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Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.

PubMed ID: 23812939, Accumulation of myocardial iron is the cause of heart failure and early death in most transfused thalassemia major patients. T2* cardiovascular magnetic resonance provides calibrated, reproducible measurements of myocardial iron. However, there are few data regarding myocardial iron loading and its relation to outcome across the world. A survey is reported of 3,095 patients in 27 worldwide centers using T2* cardiovascular magnetic resonance. Data on baseline T2* and numbers of patients with symptoms of heart failure at first scan (defined as symptoms and signs of heart failure with objective evidence of left ventricular dysfunction) were requested together with more detailed information about patients who subsequently developed heart failure or died. At first scan, 20.6% had severe myocardial iron (T2*?10ms), 22.8% had moderate myocardial iron (T2* 10-20ms) and 56.6% of patients had no iron loading (T2*>20ms). There was significant geographical variation in myocardial iron loading (24.8-52.6%; P

Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case-control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR) = 1.25, 95 % confidence interval (CI) 1.08-1.45; p trend = 0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR = 1.29, 95 % CI 1.08-1.53; p trend = 0.004), as well as T cell lymphoma (per-allele OR = 1.44, 95 % CI 1.13-1.82; p trend = 0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR = 0.77, 95 % CI 0.64-0.91; p trend = 0.003), specifically DLBCL (per-allele OR = 0.69, 95 % CI 0.55-0.86; p trend = 0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations.

Transfusion therapy has greatly improved the survival of transfusion dependent thalassemia major (TM) patients; however, the resultant iron load damages tissues including the heart, liver and endocrine organs. Among these, heart complication still remains the leading cause of mortality. Myocardial iron deposition can occur independently of other solid organ involvement; conversely, the heart may be spared despite heavy siderosis in other tissues. Iron chelation treatment diminishes the risk of hemosiderosis; however, the chelation treatment has its own toxicities and might not be available to all patients due to costs. Close monitoring of individual organ iron concentration and function is thus important for optimization of individual patient care. This review outlines the importance and clinical significance of recently available MRI techniques for monitoring cardiac iron load. J. Magn. Reson. Imaging 2012;36:1052–1059. © 2012 Wiley Periodicals Inc.

The genetic basis of chronic lymphocytic leukemia (CLL) has not been fully elucidated to date. Although it is the most common haematological malignancy in Caucasians, it is uncommon among Asians. A recent genome-wide scan of CLL in Caucasians, which was carried out in the UK, identified six variants showing strong association. We attempted to replicate these findings in 71 patients with CLL and 1273 controls in Hong Kong Chinese. Three of the six variants were significantly associated with CLL. The rs872071 variant (Odds Ratio (95% Confidence Interval) = 1.78 (1.25-2.53), P = 0.0013) in the IRF4 gene region showed the strongest association, similar to that reported in the UK study. Polymorphisms in SP140 and ACOXL were also associated with risk of CLL. Further, the mean allele frequencies of the six variants were moderately (59%) to extremely (0.5%) lower in the Chinese population compared with Caucasians. These results suggest that variants in three loci may contribute to risk of CLL among Chinese.

With transfusional iron overload, almost all the excess iron is sequestered intracellularly as rapidly mobilizable, dispersed, soluble ferritin iron, and as aggregated, insoluble hemosiderin iron for long-term storage. Established magnetic resonance imaging (MRI) indicators of tissue iron (R(2), R(2)*) are principally influenced by hemosiderin iron and change slowly, even with intensive iron chelation. Intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool that can change rapidly with iron chelation. We have developed a new MRI method to separately measure ferritin and hemosiderin iron, based on the non-monoexponential signal decay induced by aggregated iron in multiple-spin-echo sequences. We have initially validated the method in agarose phantoms and in human liver explants and shown the feasibility of its application in patients with thalassemia major. Measurement of tissue ferritin iron is a promising new means to rapidly evaluate the effectiveness of iron-chelating regimens.

Using inverse polymerase chain reaction, we identified CD44, located on chromosome 11p13, as a novel translocation partner of IGH in 9 of 114 cases of gastric, nongastric extranodal, follicular, and nodal diffuse large B-cell lymphoma (DLBCL). Notably, these translocations involving IGHSμ were detected in follicular lymphomas and exclusively in germinal center B cell-ike (GCB)–DLBCLs. CD44 is not expressed in reactive GC B cells. The IGHSμ/CD44 translocations substitute Sμ for the CD44 promoter and remove exon 1 of CD44, resulting in the overexpression of Iμ-CD44 hybrid mRNA transcripts activated from derivative 11 that encode a new CD44 variant lacking the leader peptide and with a unique C-terminus (CD44ΔEx1). When overexpressed in vitro in the CD44− GCB-DLBCL cell line BJAB, CD44ΔEx1–green fluorescent protein localized to the cytoplasm and nucleus, whereas CD44s–green fluorescent protein (standard form) localized to the plasma membrane. The ectopic expression of CD44ΔEx1 in BJAB cells enhanced their proliferation rate and clonogenic ability, indicating a possible pathogenic role of the translocation.

Background & Aims: Epstein–Barr virus (EBV) infection has been associated with some cases of gastric cancer. Methods: We studied a case of early onset gastric adenocarcinoma after nonmyeloablative hematopoietic stem cell transplantation for myeloma in a 56-year-old man. Results: The development of gastric adenocarcinoma was preceded by severe graft-versus-host disease (GVHD) necessitating strong immunosuppression, which resulted in an intense reactivation of EBV infection. Three sequential gastric biopsy examinations performed at 100, 130, and 150 days after hematopoietic stem cell transplantation showed gastritis, dysplasia, and adenocarcinoma, respectively. There was no evidence of Helicobacter pylori infection. Quantitative polymerase chain reaction for circulating EBV showed a surge of EBV DNA peaking at the time of gastritis, followed by a gradual decrease afterward with adequate control of GVHD and tailing of immunosuppression. In situ hybridization for EBV-encoded early small RNA showed absence of EBV in the gastritis specimen, but the presence of EBV in the dysplastic and carcinoma specimens. Aberrant promoter methylation of E-cadherin was observed only in the carcinoma specimens, showing that infection with EBV preceded E-cadherin methylation. Conclusions: Mucosal damage caused by GVHD, immunosuppression, and EBV reactivation combined to lead to EBV infection of the gastric cells and initiation of carcinogenesis, suggesting this case to be a genuine EBV-related opportunistic malignancy post-transplantation. An interesting proposition is that this case also might reflect a compacted timeline of events in EBV-related gastric cancers developing in immunocompetent patients.

