Leukemia Research

Editorial Board

2010-10-01

BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: A review

2010-10-01

Abstract: Chronic Myeloid Leukemia (CML) is a clonal disease characterized by the presence of the Philadelphia (Ph+) chromosome and its oncogenic product, BCR-ABL, a constitutively active tyrosine kinase, that is present in >90% of the patients. Epidemiologic data indicates that almost 5000 new cases are reported every year and 10% of these patients eventually succumb to the disease. The treatment of CML was revolutionized by the introduction of imatinib mesylate (IM, Gleevec®), a BCR-ABL tyrosine kinase inhibitor (TKI). The clinical use of specific BCR-ABL inhibitors has resulted in a significantly improved prognosis, response rate, overall survival, and patient outcome in CML patients compared to previous therapeutic regimens. However, the complete eradication of CML in patients receiving imatinib was limited by the emergence of resistance mostly due to mutations in the ABL kinase domain and to a lesser extent by molecular residual disease after treatment. The second-generation BCR-ABL TKIs nilotinib (Tasigna®) and dasatinib (Sprycel®), showed significant activity in clinical trials in patients intolerant or resistant to imatinib therapy, except in those patients with the T315I BCR-ABL mutation. Identifying key components involved in the CML pathogenesis may lead to the exploration of new approaches that might eventually overcome resistance mediated to the BCR-ABL TKIs. Here, we present an overview about the current treatment of Ph+ CML patients with the TKIs and the obstacles to successful treatment with these drugs.

Genetic variation and the risk of acute lymphoblastic leukemia

Charles G. Mullighan — 2010-10-01

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, and has long been one of the best characterized tumors at the genetic level . ALL may be of B or T lymphoid lineage, and comprises a group of disorders characterized by recurring chromosomal alterations including aneuploidy (hyper- and hypodiploidy) and chromosomal rearrangements that commonly dysregulate hematopoietic transcription factors and tyrosine kinases . These alterations are important initiating events in leukemogenesis, and influence treatment outcome, yet usually do not alone cause leukemia in experimental models. There has consequently been considerable interest in recent years in leveraging genome-wide technologies to profile inherited and somatic (tumor-acquired) genetic alterations in the leukemia genome at high resolution . This work has resulted in the identification of a remarkable range of recurring submicroscopic somatic DNA copy number alterations in ALL, most commonly loss-of-function deletions targeting genes regulating key cellular pathways including lymphoid development, cell cycle regulation and tumor suppression, regulation of apoptosis, cell signaling, and drug responsiveness . These alterations are significantly associated with ALL subtype , and also influence disease outcome .

Genome-wide association study of childhood acute lymphoblastic leukemia in Korea

2010-10-01

Abstract: We conducted a genome-wide association study of childhood acute lymphoblastic leukemia (ALL) in a case–control study conducted in Korea. Incident childhood ALL cases (n=50) and non-cancer controls (n=50) frequency-matched to cases by age and sex, recruited from three teaching hospitals in Seoul between 2003 and 2008, were genotyped using Affymetrix SNP Array 6.0 platform. ALL risks were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age and birth weight. The false discovery rate (FDR) was used for adjusting multiple tests. Of these 1 million SNPs, six SNPs in 4 genes (HAO1 rs6140264, EPB41L2 rs9388856, rs9388857, rs1360756, C2orf3 12105972, MAN2A1 rs3776932) were strongly associated with childhood ALL risk (Pdominant≤0.0001 and Ptrend<0.006). These SNPs remained significant after FDR adjustment (FDR value <0.2). Our genome-wide association study in Korea children identified a few genetic variations as potential susceptibility markers for ALL, warranting further replication studies among various ethnic groups.

DNA repair XRCC1 Arg399Gln polymorphism alone, and in combination with CYP2E1 polymorphisms significantly contribute to the risk of development of childhood acute lymphoblastic leukemia

