Leukemia Research

Editorial Board

2012-06-01

Leukemia Research welcomes a new co-editor-in-chief: Eric J. Feldman, M.D.

John M. Bennett — 2012-04-13

A changing in the guard for the editorial functions in Leukemia Research is underway. First was the appointment of David T. Bowen as Senior Associate Editor a few years ago, with his focus on challenging issues in hematologic malignancies.

Evolution of clinical trial endpoints in chronic myeloid leukemia: Efficacious therapies require sensitive monitoring techniques

Raoul Tibes, Ruben A. Mesa — 2012-03-29

Abstract: The efficacy of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) has brought treatment response assessment to the molecular level. Clinical trials endpoints for newer TKIs – such as major and complete molecular response – reflect the trend toward more-sensitive disease detection and deeper responses. Practice guidelines now formally define levels of response and link response benchmarks to outcome and treatment guidance. Efforts are ongoing to harmonize the methodology and terminology used to characterize molecular response. This review discusses the evolution of CML clinical trial endpoints in response to current therapeutic and monitoring modalities, and the implications of achieving molecular endpoints.

Genes encoding transcription factors have self-control: How important is this for cell differentiation?

Elzbieta Gocek, George P. Studzinski — 2012-03-19

A little over a hundred years ago enquiring minds started to follow up on Mendel's discoveries by looking at ways in which genes could produce phenotypic characteristics, such as the nice colors in peas . The formulation of the hypothesis of “one gene-one enzyme” is often credited to an English physician A.E. Garrod interested in inborn errors of metabolism , and several decades later supported by compelling experimental data obtained by Beadle and Tatum . In 1962 this hypothesis morphed into “one gene-one polypeptide” hypothesis, as Vernon Ingram and others realized that proteins other than enzymes seem to obey the same rules . Thus, everything looked orderly.

Blood simple: Transfusion at home for patients with MDS

Ellen Kelly Ritchie — 2012-03-19

Patients diagnosed with myelodysplastic syndromes (MDS) experience many difficulties that impair quality of life. Symptoms of the disease, primarily related to cytopenias, can be overwhelming—excessive fatigue, bruising, bleeding, night sweats, bone pain, fever, skin rash, undesired weight loss and recurrent infections. There have been only a few studies focusing on the symptoms of MDS and their impact on patient life . These studies identify excessive fatigue as one of the most debilitating symptoms. Jansen and colleagues found that there was a correlation between hemoglobin level and fatigue, while Steensma and colleagues could find no correlation between the two. Studies by Kornblith et al. and Hellstrom-Lindberg et al. looked at quality of life in the context of treatment and found that using chemotherapy or growth factors to increase hemoglobin levels alleviate fatigue. Most, but not all, literature supports the assumption that fatigue can be correlated with hemoglobin level .

“Should all eligible patients with multiple myeloma receive autologous stem-cell transplant as part of initial treatment?”

Philippe Moreau, S. Vincent Rajkumar — 2012-03-20

Multiple myeloma is probably the only malignancy in which autologous stem cell transplantation (ASCT) is performed routinely without primary curative intent . Randomized trials performed with ASCT in myeloma show no plateau in the survival curves, yet myeloma is the number one indication for ASCT in the United States. Although not curative, ASCT has become the mainstay of treatment for patients less than 65 based on improved median overall survival of approximately 12–18 months compared with chemotherapy alone in 2 randomized trials .

Combination of azacitidine and ESA in myelodysplastic patients: The need for prospective studies