FLT-3 aberrations that occur as an internal tandem duplication (ITD) or a mutation at the activation-loop position 835, D835, are common in acute promyelocytic leukaemia (APL). We investigated the clinicopathological associations and prognostic impact of FLT-3 aberrations in a cohort of APL patients. FLT-3 exons 11 and 12 were amplified by polymerase chain reaction (PCR), and the ITD was recognized as an increase in the size of the PCR product. FLT-3 exon 17 was amplified, and D835 mutation was identified by loss of an EcoRV site, followed by DNA sequencing. Of 82 patients studied, FLT-3 aberrations were detected in 35 cases (43%) at diagnosis (ITD: 16; D835 mutation: 18; ITD + D835 mutation: 1). FLT-3 ITD, but not D835 mutations, was significantly associated with higher presentation white blood cell count (WBC) and microgranular morphology. Early/induction deaths were related to male sex and high presentation WBC. There was a trend for FLT-3 ITD to be associated with non-remission (P = 0.06). For disease-free survival, high WBC was the only significant adverse factor. Male sex, high WBC and FLT-3 ITD were significant adverse factors for overall survival. These findings have important implications on the possible use of FLT-3 inhibitors in the treatment of APL.

Nasal natural killer (NK)/T-cell lymphoma (NL) frequently co-expresses Fas (Apo-1/CD95) and Fas ligand (FasL), but the tumor cells seldom undergo apoptosis. To determine the reason for failure of apoptosis, we examined Fas mRNA expression in 23 NL cases by reverse transcriptase-polymerase chain reaction and sequenced the entire coding region of the Fas gene in 15 of these cases for which the full-length Fas cDNA could be amplified. The reverse transcriptase-polymerase chain reaction analysis revealed that all of the 23 cases expressed Fas mRNA and the sequencing results showed that in addition to the commonly expressed wild-type Fas mRNA and four alternative splice variants detected in 7 cases, mutant Fas transcripts were present in 9 of the 15 (60%) cases sequenced. With confirmation of some Fas mutations at the gene level, 12 deletions in nine cases and one insertion in one case were eventually identified. To rule out any potential polymerase chain reaction artifacts, the same protocol was used to examine 10 reactive tonsils as a control. No aberrant transcripts associated with deletions were detected in these tonsils except for three alternative splice variants. All of the deletion variants detected in NL contained N-terminal preligand assembly domain but not C-terminal death domain and/or transmembrane domain. Co-detection of the wild-type allele and the mutated Fas alleles without the death domain suggested that a dominant-negative mechanism could block the apoptosis signaling. Moreover, loss of the transmembrane domain could protect the tumor cells from apo-ptosis by producing a soluble form of the Fas receptor. The actuarial 3-year survivals leveled off at 15% for patients carrying the Fas mutations and/or splice variants in the lesions and 49% for those carrying the wild type only, but the difference did not reach statistical significance on the univariate analysis (P = 0.396). Taken together, the findings in this study suggest that frequent Fas gene mutations in NL can result in resistance to apoptosis and may contribute to the pathogenesis of NL by adding to the tumor immune privilege.

Despite several reports of the molecular detection of recurrent lymphoma translocations in reactive lymph nodes (LN), cytogenetic analysis is seldom performed on such cases. We report the clinical and cytogenetic analysis results on 30 reactive LN. Of these, 17 cases yielded either no growth (n = 9) or normal metaphases only (n = 8), and seven of the 17 patients subsequently developed lymphoma. Lymphoma developed in all 10 patients with a clonal karyotype (median of 2.6 months). Three patients (1 HIV-positive) had non-clonal t(3;14) or t(3;22). Their lymphadenopathy resolved spontaneously, and none progressed to lymphoma at 4–6 years of follow-up. Molecular methods detected a small B-cell clone in one case and an oligoclonal B-cell population in the other. Cytogenetic analysis may be useful for interpreting cases of lymphoid hyperplasia. A clonal abnormality is highly predictive of concurrent and/or subsequent lymphoma. A lymphoma-specific but non-clonal abnormality does not necessarily herald the development of subsequent lymphoma. Am. J. Hematol. 70:133–138, 2002.© 2002 Wiley-Liss, Inc.

Recurrent chromosomal translocations in malignant lymphomas most commonly involve 18q21(bcl-2), 8q24 (c-myc) and 3q27 (bcl-6), with an incidence of 27%, 11% and 6%, respectively. Individual cases concurrently harbouring two of these three rearrangements have been previously reported. This report describes four patients with cytogenetic alterations affecting all three loci, which was confirmed by molecular analysis in one case. Clinically, each patient had aggressive B-cell lymphoma with disseminated disease often involving the central nervous system, poor response to chemotherapy and short survival. Activation of c-myc in association with deregulation of bcl-2, bcl-6 or both confers high-grade disease with a poor prognosis.

The purpose of this study was to compare the relative risk of second malignancies in a cohort of patients with hairy cell leukemia (HCL) against the normal population. Potential effects of type of treatment and duration of follow-up and the site distribution of cancer were also examined. Between 1976 and 1996, 117 patients were diagnosed with HCL in British Columbia who were referred to the British Columbia Cancer Agency (BCCA) for treatment. All additional malignancies were traced using a provincial population-based cancer registry and follow-up records from the BCCA. There were 90 men and 27 women. Median age at diagnosis was 53 years. The median follow-up time was 68 months. Twenty-three patients underwent primary splenectomy, 65 received interferon alpha, 24 deoxycoformycin, and 67 cladribine (2-chlorodeoxyadenosine). Thirty-six patients had an additional malignancy (30.7%) with a total of 44 tumors. Six patients (5.1%) had two or more malignancies. Twenty-five patients had malignancies diagnosed after HCL (21.3%), three concurrent with HCL (2.6%), and 12 preceding HCL (10.2%). Second tumors (n = 28 tumors) occurred at a median of 40 months after HCL (range, 3 to 167). The relative rate (RR) of second malignancy among men and women was 2.91 (P < .001) and 1.65 (P = .23), respectively, compared with age and secular trend-matched controls. There were eight prostate cancers, nine nonmelanoma skin cancers, two lung cancers, and four gastrointestinal adenocarcinomas. The RR (90% confidence interval [CI]) in the various treatment groups were: splenectomy (RR = 0.21 to 3.81), purine analogues (RR = 0.60 to 5.69), interferon then purine analogues (RR = 1.60 to 4.31), interferon alone (RR = 1.57 to 8.40). Cancer risk peaked at 2 years after HCL (RR = 4.13) and fell steadily afterwards, reaching a RR of 1.82 at 6 years. Twenty patients died, six due to HCL, 10 due to second malignancies, and four of unrelated causes. HCL patients appear to be inherently prone to malignancies. This appears to be more related to HCL tumor burden than to genetic predisposition or treatment effect. RR tends to fall with time after effective treatment. However, close monitoring for and vigorous prevention of cancer in HCL patients is advisable. © 1998 by The American Society of Hematology.

We report a 48-year-old man presenting with refractory hyperammonemia after orthotopic liver transplantation. On investigation he was found to have acquired hepatic glutamine synthetase deficiency, a rare condition that occurs after organ transplantations. The patient was started on continuous venovenous hemofiltration treatment, but the hyperammonemia did not respond. The patient was then subjected to molecular adsorption recirculation system (MARS) therapy and the ammonia level gradually improved with successive treatments. In conclusion, the response was unlikely due to the hemofiltration component of MARS alone but more probably due to the removal of putative albumin-bound toxin by the adsorption circuit that had ameliorated the internal milieu of the graft and reversed the enzyme deficiency.

