central nervous system defects. We report three cough mixture abusers with rhabdomyolysis. All suffered from folate deficiencies and also had a history of anti-psychotic drug use. This represents one more life-threatening side-effect from cough mixture abuse.

A biography of arsenic and medicine in Hong Kong and China.

Arsenic trioxide has been used in traditional Chinese medicine for over 5000 years, but lost its appeal due to its toxicity. It was rediscovered in western medicine and enjoyed a renaissance from 1830 to 1930, as the first effective chemotherapy against syphilis, parasites and leukaemia. These years were also a time of political turmoil in China. The Nanking treaty (29 August 1842) turned Hong Kong into a colony, while the Xinhai Revolution (10 October 1911) gave birth to a republic of China. Arsenic returned to China and Hong Kong with the establishment of the first medical schools from 1887 to 1920. Until 1950, oral arsenic trioxide was the standard anti-leukaemic treatment in Queen Mary Hospital. The advent of alkylating chemotherapeutic agents replaced arsenic trioxide in Hong Kong and around the world. In the 1970s, however, the specific activity of arsenic trioxide against acute promyelocytic leukaemia was re-discovered during the Cultural Revolution in Harbin, China. In 1997, Hong Kong was returned to China. In the same year, arsenic trioxide returned to the world stage. Intravenous arsenic trioxide became the worldwide standard therapy for relapsed acute promyelocytic leukaemia. Oral administration of arsenic trioxide was revived in Hong Kong in 2000. This resulted in the first locally produced, registered, patented prescription drug in Hong Kong. Pending imminent manufacture, this product is poised to revolutionise acute promyelocytic leukaemia care and may hold the key to saving the lives of acute promyelocytic leukaemia patients worldwide. The remarkable journey of arsenic in the setting of medical history of China and Hong Kong is reviewed.

A synopsis of current haemophilia care in Hong Kong.

OBJECTIVE: To provide a synopsis of current haemophilia care in Hong Kong. DESIGN: Retrospective survey. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with haemophilia A and haemophilia B. RESULTS: To date, there were 222 mild-to-severe haemophilia patients (192 type A, 30 type B) under regular public care in Hong Kong (43% were considered severe, 33% moderate, and 24% mild), which gave a crude prevalence of 6.8/100 000 male inhabitants. A total of 12.8 million units of Factor VIII and 3 million units of Factor IX were prescribed annually. This amounts to 1.83 units of FVIII per capita of the population, which is comparable to that of other developed countries. Leading causes of mortality were human immunodeficiency virus-related complications (10 cases) and cerebral bleeding (2 cases). The life expectancy of patients with severe haemophilia in Hong Kong is improving; currently the oldest patient is 60 years old. Such improved survival may be due to enhanced factor availability, prompt treatment of bleeding episodes at home, safer factor products, and better antiviral treatment. Primary prophylaxis is the accepted standard of care for severe and moderate cases, and "Factor First" has become hospital policy. However, 12 patients continue to present treatment challenges, due to the documented presence of factor inhibitors. In all, 28, 100, and 14 cases respectively were positive for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus; the youngest patients with the corresponding infections being 28, 13, and 22 years old. Comprehensive care with dedicated physiotherapy, surgical support, and radionucleotide synovectomy may reduce morbidity further. CONCLUSION: A multidisciplinary approach can further improve the future care for haemophilia patients in Hong Kong.

A synopsis of current care of thalassaemia major patients in Hong Kong.

OBJECTIVE: To provide a synopsis of current thalassaemia major patient care in Hong Kong. DESIGN: Retrospective study. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with thalassaemia major with regular transfusion. RESULTS: To date, there were 363 thalassaemia major patients under the care of the Hospital Authority. Prenatal diagnosis has helped to reduce the number of indigenous new cases, but in recent years immigrant cases are appearing. The patients have a mean age of 23 (range, 1-52) years, and 78% of them are adults. In 2009, they received 18 782 units of blood. This accounted for 9.5% of all blood consumption from the Hong Kong Red Cross. In the past, cardiac iron overload was the major cause of death (65%) and few patients survived beyond the age of 45 years. The availability of cardiac iron assessment by magnetic resonance imaging (T2 MRI) to direct the use of oral deferiprone chelation has reduced the prevalence of heart failure and cardiac haemosiderosis, which should reduce mortality and improve life expectancy. CONCLUSION: The future for thalassaemia care in Hong Kong is bright. With better transfusion and chelation, it should be possible to avoid growth and endocrine deficiencies in younger patients.