2010-10-01

Abstract: It is now well established that genetic polymorphisms impairing the DNA repair capacity can disrupt the genomic integrity and potentially modulate individual's susceptibility to various cancers. In this study, we investigated the possible association of X-ray repair cross-complimenting group 1 (XRCC1) Arg399Gln and Arg194Trp variants with the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population comprised of 190 healthy controls and 167 ALL patients. For Arg399Gln polymorphism, the heterozygous (Arg/Gln) and homozygous mutant (Gln/Gln) genotypes were significantly more common in the ALL patients than the controls (OR: 1.6, p=0.04). Particularly, the Gln399Gln genotype significantly increased the risk of disease up to 2.0-fold (OR: 2.0, p=0.04). Besides, Gln399Gln genotype has been found to be associated with considerably increased risk of ALL among females (OR=2.9, p=0.03). In case of codon 194 polymorphism, no significant associations have been found with risk of childhood ALL. In addition, none of the combinations of XRCC1 codon 194 and 399 polymorphisms have been found to be significantly associated with childhood ALL risk. In the scope of this study, we have also showed that the co-presence of XRCC1 codon 399 and CYP2E1*5B and *6 polymorphisms (data for CYP2E1 polymorphisms drawn from previously published study conducted in our lab) in the same individuals considerably increased the risk for childhood ALL to 3.7-fold with borderline significance (p=0.049). The observed combined effect was considerably more prominent among females (OR=17.4, p=0.001) and need to further investigation. This is the first study showing combined associations of XRCC1 399Gln, CYP2E1*5B and *6 alleles with the risk of development of childhood ALL.

The MIF −173G/C polymorphism and risk of childhood acute lymphoblastic leukemia in a Chinese population

2010-10-01

Abstract: Migration inhibitory factor (MIF) has recently been defined as a novel pro-tumorigenic factor that promotes cell proliferation, migration, and invasion. The MIF −173C allele results in increased MIF promoter activity and is associated with a higher serum MIF level. We hypothesized that this polymorphism may contribute to childhood acute lymphoblastic leukemia (ALL) susceptibility. We genotyped the MIF −173G/C polymorphism (rs755622) in 346 ALL cases and 516 cancer-free controls in a Chinese population and found that the variant genotype GC and the combined genotypes GC/CC were associated with a significantly higher risk of childhood ALL [adjusted odds ratio (OR)=1.39, 95% confidence interval (CI)=1.01–1.93 for GC and adjusted OR=1.38, 95% CI=1.01–1.89 for GC/CC]. In addition, we found that the increased risk was more pronounced among high-risk ALL and B-phenotype ALL patients. Our results suggest that the MIF −173G/C polymorphism is involved in the etiology of childhood ALL and is a potential candidate gene for determining cancer susceptibility. Further validations in other populations are warranted.

Differential cytogenomics and miRNA signature of the Acute Myeloid Leukaemia Kasumi-1 cell line CD34+38− compartment

2010-10-01

Abstract: The t(8;21) Acute Myeloid Leukaemia (AML) Kasumi-1 cell line with N822K KIT mutation, is a model system for leukemogenesis. As AML initiating cells reside in the CD34+CD38− fraction, we addressed the refined cytogenomic characterization and miRNA expression of Kasumi-1 cell line and its FACS-sorted subpopulations focussing on this compartment. By conventional cytogenetics, Spectral-Karyotyping and array-CGH the cytogenomic profile of Kasumi-1 cells evidenced only subtle regions differentially represented in CD34+CD38− cells.Expression profiling by a miRNA platform showed a set of miRNA differentially expressed in paired subpopulations and the signature of miR-584 and miR-182 upregulation in the CD34+CD38− fraction.

FISH analysis of circulating CD34+ cells as a new tool for genetic monitoring in MDS: Verification of the method and application to 27 MDS patients

2010-10-01

Abstract: In myelodysplastic syndromes (MDS) chromosomal anomalies can be identified in 50–80% of patients. They have a diagnostic and prognostic impact and are increasingly considered for therapeutic decisions. Cytomorphology and cytogenetic analyses of bone marrow (bm) cells define the goldstandard to diagnose MDS patients and to document treatment response. We present a novel method using peripheral blood (pb) for frequent cytogenetic monitoring: after immunomagnetic cell separation circulating CD34+ cells were analysed by fluorescence in situ hybridization (FISH). We compared FISH analyses of enriched and non-enriched pb and bm cells with conventional chromosome banding analyses of bm metaphases: analysing circulating CD34+ cells by FISH is a sensitive, reliable method to measure the abnormal cell clones in pb. This method is practicable, non-invasive, representative for the clonal situation in the bm, and has a predictive value. Its feasibility was proven in a cohort of 27 MDS patients.