2012-03-19

We read with great interest the paper by Itzkynson et al. that reported the results of the combination of erythropoietin and azacitidine in myelodysplastic syndrome (MDS) patients. Overall, 32 out of 282 patients were treated concomitantly with azacitidine and erythropoietic stimulating agents (ESA) for a relatively short period of time (median duration 5.8 months). The authors reported an overall response rate of 53% in patients treated with the combination compared to 43% in patients treated with azacitidine alone, without statistically significant difference. No differences were reported in terms of complete response (CR) and marrow response (mCR) between the two groups of subjects, whereas the rate of hematologic improvement-erythroid (HI-E) was superior in the combination group (44%) compared to azacitidine alone group (27%), with an increased rate of patients becoming transfusion independent in the former group. Again no difference in terms of progression rate was observed, whereas ESA-treated patients had a longer survival (OS), with a median of 19.6 months compared to 11.9 months for patients who did not receive ESA. With the aim to evaluate the possible effect of the above described combination, 60 MDS patients treated with azacitidine in our institute, 8 of whom received the drug in association with ESA, were retrospectively analysed. There were 44 males and 16 females, median age 69 years (range 44–83). According to WHO criteria , 35 patients were classified as refractory anemia with excess of blasts type 2 (RAEB-2), 13 patients as RAEB-1, 8 patients as refractory cytopenia with multilineage dysplasia (RCMD) and 4 patients as chronic myelomonocytic leukemia type 2 (CMML-2). IPSS stratification revealed 51 patients as intermediate-2 risk and 9 patients as high risk. Cytogenetic analysis displayed aberrations in 30 patients and a normal karyotype in the remaining 30; the most common karyotypic abnormality was monosomy 7 (10 patients, 20%), isolated or associated to complex changes. Median follow-up was 15 months. All patients were treated with the same dose of azacitidine (75mg/m2) with the same schedule (5+2+2). Median number of cycles received was 6 (range 2–21). Eight patients also received ESA in association to azacitidine, but all had started ESA shortly before (less than 3 months): 6 patients had RCMD and 2 patients RAEB-1, and all received epoetin alpha or beta at the dose of 30,000 UI/week for a median time of 6 months (range 3–11). Overall, the rate of response in the whole series of 60 patients was 63%, after a median of four cycle of azacitidine, according to 2006 IWG criteria : 15 patients (25%) achieved complete response (CR), 3 patients (5%) partial remission (PR), 20 patients (33%) hematologic improvement (HI) and 7 patients (12%) a stable disease. Fifteen patients (25%) experienced progression of disease. In the ESA group, 1 patient achieved CR, 3 patients PR, 1 patient showed a stable disease, 1 patient had HI-E and 2 patients had disease progression, with an overall rate of response of 62% (p=ns). The same rate of progression of the disease was recorded in the two groups (2/8, 25% in the ESA group and 15/52, 28% in the azacitidine group, p=ns). We did not reveal difference in terms of OS, which was 12 months in the ESA group and 19 months in the series of patients treated with azacitidine alone. Itzkynson and colleagues and also Mittelman in an editorial brought together with the original article, stated that their results had several limitations due to the retrospective nature of the study and the small number of patients treated with the combination of the two agents. Our results are also limited by the fact that only a small number of patients received the combined treatment: although shown in a small series of subjects, no statistically significant differences where revealed in our study. The apparently divergent results in our study from prior observations may depend on the different characteristics of patients treated with the drug combination; so, in our opinion, no clear and definite conclusions can at present be drawn. To answer the important questions raised by Mittelman such as whether is it true that patients treated with ESA-azacitidine have better prognosis or which are the clinical features of possibly responding patients or what are the mechanisms of action by ESA-azacitidine, a prospective clinical trial combining these two drugs in intermediate-2/high risk patients should be planned.

Transfusions at home in patients with myelodysplastic syndromes

2012-02-15

Abstract: We report descriptive data of a home care (HC) program, throughout a 5-years period (2006–2010), focusing on the reliability and the safety of transfusions at home in 211 patients affected by myelodysplastic syndromes (MDS). Our results outline the potentially relevant role of a specifically dedicated HC service in the global management of frail MDS patients for which transfusions at home may represent a valuable option to maintain a good quality of life and avoid the possible discomfort due to hospital admissions and outpatient visits.

Imatinib mesylate discontinuation in patients with chronic myeloid leukemia who have received front-line imatinib mesylate therapy and achieved complete molecular response

2012-03-07

Abstract: The aims were to investigate the feasibility of imatinib mesylate (IM) discontinuation in chronic myeloid leukemia patients who were initially treated with IM and achieved complete molecular response (CMR). Fourteen patients were included. Ten were relapsed within 9.5months after discontinuation of IM. All 7 patients with high Sokal risk were relapsed. The probability of CMR persistence at 1-year was 28.6%. All relapsed patients were still responsive to IM. A high Sokal risk and delayed acquisition of CMR were associated with relapse. IM discontinuation in patients achieved CMR after treatment with front-line IM might be feasible. Further studies are warranted.