Two patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia. Chronic graft-versus-host disease (GVHD) developed, with persistent symptomatic oral lesions. At 2 and 6 years post-HSCT, both patients developed squamous cell carcinoma (SCC) of the tongue in areas previously involved by chronic GVHD. None had any known risk factor for SCC. Histologically, moderate to severe dysplasia was present in noncancerous oral mucosa. Oral SCC is rarely described after HSCT, and a review of the reported cases showed chronic GVHD to be a common risk, suggesting that the chronic inflammation associated with GVHD might be of pathogenetic significance.

Lymphopenia is a marker of inferior survival in patients with various malignancies. However, the prognostic significance of lymphopenia in peripheral T-cell lymphoma (PTCL) is unclear. We analyzed the prognostic significance of lymphopenia in 826 patients with different types of PTCL and natural killer/T-cell lymphoma (NKTCL) from the International Peripheral T-cell Lymphoma Project. Lymphopenia was defined as an absolute lymphocyte count of less than 1,000 cells per microliter. The overall frequency of lymphopenia was 35.3%, ranging from 21.1% in ALK(+) anaplastic large cell lymphoma (ALCL) to 47.5% in angioimmunoblastic T-cell lymphoma (AITL). Lymphopenia was independently associated with an inferior overall survival (OS) in patients with the lymphoma type of adult T-cell leukemia/lymphoma (ATLL), with a 2-year OS of 15% versus 40% for those without lymphopenia (P < 0.001). Lymphopenia was also an adverse predictor of survival in PTCL, not otherwise specified, but was associated with other unfavorable prognostic factors. A trend toward inferior survival for lymphopenic patients was also observed in AITL, ALK(-) ALCL and extranasal NKTCL lymphoma, whereas no difference in survival was found in nasal NKTCL, ALK(+) ALCL, or enteropathy-associated T-cell lymphoma. In this study, lymphopenia was identified as a new adverse prognostic factor in the lymphoma type of ATLL.

In the Asia-Pacific region, autologous and allogeneic bone marrow transplantation (BMT) in patients infected with the hepatitis B virus (HBV) may be complicated by fatal hepatic failure due to viral reactivation. Survivors may suffer from accelerated hepatitis and cirrhosis. We report the first case of hepatocellular carcinoma (HCC) after autologous BMT for mediastinal B cell lymphoma. The tumor developed rampantly during a planned pregnancy 5 years after BMT. Less than 40 cases of HCC complicating pregnancy have been reported, and outcome is invariably poor. Immunosuppression and HBV reactivation after autologous BMT, as well as immune tolerance and hormonal changes associated with pregnancy may contribute to the rapid tumor growth. Biochemical and radiological surveillance for HCC should be strengthened in HBV carriers after BMT, especially in patients with the histology of chronic liver disease, or biochemical/ virological evidence of increased HBV activity.

The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 109/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.

Purpose: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas with the activated B-cell–like subtype characterized by constitutive NF-κB activation. Activating mutations of CARD11 and inactivating mutations of A20 are frequent events in DLBCL. However, the full extent of genetic alterations in the NF-κB pathway regulators and their potential prognostic value in DLBCL remain to be investigated. We investigated the genetic abnormalities of CARD11, A20, and ABIN-1/2/3 (the A20 binding inhibitor of NF-κB) and their clinicopathologic correlation in gastrointestinal DLBCL. Experimental Design: The somatic mutation and copy number changes of CARD11, A20, and ABIN-1/2/3 were investigated in 71 gastrointestinal DLBCLs by PCR/sequencing, and interphase FISH/array comparative genomic hybridization, respectively. The mutations identified were functionally characterized by NF-κB reporter assays and immunoprecipitation experiments. Results: Recurrent somatic mutations were found in CARD11 (10%), A20 (17%), ABIN-1 (4%), and ABIN-2 (3%), but not in ABIN-3. In comparison with the wild-type, all CARD11 mutants were potent NF-κB activators in vitro. On the basis of the destructive nature of the observed mutations, and the findings by reporter assays and immunoprecipitation studies, most if not all of the somatic mutations that were seen in A20, ABIN-1, and ABIN-2 could impair their normal functions. Among these genetic abnormalities, A20 somatic mutation was significantly associated with both poor overall survival and event-free survival. Conclusions: We show further evidence of NF-κB pathway genetic abnormalities in DLBCL, which are potentially valuable in the prognosis and design of future therapeutic strategies. Clin Cancer Res; 17(6); 1440–51. ©2011 AACR.

Natural killer cell lymphoma (NKCL) constitutes a rare and aggressive form of non-Hodgkin lymphoma, and there is little insight into its pathogenesis. Here we show that PRDM1 is a tumor suppressor gene in NKCLs that is inactivated by a combination of monoallelic deletion and promoter CpG island hypermethylation. We observed monoallelic deletion of PRDM1 loci in 8 of 18 (44%) NKCL cases. The other allele showed significant promoter methylation in 12 of 17 (71%) cases. In support of its role as a tumor suppressor gene, the reconstitution of PRDM1 in PRDM1-null NK cell lines led to G2/M cell cycle arrest, increased apoptosis, and a strong negative selection pressure with progressive elimination of PRDM1-expressing cells, which was enhanced when IL-2 concentration is limiting. We observed a progressive increase in PRDM1 expression-in particular, PRDM1α - in normal NK cells in response to IL-2 and in normal NK cells activated with an engineered NK cell target, K562-Cl9-mb21, suggesting its role in NK cell homeostasis. In support of this role, knockdown of PRDM1 by shRNA in normal NK cells resulted in the positive selection of these cells. We identified MYC and 4-1BBL as targets of PRDM1 in NK cells. Disruption of homeostatic control by PRDM1 may be an important pathogenetic mechanism for NKCL., link_to_OA_fulltext

Purpose: To evaluate the reduced transverse relaxation rate (RR2), a new relaxation index which has been shown recently to be primarily sensitive to intracellular ferritin iron, as a means of detecting short-term changes in myocardial storage iron produced by iron-chelating therapy in transfusion-dependent thalassemia patients. Materials and Methods: A single-breathhold multi-echo fast spin-echo sequence was implemented at 3 Tesla (T) to estimate RR2 by acquiring signal decays with interecho times of 5, 9 and 13 ms. Transfusion-dependent thalassemia patients (N = 8) were examined immediately before suspending iron-chelating therapy for 1 week (Day 0), after a 1-week suspension of chelation (Day 7), and after a 1-week resumption of chelation (Day 14). Results: The mean percent changes in RR2, R2, and R2* off chelation (between Day 0 and 7) were 11.9 ± 8.9%, 5.4 ± 7.7% and -4.4 ± 25.0%; and, after resuming chelation (between Day 7 and 14), -10.6 ± 13.9%, -8.9 ± 8.0% and -8.5 ± 24.3%, respectively. Significant differences in R2 and RR2 were observed between Day 0 and 7, and between Day 7 and 14, with the greatest proportional changes in RR2. No significant differences in R2* were found. Conclusion: These initial results demonstrate that significant differences in RR2 are detectable after a single week of changes in iron-chelating therapy, likely as a result of superior sensitivity to soluble ferritin iron, which is in close equilibrium with the chelatable cytosolic iron pool. RR2 measurement may provide a new means of monitoring the short-term effectiveness of iron-chelating agents in patients with myocardial iron overload. Copyright © 2011 Wiley-Liss, Inc., link_to_OA_fulltext