FLT3 and KIT mutated pediatric acute myeloid leukemia (AML) samples are sensitive in vitro to the tyrosine kinase inhibitor SU11657

2010-10-01

Abstract: New treatment strategies to improve the outcome of pediatric acute myeloid leukemia (AML) are required as 40% of children diagnosed with AML do not survive. Around 30% of pediatric AML patients harbour a mutation in the tyrosine kinases FLT3 (±20%) or KIT (±10%). In this study we investigated whether pediatric AML samples (N=61) were sensitive to the tyrosine kinase inhibitor SU11657 (similar to the clinically available drug sunitinib) in vitro, and whether sensitivity was related to expression of, and mutations in, FLT3 and KIT. Overall, SU11657 showed only moderate cytotoxicity. A FLT3 mutation was detected in 35% and a KIT mutation in 8% of the samples. FLT3 and KIT mutated samples were significantly more sensitive to SU11657 than WT KIT and FLT3 samples. Samples without KIT or FLT3 mutations, but with a high wild-type (WT) KIT expression were significantly more sensitive to SU11657 than samples with low KIT expression. Further clinical evaluation of SU11657 and sunitinib combined with chemotherapy would be of interest. Inclusion in clinical trials should not be restricted to patients with FLT3 or KIT mutations.

Influence of high expression of Smac/DIABLO protein on the clinical outcome in acute myeloid leukemia patients

2010-10-01

Abstract: The role of the Smac/DIABLO protein, a novel apoptosis agonist, in acute myeloid leukemia (AML) is not clearly determined. The expression of Smac/DIABLO protein in AML leukemic cells and its relationship with clinical outcome was evaluated in this study.The intracellular expression of Smac/DIABLO protein was assessed using multi-color flow cytometry in 71 newly diagnosed AML patients treated with conventional chemotherapy. It was found that the high expression of Smac/DIABLO protein was an independent prognostic factor in terms of higher complete remission rate (p<0.001) and longer overall survival (p=0.003). Moreover the low expression of Smac/DIABLO protein was associated with poor karyotype.

Combined analysis of minimal residual disease at two time points and its value for risk stratification in childhood B-lineage acute lymphoblastic leukemia

Lei Cui, Zhigang Li, Minyuan Wu, Weijing Li, Chao Gao, Guoren Deng — 2010-10-01

Abstract: The study was aimed to explore the value of minimal residual disease (MRD) for risk stratification in childhood precursor-B-acute lymphoblastic leukemia. MRD was monitored at two time points (TP1, after induction and TP2, before consolidation therapy) by quantitative detection of monoclonal immunoglobulin heavy chain gene rearrangements. This study stratified 105 patients into three MRD risk groups: standard-risk, MRD<10−4 at both TP1 and TP2; high-risk, TP1≥10−2 or TP2≥10−3; and others were classified as intermediate-risk. We incorporated this MRD risk information to refine risk stratification among these patients and developed a new classification system that predicted the treatment outcomes more successfully than did the traditional risk classification criteria.

Circulating Ki-67 index in plasma as a biomarker and prognostic indicator in chronic lymphocytic leukemia

2010-10-01

Abstract: Ki-67 is a nuclear antigen that is expressed in all stages of the cell cycle, except G0, and is widely used as a marker of cellular proliferation in human tumors. We recently showed that elevated levels of Ki-67 circulating in plasma (cKi-67) are associated with shorter survival in patients with acute lymphoblastic leukemia. The current study included 194 patients with CLL and 96 healthy control subjects. cKi-67 levels in plasma were determined using an electrochemiluminescent immunoassay. We normalized the cKi-67 level to the absolute number of lymphocytes in the patient's peripheral blood to establish the plasma cKi-67 index. The cKi-67 index showed significant correlation with lymph node involvement and Rai stage (P=0.05). Higher cKi-67 index values were significantly associated with shorter survival. Multivariate Cox proportional hazards regression analysis demonstrated that the association of the cKi-67 index with shorter survival was independent of IgVH mutation status. In a multivariate model incorporating the cKi-67 index with B2M and IgVH, only cKi-67 index and B2M levels remained as independent predictors of survival. The results of this study suggest that the plasma cKi-67 index, along with B2M level, is a strong predictor of clinical behavior in CLL.

Survivin is upregulated in myeloma cell lines cocultured with mesenchymal stem cells

Xiaofang Wang, Zhiqing Zhang, Cheng Yao — 2010-10-01

Abstract: In this study we investigated the influence of the mesenchymal stem cells on the survival of U266 and H929 myeloma cell lines. We found that both soluble factors and direct cell contact inhibited daunorubicin-induced apoptosis of U266 and H929 cells. The mRNA and protein levels of survivin were upregulated in U266 and H929 cells cocultured with mesenchymal stem cells, whereas not increased in that separated by TW insert. Antisense oligonucleotides targeting survivin downregulated the expression of survivin and increased the apoptosis of U266 and H929 cells. The results indicated that MSCs had anti-apoptotic effect on U266 and H929 cells that was mediated by survivin.