Organ-specific hemosiderosis and functional correlation in Chinese patients with thalassemia intermedia and hemoglobin H disease.

We performed MRI assessment in 37 adult Chinese patients with thalassemia intermedia and hemoglobin H disease. Despite abnormal ferritin and liver T2*, only 5% of patients had cardiac hemosiderosis. The two patients with reduced ejection fraction had normal cardiac T2*. Half of the cases showed pituitary and pancreatic iron loading. Subclinical endocrine abnormalities (HOMA, insulin growth factor) showed correlation with pancreatic, pituitary, and cardiac MRI values. Prospective data with serial functional and imaging monitoring is needed to verify the utility for chelation to improve cardiac and endocrine function in this group of patients.

Cortisol stimulation of parathyroid hormone secretion by rat parathyroid glands in organ culture.

Addition of cortisol (10(-6) to 10(-8) M) and related glucocorticoid congeners to cultures of rat parathyroid glands stimulated dose-related increases in parathyroid hormone secretion; the addition of deoxycorticosterone or cortexolone was without effect. Cortexolone, however, inhibited the stimulatory activity of cortisol when both were added to the culture medium. This direct stimulatory effect of cortisol on parathyroid gland secretion may account in part for the increased concentration of parathyroid hormone in the serum of cortisol-treated animals.

Haematopoietic stem cell transplantation in Hong Kong.

The first case of haematopoietic stem cell transplant (HSCT) was performed at the Bone Marrow Transplant Center, Queen Mary Hospital (QMH) in 1990. Since then three more transplant centres have been established: Prince of Wales Hospital (1991) mainly in paediatric transplant, Queen Elizabeth Hospital (1995) and Tuen Mun Hospital (2006) in adult autologous transplant. Up to the end of 2008, a little over 2000 transplants have been performed in Hong Kong, and QMH takes up about 85% of the total number of cases. A unified HSCT registry in Hong Kong is desirable and is yet to be established. At QMH, by the end of 2008, a total of 1708 transplant procedures have been performed with 83% (1417) being first-time transplants and the rest (291, 17%) are repeat transplants mostly for relapsed patients. The numbers of male and female patients are 955 and 753, respectively. The median age is 35.4 years (range, 3 months to 67 years) with 85.8% of the transplants performed in adults (> 18 years). The type of donor includes 34% autologous, 1% syngeneic, 38% related allogeneic and 27% unrelated allogeneic. The top five indications of the first-time transplants are acute myeloid leukaemia (25.8%), chronic myeloid leukaemia (15.9%), lymphoma (14.6%), acute lymphoblastic leukaemia (14.5%), and myeloma (8.6%). With the development of peripheral blood stem cell collection, in recent years it is performed in 50% of the allogeneic and 80% of the autologous cases. Bone marrow harvest in autologous cases is only for patients who fail peripheral blood stem cell mobilisation. Transplant outcomes are reported to the Center for International Blood and Marrow Transplant Research and long-term survivals are in general comparable to international standard.

Glucose-6-phosphate-dehydrogenase deficiency and haematopoietic stem cell transplantation in Chinese patients.

Deficiency in glucose-6-phosphate dehydrogenase (G6PD), an X-linked recessive red cell enzymopathy, is endemic in Southern Chinese. Universal screening of newborn is done in Hong Kong, Taiwan and Singapore, among other places. In Hong Kong, 4.8% of males are affected and seven common G6PD alleles account for over 99% of all defects. Male hemizygotes suffer from severe deficiency, while female heterozygotes may also be affected. Deficiency of G6PD may affect haematopoietic stem cell transplantation (HSCT) recipients and donors, before and after HSCT. Female patients with clonal erythropoiesis (eg myelodysplasia/myeloproliferative diseases) will have the male population incidence of G6PD. Quantitative enzyme level screening is prudent for donors and recipients, and should be repeated after engraftment. Cotrimoxazole prophylaxis should be avoided in known male and female carriers, including those with low-normal G6PD enzyme levels. Our experience suggested that G6PD-deficient marrow, stem cell and cord blood donor units have no engraftment problems. Post-engraftment G6PD levels correlate with those in donors. An acquired change in G6PD status may serve as a surrogate marker for engraftment. For female heterozygote donors with normal G6PD levels, skewing of lyonized X-chromosome ratio during engraftment may result in over-expression of the deficient allele. This can result in unexpected significant G6PD deficiency. Hence, a repeat G6PD screening at stable engraftment is recommended, especially before commencement of oxidative medications.