In iron overload, almost all the excess iron is stored intracellularly as rapidly mobilizable ferritin iron and slowly exchangeable hemosiderin iron. Increases in cytosolic iron may produce oxidative damage that ultimately results in cardiomyocyte dysfunction. Because intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool, measurements of ferritin iron potentially provide a clinically useful indicator of changes in cytosolic iron. The cardiovascular magnetic resonance (CMR) index of cardiac iron used clinically, the effective transverse relaxation rate (R 2*), is principally influenced by hemosiderin iron and changes only slowly over several months, even with intensive iron-chelating therapy. Another conventional CMR index of cardiac iron, the transverse relaxation rate (R 2), is sensitive to both hemosiderin iron and ferritin iron. We have developed a new MRI measure, the 'reduced transverse relaxation rate' (RR 2), and have proposed in previous studies that this measure is primarily sensitive to ferritin iron and largely independent of hemosiderin iron in phantoms mimicking ferritin iron and human liver explants. We hypothesized that RR 2 could detect changes produced by 1 week of iron-chelating therapy in patients with transfusion-dependent thalassemia. We imaged 10 patients with thalassemia major at 1.5 T in mid-ventricular short-axis planes of the heart, initially after suspending iron-chelating therapy for 1 week and subsequently after resuming oral deferasirox. After resuming iron-chelating therapy, significant decreases were observed in the mean myocardial RR 2 (7.8%, p0.90). Although the difference between changes in RR 2 and R 2 was not significant (p>0.3), RR 2 was consistently more sensitive than R 2 (and R 2*) to the resumption of iron-chelating therapy, as judged by the effect sizes of relaxation rate differences detected. Although further studies are needed, myocardial RR 2 may be a promising investigational method for the rapid assessment of the effects of iron-chelating therapy in the heart. © 2010 John Wiley & Sons, Ltd., link_to_OA_fulltext

Thalassemia, the most common monogenic disease, is caused by defective and imbalanced production of globin, the protein component of hemoglobin (1,2). Some severely affected individuals develop iron overload as a consequence of regular red blood cell transfusion. Progressive iron accumulation eventually produces potentially lethal injury in the heart, liver, pancreas, and other organs; overall, approximately 67% of patients with thalassemia major die of heart disease (3). Chelating agents being able to bind the excess iron and promote its excretion have been developed, but reliable means to evaluate the effectiveness of treatment are urgently needed because repeated biopsies of liver and heart are not practical clinically (4,5). In the past decade, considerable efforts have been made to develop MRI as a safe, noninvasive, reliable, and quantitative means of measuring tissue iron in various patients with iron overload (6–12). The application of the MR transverse relaxation times T2* and T2 (or the corresponding rates R2* = 1/T2* and R2 = 1/T2) has been successfully demonstrated by several groups for quantitative assessment of the iron concentration in the heart and liver, and mainly at low magnetic field strength (1.5 Tesla [T] or less) (7–9,12–19). T2* measurement can be routinely performed with a single-breathhold multi-echo gradient echo (MEGE) acquisition. However, it is known to be more sensitive to static magnetic field (B0) inhomogeneity and susceptibility effects from the lung–heart interface (20) and possibly the boundaries of cardiac veins (21). Clinically, T2* measurement of myocardial iron is presently the gold standard for monitoring and adjusting chelation in thalassemia patients. In comparison, reliable measurement of myocardial T2 often requires long image acquisition time with single spin-echo (SE) sequences (12). More recent development includes the use of respiratory-navigated free-breathing multi-echo spin-echo (MESE) or accelerated single-breathhold MESE acquisitions (14,15,22,23). With a signal-to-noise ratio (SNR) increase and several other technical improvements, 3T MRI has become an increasingly available and accepted platform for routine clinical investigations and services. However, quantitative cardiac MR at 3T is technically challenging, in part because of substantially increased B0 and B1 inhomogeneity and specific absorption rate (SAR) (24–28). In a recent study, T2* has been investigated and calibrated against liver iron concentration from liver biopsies at 3T (29). However, T2* decreases substantially at 3T, thereby making it difficult to measure the heart and liver T2* reliably in patients with severe iron overload. Although a previous study has shown that T2 is a highly specific index for iron deposition (30), quantitation of myocardial T2 at 3T has not been reported so far in either normal subjects or patients with thalassemia major and other transfusion-related hemosiderosis. In this study, we aimed to investigate the feasibility of quantifying myocardial T2 at 3T in thalassemia and iron overloaded patients using a single-breathhold MESE sequence. Both T2 and T2* measurements at 3T were compared with those obtained at 1.5T in the same patients.

Chronic myeloid leukemia (CML) in Asia has an incidence rather lower than in Western countries yet tends to afflict a younger population. As in the West, imatinib mesylate (IM, Glivec) has supplanted busulphan, hydroxyurea and interferon-alpha as first-line treatment. Its use has resulted in a dramatic decline in the number of hematopoietic stem cell transplantations (HSCT) performed. Although it is expensive, IM induces a complete cytogenetic response in 60-90% of newly diagnosed patients, and up to 10% for those in blastic phase. The standard dose of 400 mg is well tolerated by most patients, although adverse events have been observed, including drug-induced cytopenia. Through the Glivec International Patient Assistance Program, the majority of CML patients has access to IM and can expect prolonged survival, even in the absence of HSCT. However, just as in Western countries, resistance to imatinib has emerged in Asian countries. They will require the novel tyrosine kinase inhibitors (dasatinib, nilotinib) becoming available through either clinical trials or market approval. This review examines the available data on CML in China, Hong Kong, India, the Philippines, Singapore, South Korea, Taiwan and Thailand.