Tumor necrosis factor alpha−308 and Lymphotoxin alpha+252 genetic polymorphisms and the susceptibility to non-Hodgkin lymphoma in Egypt

2011-12-19

Abstract: Genetic polymorphism within the regulatory regions of tumor necrosis factor-alpha (TNF-α) and Lymphotoxin-alpha (LT-α) may be involved in the development of lymphoid malignancies. The aim of the current study was to investigate the effect of TNFα−308 and LTα+252 genetic polymorphism on susceptibility to non-Hodgkin lymphoma (NHL) in Egypt. Genotyping of the studied genes by restriction fragment length polymorphism polymerase chain reaction was conducted on 84 NHL and 100 healthy controls and revealed that TNFα−308 homotype (AA) was significantly higher in NHL patients and conferred sixfold increased risk of NHL (OR=5.9, 95%CI=2.3–16.1). Moreover, TNFα/LTα high-producer haplotypes were significantly higher in NHL patients and conferred increased risk of NHL (OR=4.59, 95%CI=2.19–9.42).

The impact of the dose of natural killer cells in the graft on severe acute graft-versus-host disease after unrelated bone marrow transplantation

2011-12-15

Abstract: The impact of lymphocyte subpopulations on the outcome of bone marrow transplantation (BMT) remains uncertain. We investigated the relationship between the lymphocyte subpopulations of bone marrow grafts and the outcome of BMT. A total of 121 patients who underwent BMT at Kanagawa Cancer Center between 2000 and 2009 were analyzed. Grade III–IV acute graft-versus-host disease (GVHD) occurred in 35.9% of patients who received unrelated BMT with a CD56 cell dose ≤2.80×106/kg versus only 9.7% of patients with a CD56 cell dose >2.80×106/kg (P=0.017). In patients receiving related BMT, the cumulative incidence of grade III–IV acute GVHD did not differ significantly in relation to the CD56 cell dose. On multivariate analysis, older donor age (hazard ratio (HR): 1.09, 95% confidence interval (CI): 1.03–1.15, P=0.004) and a high dose of CD56 cells (>2.80×106/kg) (HR: 0.15, 95%CI: 0.03–0.92, P=0.040) were significant determinants of grade III–IV acute GVHD after unrelated BMT. None of the lymphocyte subpopulations had a significant impact on the outcome of transplantation, including the rate of neutrophil engraftment, relapse, relapse-free mortality, and overall survival. Our findings suggest that a high natural killer cell dose prevents severe acute GVHD after unrelated BMT, while sparing the graft-versus-leukemia effect.

RT-PCR diagnosis of recurrent rearrangements in pediatric acute lymphoblastic leukemia in Argentina

2012-01-09

Abstract: The present study was performed to establish the prevalence of the recurrent fusion transcripts in Argentinean pediatric patients with acute lymphoblastic leukemia (ALL). A total of 380 newly diagnosed children (including 50 infants and 44 T-ALL) were screened by RT-PCR; the incidence of recurrent rearrangements was: ETV6-RUNX1, 12.9%; TCF3-PBX1, 5.0%; BCR-ABL1, 1.6%; and MLL rearrangements, 10.5%. STIL-TAL1 was detected in 22.7% of T-ALL cases. In B-ALL cases, the pEFS was significantly influenced by the presence of genetic alterations. RT-PCR studies improved patients’ stratification and also the overall outcome of children treated in a pediatric hospital from a developing country.

Clinical experience of bendamustine treatment for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Spain

2011-12-09

Abstract: Bendamustine is a alkylating agent with a purine-like benzamidazole ring currently approved in Europe for indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. Our aim was to analyze retrospectively the efficacy and toxicity of bendamustine in NHL and CLL in Spain in the bendamustine Compassionate Use Program. Patients with relapsed/refractory NHL or CLL were eligible. Any regimen containing bendamustine was eligible. 109 patients were included from 22 institutions. Forty-nine patients had indolent NHL, 18 aggressive NHL and 42 CLL, being 44 patients (40%) refractory to previous treatment. 63% of patients had adverse events grade 3–4, mainly hematological. Overall response rate (ORR) was 66%, complete responses 30%. ORR observed in refractory patients was 45%. The median progression-free survival (PFS) was 13 months. Outcome was influenced by histology, number of previous treatments, resistance to previous chemotherapy and type of response achieved with bendamustine. Alone or in combination, bendamustine shows a meaningful clinical antitumor activity in patients with relapsed or refractory NHL or CLL, with an acceptable toxicity profile.