The efficacy and safety of the low-thalidomide dose CTD (cyclophosphamide, thalidomide, dexamethasone) regimen in patients with multiple myeloma—A report by the Polish Myeloma Study Group

2010-10-01

Abstract: Multiple myeloma (MM) remains an incurable disease, but response rates to new drugs are promising, offering the majority of patients a significant prolongation of overall survival.The objective of this study was to evaluate time to progression (TTP), event-free survival (EFS), and overall survival (OS) in MM patients treated with a combination of cyclophosphamide (CY), thalidomide (THAL) and dexamethasone (DEX).This study included 132 untreated and relapsing/resistant patients treated with the low-thalidomide dose CTD regimen. The patients received CY 500mg/m2 i.v. or 625mg/m2 orally at day 1, THAL 100mg/day á la longue and DEX 20mg/day at days 1–4 and 8–11, every 28 days. Patients received 6–9 cycles; ORR by 3 months was 59.1%, by 6 months 65.6% and by 9 months 75.6%. In patients responding to CTD therapy (CR, nCR, PR), the probability of survival for 20 months was 89.3%. The outpatient low-thalidomide dose CTD regimen is well tolerated and produces a significant response rate both in untreated and relapsing/resistant MM patients.

Abnormal phenotype of bone marrow plasma cells in patients with chronic myeloid leukemia undergoing therapy with Imatinib

2010-10-01

Abstract: Imatinib induces several effects on the immune system, including hypogammaglobulinemia and has been associated with multiple myeloma in some patients. We studied the phenotype of plasma cells from patients with chronic myeloid leukemia (CML) undergoing therapy with Imatinib mesylate (Glivec). Bone marrow samples from 30 CML patients were evaluated and plasma cells were identified by multiparametric flow cytometry. In 21 patients an abnormal plasma cell phenotype, characterized by the absence of CD19, was registered, with 12 patients expressing also the CD56 molecule. A significant correlation between abnormal plasma cell phenotype and reduced γ-globulin levels was found. Immunofixation was always negative.Therapy with Imatinib for CML seems to induce a plasma cell phenotype with the same characteristics as monoclonal gammapathies. These findings deserve further studies and suggest to monitor plasma protein electrophoresis and γ-globulin levels in all patients treated with Imatinib.

Validation of the International Prognostic Scoring System (IPSS) for Waldenstrom's macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH)

2010-10-01

Abstract: The recently proposed, ISSWM staging system for symptomatic patients with WM was based on patients treated with alkylating agents and nucleoside analogs and has not been externally validated nor has been validated for cause-specific survival (CSS). We independently validated ISSWM both for overall survival (OS) and for CSS and assessed whether addition of elevated serum LDH may add to the strength of ISSWM in 335 patients treated upfront mainly with alkylating agents (43%), and rituximab-based therapies (47%). ISSWM could discriminate three groups with significantly different OS and CSS (p<0.01 for both). High serum LDH was predictive of shorter OS and CSS (p<0.01). The combination of high risk according to ISSWM and elevated serum LDH identified a subset of patients for whom innovative treatment approaches are needed.

Hypoplastic myelodysplastic syndrome (h-MDS) is a distinctive clinical entity with poorer prognosis and frequent karyotypic and FISH abnormalities compared to aplastic anemia (AA)

2010-10-01

Abstract: The aims of the present study are two-fold: (1) to define the clinical features of hypoplastic myelodysplastic syndrome (h-MDS) in comparison with aplastic anemia (AA) and (2) to evaluate the prognostic roles of karyotyping and fluorescent in situ hybridization (FISH) in these hypoplastic marrow syndromes.Based on a medical record review at Seoul National University Hospital, the records of 409 patients diagnosed with either h-MDS or AA were evaluated. Of these patients, 358 had been diagnosed with AA and 51 with h-MDS (median age, 39 years). At diagnosis, 235 and 165 patients underwent karyotyping and FISH analysis, respectively. Karyotypic abnormalities and trisomy 8 and trisomy 1q FISH abnormalities were found more frequently in h-MDS patients than in AA patients. Median overall survival (OS) of h-MDS patients was shorter than that of AA patients (83 vs. 201 months, P=0.007), with the OS of h-MDS patients falling between that of severe and very severe AA patients. Patients with h-MDS had more frequent leukemic conversion (P<0.001) than did AA patients. In AA patients, karyotypic abnormality was not prognostic (P=0.646), while in h-MDS patients, abnormalities in trisomy 1q FISH (P=0.002) and in 20q deletion FISH (P=0.005) were predictive of poor prognosis.In conclusion, the prognosis for h-MDS patients falls between that of severe and very severe AA patients. Moreover, h-MDS is frequently accompanied by karyotypic and FISH abnormalities and is prone to leukemic conversion. Trisomy 1q and 20q deletion FISH abnormalities may have important prognostic roles in patients with h-MDS.