To the editor: Recent data suggest that the incidence of multiple myeloma may be increasing in Taiwan over the past 25 years,[1][1] which elevates concern that myeloma incidence may be increasing in Asia. If true, this may reflect changes in lifestyle, occupational and environmental exposures, and

The BCL10 gene, originally identified through its recurrent involvement in t(1;14)(p22;q32) of the mucosa-associated lymphoid tissue (MALT) lymphoma, encodes a cytosolic protein composed of 233 amino acid residues with proapoptotic and proinflammatory activities.[1][1] B-cell chronic lymphocytic

The presence of extra copies of alpha-globin gene has been shown to worsen the degree of anemia in beta-thalassemia heterozygotes. We describe the clinical phenotype of eight Chinese subjects with heterozygosity for both triplicated alpha-globin gene and a beta0-thalassemia allele. They were identified through genotyping of beta-thalassemia intermedia and major patients, and through community-based thalassemia screening program in Hong Kong. Standard molecular techniques were used in the determination of genotype. All subjects in this series showed five copies of alpha-globin genes (alphaalphaalpha/alphaalpha) in association with a beta0-thalassemia allele. Although genotypically identical, six subjects showed a beta-thalassemia intermedia phenotype while two were clinically indistinguishable from beta-thalassemia minor, implying the presence of genetic modifying factors that remained undefined. Triplication of alpha-globin gene and heterozygosity for beta0-thalassemia accounted for 15% of beta-thalassemia intermedia patients at our locality and was associated with a mild clinical phenotype. This genotype was not found among beta-thalassemia major patients. They presented in adulthood and were usually not transfusion dependent. When compared with simple beta-thalassemia heterozygotes, they showed obvious red cell abnormalities (hypochromasia, anisopoikilocytosis, circulating normoblasts), lower hemoglobin (Hb) and higher HbF levels. The presence of triplicated alpha-globin genes should always be considered in apparent beta-thalassemia carriers who were more symptomatic than expected, so that unnecessary investigations for the cause of anemia could be avoided. Finally, triplication of alpha-globin genes should be looked for in families with children affected by beta-thalassemia intermedia in which only one parent showed a picture of beta-thalassemia on Hb analysis.

Using polymerase chain reaction (PCR), we examined a panel of 10 microsatellite markers (BAT26, BAT40, D2S123, D4S171, D8S87, D10S197, D12S89, Tp53, D18S58, PLCpr) covering nine chromosomal arms for microsatellite instability (MSI) in 29 patients with primary MDS. Bone marrow DNA was compared with corresponding constitutional DNA derived from buccal epithelial cells. Apart from BAT26 and BAT40 that were mononucleotide (poly A) repeats, the others were dinucleotide (CA) repeats. The patients comprised 10 cases of refractory anemia (RA), three cases of refractory anemia with ringed sideroblasts (RARS), nine cases of refractory anemia with excess of blasts (RAEB), four cases of refractory anemia with excess of blasts in transformation (RAEBt), and three cases of chronic myelomonocytic leukemia (CMML). Serial samples were available in seven patients, in which four showed transformation into higher disease grade or acute myeloid leukemia (AML). Genetic alterations at one locus (three at D2S123, one at D4S171) were evident in four cases, and loss of heterozygosity at Tp53 was detected in one case. Accordingly, none of the 29 patients with primary MDS nor the seven with disease progression in this study exhibited MSI. This shows that MSI may not be important in the pathogenesis or progression of MDS in contrast to other genetic mechanisms, notably recurrent chromosomal abnormalities that dysregulate the expression or function of genes controlling cell growth, differentiation and apoptosis.

Acute renal tubular necrosis due to grass carp ingestion in a myeloma patient after allogeneic stem cell transplantation

Cytogenetic and molecular analyses have demonstrated that alteration of 3q27 and/or BCL6 is one of the most common genetic abnormalities in B-cell lymphomas.[1][1] BCL6 translocations involve not only immunoglobulin (IG) genes but also a number of non- IG loci as partners.[2][2] Using the relatively

Abstract 898 Burkitt Lymphoma (BL) is a highly proliferative form of non-Hodgkin lymphoma and is characterized by translocation of the C-MYC gene to the immunoglobulin gene loci resulting in deregulation. The role of collaborating gene mutations in BL is largely unknown. We performed whole exome sequencing and gene expression profiling of 57 Burkitt lymphoma and 94 DLBCL exomes. Mutational analysis revealed that ID3 is recurrently mutated in 38% of Burkitt lymphoma samples. ID3 mutations did not occur in any of the 94 DLBCL cases. ID3 gene expression was also found to be a distinguishing feature of Burkitt lymphomas (P We explored the biological significance of ID3 mutations by initially comparing the gene expression profiles of BL cases that had mutated and wild-type ID3. Gene set enrichment analysis showed that those samples with mutated ID3 had higher expression of genes that were involved in cell cycle regulation, specifically those involved in the G1-S transition (P=0.01). In order to experimentally investigate the functional consequences of ID3 mutation, we generated mutant constructs corresponding to six different ID3 mutations observed in BLs. These mutant constructs were cloned into lentiviral vectors and overexpressed in BL cells that were wild type for ID3. We then performed cell cycle analysis for these wild type cells expressing GFP controls or the mutant constructs. We found that BL cells expressing each of the six mutant constructs demonstrated significant cell cycle progression from G1 to S phase compared to wild-type (P=0.01). Separately, we tested the effects of expressing mutant ID3 in cell proliferation assays and found that cells expressing mutant ID3 were considerably more proliferative than those expressing wild type (P=0.03). Conversely, we over-expressed the wild type form of ID3 in BL cells that had mutated ID3. These experiments completely rescued the observed phenotypes of the mutant ID3 constructs, with reduced cell cycle progression through increased G1 phase and decreased S-phase (P=0.04). We also noted decreased cell proliferation in these cells (P=0.03). These experiments support a role for ID3 as a novel tumor suppressor gene in Burkitt lymphoma. ID3 is a basic helix loop helix (bHLH) protein that binds to other E-proteins, blocking their ability to bind DNA. ID3 has been shown to be involved in a variety of biological processes including development and T and B cell differentiation. ID3 knockout mice have been shown to develop T cell as well as B cell lymphomas. Our data implicates this gene for the first time as a tumor suppressor in human cancer. Disclosures: No relevant conflicts of interest to declare.