Penile lichen sclerosus after allogeneic stem cell transplantation.

Graft-versus-host disease (GVHD) often complicates allogeneic stem cell transplantation (SCT) and affects mainly the gut, liver, lung and skin. The microscopic morphological features of late-phase sclerodermatous chronic GVHD in the skin, namely epidermal atrophy, lymphoplasmacytic infiltration, dense dermal fibrosis and adnexal atrophy, are histologically indistinguishable from those in sporadic systemic sclerosis, morphoea and the related condition of lichen sclerosus. Mucosal orifices including those of the genitourinary system may be severely affected. We present three SCT recipients with chronic GVHD and severe posthitis leading to phimosis requiring surgery. The excised prepuces showed features of lichen sclerosus including epidermal atrophy and a subepidermal zone of eosinophilic, homogeneous and hyalinized collagen above a band-like lymphoplasmacytic infiltrate. These cases add further evidence to support the notion that penile lichen sclerosus should be included within the expanding sclerodermoid spectrum of late-stage cutaneous chronic GVHD.

Restoration of parathyroid responsiveness in vitamin D-deficient rats by parenteral calcium or dietary lactose.

The effects of treatment with vitamin D, calcium, or lactose on the responsiveness of vitamin D-deficient rats to parathyroid hormone were compared. In the absence of vitamin D, parenteral calcium or dietary lactose administration resulted in increases in serum calcium concentration although not to the normal values obtained in animals given vitamin D. Dietary lactose also partially restored the low bone calcium content of vitamin D-deficient rats. Untreated vitamin D-deficient rats showed no significant changes in serum calcium concentration after parathyroidectomy or parathyroid extract administration. Vitamin D, lactose, and calcium all restored responsiveness to parathyroid hormone; serum calcium concentration decreased after parathyroidectomy and showed a dose-related increase in response to parathyroid extract. Hence, the unresponsiveness to parathyroid hormone in vitamin D deficiency may be due to a lack of calcium at a local site of action, presumably bone, rather than to the absence of vitamin D as a specific cofactor.

Hormone synthesis and secretion by rat parathyroid glands in tissue culture.

Rat parathyroid glands maintained in organ culture secrete biologically active parathyroid hormone (PTH) and synthesize and secrete labeled proteins from (3)H- or (14)C-labeled amino acids added to the medium. The amounts of biological activity and labeled protein in the medium are both inversely proportional to the calcium concentration. Some of the labeled low molecular weight protein was identified as PTH which had been synthesized and secreted in culture by preliminary isolation on Sephadex G-100 columns and further purification using an antibody to bovine PTH which cross-reacted with rat PTH. The cross-reacting antibody inhibited the biological effects of rat PTH and caused hypocalcemia in intact rats. The antibody bound some of the labeled low molecular weight protein of the medium at neutral pH so that it migrated as a large molecular weight complex on Sephadex. Biologically active, labeled PTH was recovered by dissociation of this complex in acid and rechromatography.

Challenges and pitfalls in prenatal screening in pregnancies involving allogeneic stem cell transplantation recipients.

Increasing numbers of successful pregnancies are reported in recipients of allogeneic hemopoietic stem cell transplantation (HSCT). These may occur naturally, or more commonly, through assisted reproduction. The pregnancy outcomes are usually normal. There are currently no guidelines on the prenatal management of pregnancies involving HSCT recipients. HSCT recipients are unique in that their red cells, lymphocytes and even the DNA in the circulation are donor derived. As a result, typical prenatal screening tests in parents, including mean cell volume (MCV), hemoglobin pattern, blood group, infective serology and DNA screening, are all affected. The MCV cannot be used as guide for iron and folate supplements, or for thalassemia and sickle cell anemia screening. Such screening must be based on pre-HSCT indices and pre-HSCT DNA samples. The risks for hemolytic disease of newborn and hepatitis B virus transmission have to be re-evaluated, based on both pre- and post-HSCT patient as well as donor blood group and serology results. Good communication between obstetricians and the HSCT physician is paramount to promote successful pregnancies in this distinct patient population.