Comparative analysis of MVA-CD40L and MVA-TRICOM vectors for enhancing the immunogenicity of chronic lymphocytic leukemia (CLL) cells

2010-10-01

Abstract: Adenoviral transduction with CD40L and poxviral transduction with B7-1, ICAM-1, and LFA-3 (TRICOM) have been used to enhance the antigen-presenting capacity of chronic lymphocytic leukemia (CLL) cells. This study compares the same vector (modified vaccinia virus strain Ankara (MVA)) encoding CD40L or TRICOM for its ability to enhance the immunogenicity of CLL cells. CLL cells from some patients showed differential responses to each vector in terms of induction of autologous T-cell responses. This study supports the rationale for the use of CLL cells modified ex vivo with pre-specified recombinant MVA vectors as a whole tumor-cell vaccine for immunotherapy in CLL patients.

Targeting integrin linked kinase and FMS-like tyrosine kinase-3 is cytotoxic to acute myeloid leukemia stem cells but spares normal progenitors

Andrew L. Muranyi, Shoukat Dedhar, Donna E. Hogge — 2010-10-01

Abstract: Acute myeloid leukemia (AML) is maintained by rare leukemia-initiating cells (L-ICs). FLT3 and/or PI3K pathways are often dysregulated in AML and may be important for L-IC survival. The presence of PI3K pathway intermediate integrin linked kinase (ILK), and FLT3 was confirmed in five L-IC-enriched AML patient samples. Treatment of AML cells with QLT0267, an inhibitor of ILK and FLT3, decreased survival of long-term suspension culture-initiating cells and NOD/SCID mouse L-IC. In contrast, little toxicity toward normal bone marrow progenitors was observed, demonstrating that candidate leukemic stem cells can be eliminated by inhibition of these targets while normal hematopoietic counterparts are spared.

NFκB modulators in a model of glucocorticoid resistant, childhood acute lymphoblastic leukemia

Lindsay Nicholson, Andrew G. Hall, Christopher P. Redfern, Julie Irving — 2010-10-01

Abstract: Glucocorticoids (GCs) are pivotal agents in the treatment of childhood acute lymphoblastic leukaemia (ALL) but the molecular basis of GC-resistance remains unclear. Expression-array studies have shown that commonly upregulated genes associated with GC-sensitivity include GR, glucocorticoid-induced leucine zipper (GILZ) and IκBα, which all negatively interact with components of the pro-survival NFκB pathway and therefore may be critical determinants of GC-sensitivity. We have investigated these regulators and their effect on NFκB activity in GC-resistant descendents of the B-lineage ALL cell line, PreB 697. We show that while differential up regulation of the modulators (GILZ, GR and IκBα) was demonstrated in GC-sensitive compared to GC-resistant sub-lines, this was not coupled with altered nuclear translocation or functionality of the RelA, p50 or c-Rel subunits of NFκB. Thus, GC-resistance in the PreB 697 cell line model is not mediated by NFκB, however further investigation of the impact of these GC-sensitive associated proteins on other survival pathways, such as the RAS-RAF-MEK-ERK pathway, is warranted.

Engineered regulatory T cells prevent graft-versus-host disease while sparing the graft-versus-leukemia effect after bone marrow transplantation

Jiang Cao, Chong Chen, Lingyu Zeng, Li Li, Zhenyu Li, Kailin Xu — 2010-10-01

Abstract: Regulatory T cells (Tregs) can prevent graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Here we developed a lentivirus-based strategy to ectopically express Foxp3 in mouse CD4+CD25− T cells. These cells shared similar immunophenotypes and biological features of natural Tregs. Co-injection of engineered Tregs with donor bone marrow cells and splenocytes prevented recipients from lethal GVHD. Furthermore, we showed that graft-versus-leukemia (GVL) effect against EL4/DsRed leukemic cells was maximally preserved while GVHD was minimized during exposure to engineered Tregs in a mouse leukemia model. These findings provide a novel approach to preventing GVHD while maintaining GVL effect during BMT.