Abstract 679 Background: Peripheral T-cell lymphoma (PTCL) represents approximately 10–12% of all non-Hodgkin lymphoma (NHL) in the Western world, with a higher incidence in Asian populations. The World Health Organization classification recognizes a number of distinctive subtypes of PTCL including angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), extranodal NK/T-cell lymphoma of nasal type (ENKTCL), and many other rare entities that present mainly as extranodal PTCL. However, with current immunophenotypic and molecular markers, about 30–50% of PTCL cases are not classifiable and are categorized as PTCL-not otherwise specified (PTCL-NOS). With the exception of ALK(+)ALCL, the PTCLs generally have a poor outcome and, thus a better understanding of the biology of these diseases is greatly needed to improve the long-term survival of these patients. Methods: In the current study, we performed gene expression profiling analysis on a large and well- characterized series of PTCL and ENKTCL cases (n=372) from the Lymphoma Leukemia Molecular Profiling Project (LLMPP), the International Peripheral T-cell Lymphoma Project (IPTCL) and other major institutions to define robust molecular classifiers, oncogenic pathways and prognosticators for the more common PTCL entities, as well as unique molecular and prognostic subgroups within PTCL-NOS. Molecular signatures for diagnosis and prognosis were generated in training data sets and validated in separate cohorts. Results: Robust molecular classifiers for AITL, two types of systemic ALCL (ALK(+) and ALK(-)), ATLL and ENKTCL were identified (Figure 1). These classifiers reflect the pathobiology of the tumor cells, as well as their microenvironment, and represent a refinement of what we reported previously (Iqbal et.al Blood, 2010; Iqbal et.al Leukemia. 2011). Importantly, ALK(-)ALCL can be differentiated from ALK(+)ALCL and PTCL-NOS with a unique gene expression signature. Approximately 14% of PTCL-NOS were re-classified as ALK(-)ALCL and showed expression of CD30 protein, TIA-1 or granzyme B by immunohistochemistry. ENKTCL can be separated molecularly into NK-cell lymphoma and gd-PTCL, the latter of which was also identified in 9% of PTCL-NOS. The remaining PTCL-NOS cases could be separated into two major subgroups related to T-cell differentiation and characterized by either high expression of GATA3 (30%) or TBX21(T-BET) (45%) and many of the corresponding target genes (Figure 2). Cases with high expression of GATA3 had poor overall survival and showed enriched Wnt and mTOR pathways, but no prominent microenvironment signature. The high TBX21 subgroup had a remarkably good outcome for patients with a high plasma cell-like gene expression signature, but poor overall survival when expressing a high cytotoxic signature (Figure 3). The molecular prognosticator for AITL largely reflected the role of the tumor microenvironment, with the presence of a high B-cell signature correlating with favorable outcome, whereas high dendritic cell/monocyte signatures were associated with inferior survival. Conclusion: We have organized the most comprehensive molecular profiling study of PTCL, and have not only refined the molecular diagnostic and prognostic signatures for the common subtypes of PTCL, but also segregated PTCL-NOS in meaningful biological and prognostic subtypes. Molecular diagnostic and prognostic signatures of PTCL frequently include components of the tumor-host interactions, highlighting the importance of the microenvironment in PTCL biology. This study provides an important framework for additional analysis to identify novel therapeutic targets to improve the outcome of patients with PTCL. Disclosures: No relevant conflicts of interest to declare.

Abstract 433 Burkitt lymphoma (BL) is a relatively uncommon lymphoma, but is clinically important because it is curable when diagnosed properly. BL is also an important model disease for studying cancer. Chromosomal translocations of the MYC gene are a defining feature of BL. Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma in adults and demonstrates overlapping morphology, immunophenotype and clinical behavior with BL. The genetic causes and the role of specific mutations in BL are largely unknown. Th e decoding of the human genome and the advent of high-throughput sequencing have provided rich opportunities for the comprehensive identification of the genetic causes of cancer. We began by sequencing 2 complete lymphoma tumor genomes (and paired normal tissue) derived from DLBCL and BL respectively. The pattern of somatic base alterations in both DLBCL and BL genomes indicated a predominance of G→A/C→T and A→G/T→C transitions (P In order to comprehensively identify genes that are recurrently mutated in DLBCL and BL, we obtained a total of 95 cases of DLBCLs and 60 cases of BL. The DLBCL cases were divided into a discovery set (N=34) and a prevalence set (N=61). The Burkitt cases were also divided into discovery and prevalence sets (N=15, N=45 respectively). For each of the discovery set cases we also obtained paired normal tissue. We performed whole-exome sequencing for all of these using the Agilent solution-based system of exon capture, which uses RNA baits to target all protein coding genes (CCDS database), as well as ∼700 human miRNAs from miRBase (v13). In all, we generated over 6 GB of sequencing data using high throughput sequencing on the Illumina platform. We identified 525 candidate cancer genes that were recurrently somatically mutated in DLBCL and BL. We found that each tumor had an average of 20 gene alterations, which is fewer than most other solid tumors sequenced to date. Commonly implicated biological processes comprising these genes included signal transduction (e.g. PIK3CD, PDGFRA) and chromatin modification (e.g. MLL3, SETD2), affecting 17.2% and 14.8% of the total genetic events respectively. We found several genes related to cancer that were commonly mutated in both BL and DLBCL, including MYC, BTG1 and SETD2. Mutations in MYC were much more common in BL compared to DLBCL, suggesting that mutation of MYC might serve as an independent oncogenic mechanism in BL, in addition to chromosomal translocations. Many known cancer genes were found to be exclusively mutated in BL including SMARCA4, a gene known to regulate the expression of CD44 which is implicated in tumorigenesis. This study represents one of the first in-depth analyses of a BL genome and one of the largest applications of exome sequencing in cancer. Our data provide the most comprehensive genetic portrait of human BL to date, and provides a significant first step to identifying the genetic causes of the disease. Disclosures: No relevant conflicts of interest to declare.

Abstract 803 Diffuse large B-cell lymphomas (DLBCL) is the most common form of lymphoma and these tumors demonstrate a striking molecular and clinical heterogeneity. Gene expression profiling has shown that these tumors can be divided into at least two groups, activated B cell-like (ABC) and germinal B cell-like (GCB), as well as a number of other cellular processes underlying survival and tumor biology. However, the molecular mechanisms which lead to the differential gene expression patterns are not well understood. Alternative splicing is a process through which individual exons that comprise genes that are assembled into different gene isoforms with potentially different function. Alternative splicing has been shown to be a ubiquitous mechanism of gene regulation in eukaryotes and a number of cancers. The role of alternative splicing in DLBCL is unknown. We hypothesized that alternative splicing might play an important role in DLBCL. We measured genome-wide expression of over 1 million exons in 106 primary DLBCL tumors using Affymetrix Exon 1.0 ST microarrays. The same cases were also profiled for gene expression using a conventional Affymetrix Gene microarray for comparison, and further sub-classified as the molecular subgroups of DLBCL and for independent assessment of gene expression associated with known biological processes. We identified those genes as alternatively spliced which had at least one exon that was significantly different (P We further investigated whether lineage-specific effects were responsible for some of the observed differences in splicing in the molecular subgroups of DLBCLs. We obtained normal resting B cells from healthy donors and stimulated them with IgM and CD40-ligand to generate activated B cells. We found that the gene-isoforms expressed highly in activated normal B cells were significantly enriched in ABC-DLBCLS (P Our data indicate that alternative splicing provides an additional and significant component of regulation that encompasses nearly every biological process that is known to be important in DLBCL. Future studies that examine the role gene expression will need to recognize the specific isoforms that result in proteins with altered function. Disclosures: No relevant conflicts of interest to declare.