Long-term results of allogeneic bone marrow transplantation for 108 adult patients with acute lymphoblastic leukemia: favorable outcome with BMT at first remission and HLA-matched unrelated donor.

We analyzed the outcome of 108 adult acute lymphoblastic leukemia patients undergoing allogeneic bone marrow transplantation (BMT). Philadelphia (Ph) chromosome occurred in 35.2% patients at diagnosis. Two-thirds of patients received allogeneic BMT in first complete remission (CR1) BMT. Salvage BMT was performed in 21 and 16 patients at second complete remission (CR2) and beyond CR2. Donors were human leukocyte antigen-identical siblings in 87 patients, and match-unrelated donors in 21 patients. Conditioning contained total body irradiation (TBI) in 92.6% patients. Overall survival (OS) for BMT at CR1 and BMT beyond CR1 were 46.2 and 20.3% at 15 years. Multivariate analyses (including age, sex, disease status, donor type, acute graft-versus-host disease (aGVHD), stem cell source, cytogenetics, grade 1/2 aGVHD and TBI-containing conditioning regimen) identified age<35, BMT at CR1 and grade 1/2 aGVHD as favorable factors for OS. Disease-free survival (DFS) for BMT at CR1 and beyond CR1 were 45.8 and 15.9% at 15 years, respectively, with BMT at CR1, age<35 and grade 1/2 aGVHD being favorable factors for DFS. Importantly, conventional adverse risk factors such as the Ph chromosome, B-cell phenotype and high leukocyte count were not associated with inferior survivals. In summary, the adverse impact of Ph chromosome, B-cell phenotype and high leukocyte count was overcome by allogeneic BMT. Matched unrelated donor transplantation appears promising.

G6PD deficiency from lyonization after hematopoietic stem cell transplantation from female heterozygous donors.

To determine whether during hematopoietic stem cell transplantation (HSCT), X-chromosome inactivation (lyonization) of donor HSC might change after engraftment in recipients, the glucose-6-phosphate dehydrogenase (G6PD) gene of 180 female donors was genotyped by PCR/allele-specific primer extension, and MALDI-TOF mass spectrometry/Sequenom MassARRAY analysis. X-inactivation was determined by semiquantitative PCR for the HUMARA gene before/after HpaII digestion. X-inactivation was preserved in most cases post-HSCT, although altered skewing of lyonization might occur to either of the X-chromosomes. Among pre-HSCT clinicopathologic parameters analyzed, only recipient gender significantly affected skewing. Seven donors with normal G6PD biochemically but heterozygous for G6PD mutants were identified. Owing to lyonization changes, some donor-recipient pairs showed significantly different G6PD levels. In one donor-recipient pair, extreme lyonization affecting the wild-type G6PD allele occurred, causing biochemical G6PD deficiency in the recipient. In HSCT from asymptomatic female donors heterozygous for X-linked recessive disorders, altered lyonization might cause clinical diseases in the recipients.

HLA associations, microsatellite instability and epigenetic changes in thyroid lymphoma in Chinese.

In Chinese, autoimmune thyroid disease (AITD) is very common but lymphoma of the thyroid is a rare disease. Southern Chinese AITD is common in females and is strongly linked to the HLA haplotype A2B46DR9. We studied the HLA association, aberration p15, p16 and p73 promoter methylation and microsatellite instability in Chinese primary thyroid lymphoma patients to elucidate their relationship with AITD and the relationship between thyroid diffuse large cell lymphoma (DLCL) and marginal zone lymphomas (MZL). Despite a female preponderance (8:1) and the finding of cases with histological and immunological evidence of AITD, a significant HLA association was not found. MSI was absent, but aberrant promoter methylation was found in both thyroid MZL and DLCL and p73 methylation was unexpectedly common.