A fluorescent biomarker of the polyamine transport system to select patients with AML for F14512 treatment

2010-10-01

Abstract: The polyamine transport system (PTS), hyperactive in cancer cells, can constitute a gate to deliver F14512, a novel spermine epipodophyllotoxin conjugate recently selected for clinical development in AML phase I. We investigated in vitro the high antiproliferative effect of F14512 against 13 leukemia cell lines, and demonstrated a statistically significant correlation with the level of PTS activity, using a novel fluorescent marker F96982. This labelling protocol was then adapted for clinical applications for blood, bone marrow and AML samples with CD45 gating. Within the patient samples, the PTS activity varied significantly in AML cells, as compared to normal lymphocytes. In conclusion, the identification of PTS-positive AML with F98982 probe offers new perspectives to select patients prone to respond to F14512.

Differential NOD/SCID mouse engraftment of peripheral blood CD34+ cells and JAK2V617F clones from patients with myeloproliferative neoplasms

Tsz-Kan Fung, Alice M.S. Cheung, Yok-Lam Kwong, Raymond Liang, Anskar Y.H. Leung — 2010-10-01

Abstract: We evaluated the NOD/SCID engraftment of CD34+ cells from polycythemia vera (PV) and secondary polycythemia patients (SP) and the JAK2V617F clone before and after transplantation. Peripheral blood CD34+ cells were transplanted intra-femorally. In the injected BM, successful engraftment (>0.1%) occurred in 8/26 mice transplanted with CD34+ cells from 5/13 PV patients (median: 4.26%, range: 0.3–5.56%), in contrast to 0/14 mice from 9 SP patients (P=0.017). The engrafting PV cells were of multi-lineage. JAK2V617F/total JAK2 ratios decreased after transplantation (initial: 65.9% versus 6-week: 13.0%, P=0.001). Essential thrombocythemia (ET) BM cells also exhibited a similar decrease in JAK2V617F clone. The results suggested that events in addition to JAK2V617F are involved in the pathogenesis of PV and ET.

Reversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents

2010-10-01

Abstract: The purpose of this analysis was to assess the effect of novel agent-based regimens on the improvement of renal impairment (RI) in newly diagnosed patients with multiple myeloma. Ninety-six consecutive patients with RI received conventional chemotherapy (CC)-based regimens (n=32), IMiDs-based regimens (n=47) or bortezomib-based regimens (n=17) as frontline therapy. Improvement of RI was more frequent in patients treated with novel agents (79% in IMiD- and 94% in bortezomib-treated groups versus 59% in CC-treated group; p=0.02). Bortezomib-based regimens and CrCl>30ml/min at baseline independently correlated with a higher probability of at least renal partial response (PRrenal) and with a shorter time to PRrenal or better. Thus bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients with RI.

Persistent detection of a novel MLL–SACM1L rearrangement in the absence of leukemia

2010-10-01

Abstract: Most chromosomal rearrangements including the mixed lineage leukemia (MLL) gene are manifested as leukemia and predict a poor prognosis. Although more than 50 MLL-rearrangement partners are characterized, MLL-related leukemogenesis remains to be understood. Here we report a case of a 3-year old boy bearing a novel MLL-rearrangement with the suppressor of actin mutations 1-like (SACM1L) gene in the absence of leukemia. Bone marrow cells harboring the MLL–SACM1L rearrangement appeared during chemotherapy for acute lymphoblastic leukemia with hyperdiploidy and were continuously detected over 7 years without clonal expansion.

Central nervous system involvement at second relapse in acute promyelocytic leukemia treated with ATRA and chemotherapy