Abstract 1082 Background: The prognosis of patients with APL has improved with all trans-retinoic acid (ATRA) and arsenic trioxide (As2O3) therapy. An increasing frequency of isolated CNS relapse is reported in APL survivors and intrathecal prophylaxis has been proposed. We have used oral As2O3 as prolonged maintenance therapy for APL patients in first remission (CR1) and beyond. During oral As2O3 therapy, elemental arsenic penetrates the CNS at meaningful levels. The risk factors for CNS APL in this setting are unknown. Material and methods: From 2001 to 2009, consecutive APL patients in ATRA +/− chemotherapy-induced CR1, or As2O3 +/− chemotherapy-induced CR2 and beyond, were given As2O3 maintenance therapy, comprising oral As2O3 therapy (10mg daily) and ATRA (30mg twice daily), given two weeks every two months for two years. CNS leukemia was diagnosed by the presence of typical APL cells in the cerebrospinal fluid (CSF). Patients with CNS leukemia were treated with intrathecal methotrexate (12 mg twice weekly until clearing of CSF) and oral-As2O3, ATRA and ascorbic acid. Results: A total of 102 APL patients (46 men, 56 women) at a median age of 43 (13–43) years received oral As2O3 maintenance during CR1 (n=63) and CR2 or beyond (n=39). The median follow-up period was 55 (8–143) months. At initial presentation, the hematological parameters were hemoglobin: 8.5 (3–14.6) g/dL, white cell count: 10.1 (0.3–121) × 109/L (with 21 cases >10 × 109/L) and platelet count: 35 (3–162) × 109/L (with 67 cases 15 × 109/L) developing either during ATRA or As2O3 treatment occurred in 62 patients. For the whole cohort, the median peak leucocyte count at any time point in the clinical course was 29.3 (0.8–243) × 109/L. Eight patients (7 men, 1 woman, median age 49 years) developed CNS leukemia, at a median of 42 (1–56) months from commencement of As2O3 maintenance. All had a history of elevated peak WCC, at a median of 69.5 (26–123) × 109/L. Symptoms included headache (n=3), dizziness (n=2), confusion, blurred vision and leg weakness. The median CSF cell count was 35 (7–2500) × 106/L. Concurrent marrow morphologic relapse was found in 4 cases (first relapse, R1, n=1; R2, n=3). Four patients had normal blood counts and marrow morphology (still in CR1, n=1; CR2, n=3), although their peripheral blood cells were positive for PML-RARA by polymerase chain reaction. All patients responded completely to treatment initially, but recurrent CNS leukemia still occurred in 4 cases after 12–16 months. Additional treatment including cranial radiotherapy (n=6), systemic high dose cytarabine (n=2) and autologous hematopoietic stem cell transplantation (n=1). Three patients ultimately died of refractory APL at a median of 13 months after CNS relapse. On univariate analysis, risk factors for CNS relapse were male gender (RR 6.8, p=0.001), and leucocytosis at any time point (for WCC > 15×109/L, RR 8.4, p=0.004; for WCC > 20×109/L, RR 12.1, p Conclusions: With prolonged survival of APL patients, CNS leukemia is emerging as an important problem that curtails survival. Based on the use of oral As2O3 maintenance, patients who at any time point in the clinical course developing a leucocytosis of > 15–20 × 109/L are at high risk of CNS relapse and should be considered suitable candidates for CNS prophylaxis. Disclosures: Off Label Use: Oral arsenic trioxide for maintenance of APL in remission. Kwong:HKU: YL Kwong is an employee of the University of Hong Kong that holds a patent for oral arsenic trioxide.

Abstract 313 Background: Natural Killer (NK) cell lymphomas (NKCL) are rare with aggressive clinical behavior. The majority of these cases belong to extra-nodal NK/T-cell lymphoma of nasal type (ENKTL) of the current World Health Organization (WHO) classification scheme. ENKTL also includes peripheral T-cell lymphomas (PTCL) that are similar in many respects to the NK cell counterpart. Due to rarity of the disease and difficulty in obtaining adequate biopsy specimens, the molecular mechanisms underlining ENKTL are largely unknown. We profiled a series of NK-cell lymphoma cases and many well- characterized cell lines of NK- and T-cell lineages to define molecular classifiers that can distinguish NKCL from PTCL, including lymphomas of cytotoxic T-cells. We also evaluated oncogenic pathways in these tumors and the therapeutic potential of a novel inhibitor of a cell cycle regulator (aurora kinase A). Patients and Methods: The gene expression profiling (GEP) of ENKTL (n=21) and PTCL-U (n=50) cases were performed using HG U133 plus 2 arrays (Affymetrix Inc, CA). GEP of other PTCL subtypes (n=90), normal NK and T cells (resting and activated), NK and T cell lines (n=14) and indolent NK- cell/large granular lymphocytic proliferation (NK-LGLP) (n=5) were used for comparative analysis. Immunohistochemistry (IHC) was used to validate the GEP findings. A novel aurora-kinase-A inhibitor (MK-8745) was obtained from Merck & Co (Merck & Co., Inc. NJ, USA) and incubated with the cell lines for 2 -24 hours at 0.1-1 μM concentrations. Results: The ENKTL showed a male predominance (2:1) with a median age of 55 years at diagnosis and aggressive clinical behavior [5-year OS ( Conclusion: The NKCL molecular classifier identified lymphomas of NK-cell origin as well as a unique subset of γδ T cell lymphoma. These tumors are derived from cytotoxic cells of the innate immune system associated with epithelial surfaces. They have a different GEP from the T-cell lymphomas derived from αβ cytotoxic T-cell and even other γδ T cell lymphoma such as HSTCL which may be derived from an ontogenically and functionally distinct subset of γδ T cells. The role of enriched pathways in NKCL pathogenesis and biology requires further investigation. The effectiveness of the Aurora-kinase A inhibitor in inducing apoptosis of NK-cell lines suggests that it may be a candidate for use in clinical trials in NKCL. Disclosures: No relevant conflicts of interest to declare.

Abstract 2064 Poster Board II-41 Background. Arsenic trioxide (As2O3) is a standard medication in the management algorithm of patients with acute promyelocytic leukemia (APL). With the advent of oral As2O3, outpatient treatment, convenient dosing and long-term post-remission maintenance therapy have become possible. The pharmacokinetics, efficacy and safety profile of short-term oral As2O3 therapy are well-defined. With prolonged oral-As2O3 therapy, possible accumulation of elemental arsenic and its possible long-term side effects must be determined. Materials and methods. Paired peripheral blood (PB) and bone marrow (BM) (aspirate and trephine biopsy) specimens were prospectively collected as part of an oral-As2O3 treatment protocol of patients. The samples were separated into plasma (P), white blood cell (WBC) and red blood cell (RBC) fractions. Elemental arsenic was measured by inductively coupled plasma-mass spectrometry (ICP-MS, ELAN DRCplus 6100, PerkinElmer-SCIEX, Canada) after dilution with 2% nitric acid +/– 3% methanol. Bone marrow trephine biopsies were dried at 65°C overnight, completely digested with acid, and diluted to appropriate concentrations. Results. There were 15 male and 11 female APL patients. Seven WBC specimens could not be analyzed due to inadequate material. Specimens were collected at 1 month (Group 1), 2–12 months (Group 2) and 24–41 months (Group 3) after cessation of oral-As2O3 treatment. The median cumulative dose of oral-As2O3 was 1980 (560–3680) mg. As control, samples were obtained from 12 anonymous individuals, whose specimens were collected as part of their diagnostic evaluations. These controls had no known medicinal exposure to arsenic. The mean elemental arsenic levels in the specimens were shown below. Elemental arsenic levels in group 1 were significantly higher than groups 2 and 3 in all specimens tested. However, groups 2 and 3 were comparable to controls, indicating that arsenic was rapidly excreted once oral-As2O3 treatment was stopped. In group 1 patients, all specimens tested showed comparable arsenic levels. In group 2 patients, arsenic levels were significantly higher in BM–WBC (but not PB-WBC) as compared with PB-P and BM-P (p=0.043 for both). In group 3 patients, all cellular specimens tested showed comparable arsenic levels to plasma levels. Conclusion. Immediately after cessation of treatment when plasma arsenic level was still high, elemental arsenic was distributed comparably in different compartments. However, when plasma arsenic levels started to decline, preferential concentration of arsenic occurred in the cellular compartments. This could be related to transfer of arsenic in bones to the developing hematopoietic cells in the marrow milieu. Finally, two or more years after cessation of As2O3 therapy, elemental arsenic levels returned to control levels; a reassuring observation that long-term arsenic accumulation did not take place when oral-As2O3 was used therapeutically during a finite period of time. Disclosures: Off Label Use: Oral arsenic trioxide is a novel preparation or arsenic trioxide currently under consideration for registration in Hong Kong for APL treatment. The University of Hong Kong holds the patent for the product.