A magnetic resonance imaging study of iron overload in hemopoietic stem cell transplant recipients with increased ferritin levels.

We performed a study of magnetic resonance imaging (MRI) assessment of hemosiderosis in the heart (T2/T2*), liver (T2*), pancreas (T2*), and pituitary gland (T2/T2*/SIR) in 20 hemopoietic stem cell transplant (HSCT) recipients (median peak ferritin levels 7615 pmol/L, range 3411 to 33000 pmol/L). MRI reading was abnormal in the heart (5%), liver (85%), pancreas (40%), and pituitary gland (55%). The heart T2 correlated with peak ferritin levels (P=.024), while the liver T2* correlated with current ferritin (P=.038) values only. Pancreatic T2* values correlated with pituitary T2 and signal intensity ratio values. The ejection fraction was abnormal in 10% of cases and did not correlate with ferritin level or heart T2. The peak liver enzymes correlated with peak ferritin (P=.025), but the current liver enzymes were mostly normal. Pancreatic assessments (fasting glucose, insulin, beta cell function, insulin reserve, and C-peptide) and pituitary growth hormone axis assessments (growth hormone, insulin growth factor-1, and insulin growth factor binding protein-3) were abnormal in 40% to 70% of cases. They were unrelated to pancreas or pituitary MRI values. Interestingly, endocrine assessments correlated with heart T2 values and peak (but not current) ferritin levels. We concluded that iron overload may contribute to organ damage after HSCT, and MRI assessment may be useful in its detection and treatment monitoring.

Long-term donor health and its relationship with outcome of allogeneic hematopoietic stem cell transplantation.

Data on long-term follow-up of donors for hematopoietic stem cell transplantation (HSCT) are limited. Donors of 612 adult allogeneic HSCT were studied, at a median of 81 (14-181) months post-HSC donation. Nine donors had severe health problems. Five donors died from aggressive malignancies or terminal illness, at a median of 41 (16-57) months post-donation. Notably, all their recipients had leukemic relapses. In contrast, donors of recipients in remission were all living. This observation might be due to an inherent depressed immunosurveillance in the donors, or selection of donors with suboptimal health for desperate patients with poor risks pre-HSCT.

A prospective study of respiratory ciliary structure and function after stem cell transplantation.

We prospectively investigated the morphological and ciliary function abnormalities in 19 consecutive Chinese patients undergoing hemopoietic stem cell transplantation (HSCT) and studied their relationship with pulmonary complications. The percentage of structural ciliary abnormalities preceding HSCT was comparable to normal controls, but increased up to 1-year post-HSCT. However, the abnormalities did not correlate with ciliary or pulmonary function. Ciliary beat frequency (CBF) for patients undergoing autologous and allogeneic SCT was lower than that of matched controls, with a further decline at one year. There was, however, no significant change in pulmonary function for the whole cohort. There was considerable variation in CBF and ciliary abnormalities in all cases during 3-month interval assessments. Regular ciliary assessment did not predict the only two patients who eventually suffered from bronchiolitis obliterans (BO). We conclude that structural and functional ciliary abnormalities are common in recipients of HSCT, and predict post-HSCT deterioration. However, there is no evidence to show that CBF monitoring may be of prospective benefit.

Tumor necrosis factor alpha promoter polymorphism and the risk of chronic lymphocytic leukemia and myeloma in the Chinese population.

The -308 GA promoter polymorphism of tumor necrosis factor alpha (TNFalpha) has been reported to be associated with an increased risk of lymphoid malignancies in Caucasians. We studied the incidence and prognostic significance of this polymorphism in Chinese patients with plasma cell myeloma (PCM), chronic lymphocytic leukemia (CLL) and lymphomas. Despite a far lower incidence of PCM and CLL in the Chinese population compared with Caucasians, the rates of TNFalpha-308A were similar to those in Caucasians, both in the study and control populations. Similarly, there was no increased rate of TNFalpha-308A in all the lymphomas studied, irrespective of lineage. However, TNFalpha-308A is significantly associated with female CLL cases and confers a strong negative prognostic impact for Chinese CLL. These argue for a possible biological role for increased TNFalpha production in CLL progression in low-risk individuals.