2010-10-01

Acute promyelocytic leukemia is highly curable with molecularly targeted therapy against its specific genetic abnormality. The combination of all-trans retinoic acid (ATRA) and anthracycline based chemotherapy and maintenance treatment has improved the outcome of acute promyelocytic leukemia (APL), but relapse still occurs in 10–25% of the patients . Extramedullary (EM) relapses were very rare in past however recently, there has been increasing concern about risk of EM involvement of APL at relapse after prior induction treatment with ATRA. Amongst EM relapse in APL, the central nervous system (CNS) is the most common and at least 10% of relapses involve the CNS . The reported incidence of CNS relapses in APL ranges from 0.6% to 2% . The risk factors associated with CNS relapse include high white blood cell (WBC) count at presentation, younger age, BCR3 isoform , microgranular morphology (M3v), relapse risk score, occurrence of CNS haemorrhage during induction and possibly with the use of ATRA and the development of differentiation syndrome during induction . In high risk APL patients with a high presenting WBC count, some have argued in favour of CNS prophylaxis with intrathecal chemotherapy. Available data about disease outcome after CNS relapse are limited and contradictory, one study reporting similar survival rates in CNS relapsed and isolated marrow relapse and other indicating significantly lower survival rates in CNS relapse cases compared to bone marrow relapse . The optimal management of APL patients with CNS involvement at first relapse, whether isolated or associated with bone marrow involvement, has not been assessed critically. Very limited data is available for APL management after second CNS relapse. Further to the best of our knowledge only one study has reported incidence of CNS involvement at second relapse after Arsenic trioxide induced remission of first relapse .

Localized graft-versus-host disease of the skin provoked by radiotherapy

Niels W.C.J. van de Donk, Marijke R. van Dijk, Henk M. Lokhorst — 2010-10-01

In multiple myeloma allogeneic stem cell transplantation (allo-SCT) is associated with the highest rate of molecular remissions and a lower risk of recurrence compared with other treatment options including autologous SCT . This is due to the graft-versus-myeloma effect, which was proven by the achievement of sustained complete remissions by donor lymphocyte infusions (DLIs) without any other therapy in patients with relapse after both myeloablative and non-myeloablative allo-SCT . However, because of high treatment-related mortality especially after myeloablative conditioning and the introduction of novel agents such as bortezomib and the immunomodulatory drugs thalidomide and lenalidomide, the value of this approach remains to be determined in clinical trials.

A case of blast clearance on sorafenib in relapsed FLT3-ITD acute myeloid leukemia: Evidence of efficacy continues to mount

Mark J. Fesler, John M. Richart, Paul J. Petruska — 2010-10-01

Sorafenib, a multi-targeted tyrosine kinase inhibitor FDA approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, inhibits the FLT3 (fms-like tyrosine kinase receptor-3) protein on the surface of acute myeloid leukemia (AML) cells and has been utilized in a compassionate use, single agent setting by German physicians to treat relapsed FLT3-ITD positive AML with success . A different FLT3 inhibitor, lestaurtinib, produced negative results in relapsed FLT3-ITD positive AML ; however, a recent report demonstrates that more selective FLT3 inhibitors (sorafenib) have greater in vitro activity than less selective FLT3 inhibitors (lestaurtinib) in relapsed AML samples . We present a case of sorafenib use in relapsed FLT3-ITD positive AML which supports both the in vitro finding and the in vivo efficacy demonstrated in the German report.

Sorafenib induces sustained molecular remission in FLT3-ITD positive AML with relapse after second allogeneic stem cell transplantation without exacerbation of acute GVHD: A case report

2010-10-01

Relapsed acute leukemia after allogeneic stem cell transplantation (SCT) has a very poor prognosis and treatment still remains a challenge . Infections and/or severe acute GvHD often preclude conventional myeloablative chemotherapy. Cellular therapies with donor lymphocyte infusions (DLI) or a second allogeneic SCT do not induce stable remissions in the majority of high-risk AML patients .

Facilitating studies of cell proliferation in chronic lymphocytic leukemia

Derek C. Macallan, Julien Defoiche, Luc Willems — 2010-10-01

We read with interest the report by Hayes et al., “Isolation of malignant B cells from patients with chronic lymphocytic leukemia (CLL) for analysis of cell proliferation: Validation of a simplified method suitable for multi-center clinical studies.” The authors describe helpful developments for analyzing in vivo proliferation rates of leukemic cells in patients with CLL. They rightly point out that, to be useful, “… this technology must have improved ease of use for patients, providers and researchers alike” and their proposed developments do indeed contribute towards this goal by introducing simpler protocols for blood collection, separation and analysis.

Intravascular large B-cell lymphoma, an exclusively small vessel disease? A case report and review of literature

Xin Yao, Ayman Saad, Christopher R. Chitambar — 2010-10-01

Intravascular large B-cell lymphoma (IVLBCL) is an extranodal diffuse large B-cell lymphoma (DLBCL) characterized by the presence of neoplastic lymphocytes only in the lumina of small vessels, particularly capillaries . Although primary cardiac lymphoma extending to superior vena cava (SVC) and renal lymphoma extending to inferior vena cava can be seen occasionally, lymphoma residing exclusively in large-sized blood vessels is very rare. With the advent of advanced imaging studies, IVLBCL in large vessels has been increasingly seen . We report a case with recurrent lymphoma exclusively in the SVC. This case highlights that IVLBCL can occur in large blood vessels. Further considerations are required to classify this type of lymphoma. Awareness of this disease will result in appropriate use of diagnostic studies and avoid unnecessary surgical procedures.