Background: The use of magnetic resonance imaging (MRI) for organ specific iron assessment has allowed better tailoring of chelation therapy. Since endocrine failure is common in thalassemia major (TM) patients, we explored the utility of rapid T2* MRI assessment of hemosiderosis in the pancreas and pituitary. The results were correlated with standard T2* heart and liver MRI assessments and clinical data. Material and methods: A total of 180 TM patients (M:F = 91:89, median age, range 12–48) were scanned on a 1.5 T scanner. (Sonata, Siemens Medical, Erlanger, Germany). T2* myocardium was assessed by a cardiac gated single breath hold 8-echo sequence (CMRtools; London, UK). The T2* liver, pancreas and pituitary were performed by a breath hold 20-echo sequence. Subcutaneous deferoxamine was used for chelation, except for addition of deferiprone in 24 cases for 1 year. Results: There was a high incidence of hemosiderosis of heart (severe T2* Conclusions: MRI pituitary and pancreatic evaluation is viable in a cohort of poorly chelated Chinese thalassemia major patients on subcutaneous deferoxamine treatment. However, an abnormal cardiac T2* result is a good surrogate for endocrine iron overload and appeared more relevant in predicting endocrine complications.

To the Editor: A 42-year-old Chinese woman suffered from acute lymphoblastic leukemia (ALL) with t(9;22) and achieved complete remission with induction chemotherapy without imatinib mesylate (STI-571). She had one 40-year-old HLA identical sister from Fujian province, China. However, repeated human T cell lymphotrophic virus (HTLV-1+2) serology (Serodia, Fujirebio, Tokyo, Japan) on two occasions, 3 months apart, showed indeterminate HTLV-1 results, with Western blot reactivity to p21, p19, p26, p28, and p36 but not p32, p24, or GD21 (HTVL WB, version 2.4, Genelabs Diagnostics, Singapore). Both the donor and her spouse denied venereal exposure, overseas travel, or use of blood products or intravenous drugs. Polymerase chain reaction (PCR) tests for HTLV DNA sequences GD21, Gp46, and Pol on donor serum, whole blood, and mononuclear cell pellet were repeatedly negative [1]. After counseling, stem cell transplantation (SCT) was performed using cyclophosphamide and total body irradiation conditioning, and G-CSF mobilized peripheral blood stem cells were infused (9.88 10 8 /kg mononuclear cells, 2.07 10 6 /kg CD34). The patient engrafted with Grade 2 GVHD and cytomegalovirus re-activation was treated with steroids and gancyclovir. However, ALL relapsed on day 75. A second complete remission was achieved with STI-571, and a second unrelated donor SCT was planned. HTLV-1 serology and PCR in the recipient remained negative at 5 months. This is the first report of the use of HTLV-1 indeterminate donors for HSCT. Indeterminate HTLV status can be due to low-level viraemia or may be due to interfering virus or autoimmune conditions. The risk of true infection is higher in endemic areas. Although the local incidence of HTLV-1 seropositivity is below 0.004% [1], the proximity of Fujian to endemic areas (Japan and Taiwan) warranted extra caution. Among indeterminate Western results, certain HTLV Western blot patterns have stronger correlations with PCR positivity, and subsequent confirmed seropositivity for HTLV-1 [2]. However, in our case the Western blot pattern fall into the low risk category, and viral DNA detection was negative in all specimens. Hence, infective HTLV-1 viral particles were very unlikely to be present. Inadvertent transmission of HTLV-1 after SCT has been reported [3] and leads to early seroconversion due to transmission of infected lymphocytes. The negative HTLV tests at latest follow-up suggested that HSCT-related transmission of viral infection has not occurred in our case. The FDA required that all blood, tissue, and organ donors are screened for HTLV-1, but there is no absolute consensus on the use of HTLV-1 positive donors. The world marrow donor association listed HTLV-1 positivity as a contraindication to voluntary donation [4], but the national marrow match registry allows the use of such donors (except for cord blood) under certain circumstances. For HTLV-1 indeterminate status, there are no guidelines at all. In our case, the superior availability and outcome of matched sibling over unrelated HSCT justified the theoretical risk of HTLV-1 indeterminate serology [5]. It is uncertain whether the serological abnormality in the donor may be associated with inferior immunity leading to weakened graft versus leukemia effect and early relapse. WING Y. AU

Background: Due to their lower incidence, pathological heterogeneity and varied geographical distribution, the clinicopathological features and prognostic factors in mature T/NK cell lymphomas have not been comprehensively studied in international studies. Materials and methods: Consecutive adult new cases of mature T cell neoplasms from 1990–2002 from 21 clinical centers in 13 countries were reviewed. NK/T nasal/nasal type lymphoma was defined by standard WHO criteria after central review. Results: Among 1159 cases of proven T cell lymphomas, 136 cases (11.7%) of NK/T lymphomas were registered (nasal 68%, nasal-type 26%, aggressive or unclassified 6%). Its incidence among T cell lymphoma was higher in Oriental (22%) than in Western countries (4%) and in Continental Asia (43%) than in Japan (11%, 19% excluding ATLL), where nasal-type subcategory is particularly uncommon (6% vs 42%). The median age was 49 years with male to female ratio of 2:1. The nasal-type cases had higher stage (p=0.0002) and LDH (p=0.01), more B symptoms (p=0.042), bulky disease (p=0.026) and poorer performance status (p50% (p=0.05), transformed T cell >40% (p=0.022), raised CRP (p=0.025), hemoglobin Conclusion: The prognosis of nasal/nasal-type lymphoma is distinctly worse than other categories of peripheral T cell lymphomas. The clinical feature, treatment response and epidemiology of nasal type lymphoma is different from that of nasal NK lymphoma and the poor response preclude the finding of any favorable prognostic factors. There are still grounds for developing a better prognostic model for nasal cases to triage patients to more aggressive or novel treatment.