Is there still a role for G-banding in CLL?

2010-10-01

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder characterized by progressive monomorphic lymphocytosis caused by clonal accumulation of CD5+ CD19+ B cells in peripheral blood, bone marrow and lymphoid organs . Clinical course is heterogeneous. Molecular and biologic factors have been found to be useful predictors of response to treatment and survival among newly diagnosed patients. Immunoglobulin heavy chain gene mutation status, ZAP-70 and interphase cytogenetics are established risk factors .

ABVD associated with imatinib for coexisting chronic myeloid leukaemia and relapsed Hodgkin lymphoma

2010-10-01

A 30-year-old Caucasian male has been referred to our institution in June 2009 because for 3 months he presented recurrent fever, night sweats and asthenia. Nine years before the patient has been diagnosed with nodular sclerosis classical HL; at that time a computer tomography (CT) scan demonstrated a mediastinal bulky, epatho-splenomegaly and multiple liver lesions; the diagnosis was performed on specimens obtained from mediastinal mass. Bilateral bone marrow biopsy was negative for HL involvement. The stage was defined as IV B. He was treated from November to July 2000 with eight cycles according to ABVD schedule (doxorubicin, bleomycin, vinblastine and dacarbazine) achieving a complete remission (CR). The patient remained in good clinical condition until March 2009, and did not present any clinical or radiographic sign of relapse. In June 2009, at a physical examination he presented severe enlargement of the liver and the spleen, without superficial lymphadenopaty. Abdominal ultrasound and CT scan confirmed epatosplenomegaly (bipolar diameter of the liver and the spleen, 17.5cm and 20cm, respectively) and demonstrated the presence of abdominal lymphadenopaty (diameter iliac lymph node 5cm; retroperitoneal iliac lymph node 3.2cm; peri-aortic lymph node 2.2cm). The analysis of peripheral blood revealed leukocytosis (WBC count 116.3×109/L, with 74 neutrophils, 1% lymphocytes, 1% monocytes, 5% eosinophils, 3% basophils, 13% immature granulocytes, 3% blasts), haemoglobin and platelets count were normal. A high serum level of LDH (1704IU/dL) and hyperuricemia (10.2mg/dL) were present. A bone marrow smear was hypercellular with 4% blasts, 76% of granulopoietic lineage, erythropoietic precursors had megaloblastic appearance and megacaryocytes showed dysplastic aspects. Bone marrow biopsy confirmed these features. Cytogenetic analysis performed according to QFQ banding: 12 cells were evaluable and characterized by the presence of t(9;22)(q34;q11) in all analyzed mitoses; no other abnormalities were found. The molecular biologic study performed by the reverse-transcriptase chain reaction (RT-PCR) technique demonstrated the p210 rearrangement (b3a2). These data allowed us to make the diagnosis of Philadelphia positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase (intermediate Sokal and Hasford score). The staging was completed with a lymph node biopsy that demonstrated nodular sclerosis classical HL relapse; it was performed a by positron emission tomography (PET) that confirmed nodal involvement and (18)F-fluoro-2-deoxyglucose ((18)F-FDG) increased uptake in bone marrow, liver and spleen.

B-cell acute lymphoblastic leukemia as evolution of a 8p11 myeloproliferative syndrome with t(8;22)(p11;q11) and BCR-FGFR1 fusion gene

2010-10-01

Rearrangement of fibroblast growth factor receptor 1 (FGFR1) gene, mapped on chromosome band 8p11, is the genetic hallmark of a rare atypical chronic myeloproliferative disorder that is usually characterized by myeloid hyperplasia, eosinophilia and high incidence of T-lymphoblastic lymphoma referred as 8p11 myeloproliferative syndrome (EMS) .

Overdose with 16,000mg of imatinib mesylate

2010-10-01

The gold standard treatment of chronic myeloid leukemia (CML) is imatinib mesylate (Glivec, Gleevec, STI-571), a selective tyrosine kinase inhibitor against BCR/ABL. We report on a 53 years old woman, who ingested 16,000mg in a suicide attempt.