A combination of thalidomide and arsenic trioxide is effective and well tolerated in patients with myelodysplastic syndromes

Wei Wei, Fan Zhou, Yizi Zhang, Lieping Guo, Haotian Shi, Jian Hou — 2012-01-27

Abstract: Twenty-two patients with myelodysplastic syndromes (MDS) were treated with thalidomide plus arsenic trioxide (ATO). Twenty-two MDS patients receiving supportive care were used as controls. The remission was achieved in 4 patients (18.2%) receiving thalidomide/ATO, and none in the control group (p<0.05). Fifteen of 22 patients in the treatment group achieved hematologic improvement (68.2% vs. 27.3% in the control, p<0.05). The progression-free survival was longer in the treatment group than that in the control (26 vs. 10 months, p<0.05). The overall survival was also longer in the treatment group than that in the control (36 vs. 16 months, p<0.05). No severe adverse reactions were observed. These preliminary findings suggest that thalidomide/ATO combination treatment is effective and safe for MDS.

A comprehensive cytogenetic classification of 1466 Chinese patients with de novo acute lymphoblastic leukemia

2012-01-20

Abstract: Cytogenetics and molecular cytogenetics of 1466 Chinese patients with de novo acute lymphoblastic leukemia (ALL) were studied. Cytogenetic results were available in 1175 patients. Cross-correlations of 23 subclasses of cytogenetic abnormalities were described. Childhood cases had higher incidences of normal karyotype, t(1;19), +8, 12q−, +21, +22 and high hyperdiploidy with 51–65 chromosomes, and lower incidences of t(9;22) and −5/5q− than adult ones (all p<0.05). Relationships of cytogenetic subclasses with immunophenotyping subgroups of ALL were studied. Our study presents the cytogenetic characteristics of a large series of Chinese ALL patients.

Evaluation of dysplasia through detailed cytomorphology in 3156 patients from the Düsseldorf Registry on myelodysplastic syndromes

2012-03-15

Abstract: Using the Düsseldorf MDS registry with standardized cytomorphology we here describe dysplastic features in detail, concentrating on 16 different dysplastic features in the blood and 19 in the marrow in 3156 patients. The most frequent dysplastic features were megaloblastoid changes and bi- and multinuclearity in the erythropoiesis, pseudo-Pelger cells and hypogranulation in the granulopoiesis and micromegakaryoctes and mononuclear megakaryocytes in the megakaryopoiesis. The frequency of dysplastic changes did not differ significantly among the WHO types with the exception of MDS with del(5q) and CMML types. No single sign of dysplasia is exclusive for the diagnosis of MDS.

Post-transcriptional modulation of C/EBPα prompts monocytic differentiation and apoptosis in acute myelomonocytic leukaemia cells

2012-02-20

Abstract: CCAAT/enhancer binding protein alpha (C/EBPα) induction induces monocytic differentiation even in acute myeloid leukaemia (AML). In this study, the induction/activation of C/EBPα in myelomonocytic AML was investigated using a combination of all-trans retinoic acid (ATRA) and RAD001 (Everolimus), a mammalian target of rapamycin complex 1 (mTORC1) inhibitor. Combining these agents increased PU.1, C/EBPɛ and C/EBPα expression, increased the p42/p30 C/EBPα ratio, and decreased C/EBPα phosphorylation at serine 21, and was accompanied by growth inhibition, induction of CD11b expression and apoptosis in AML cell lines. Thus, agents that induce sufficient levels of C/EBPα expression might be useful in treating AML.

Gli inhibitor GANT61 causes apoptosis in myeloid leukemia cells and acts in synergy with rapamycin

Deng Pan, Yan Li, Zhe Li, Yazhu Wang, Pingping Wang, Ying Liang — 2012-03-09

Abstract: Aberrant reactivation of Gli signaling has been described in a wide variety of human cancers and rapamycin can down-regulate Gli pathway in some solid tumors. In this study, we attempt to define the cytotoxic effect of Gli inhibitor on AML cells. And the regulation action of rapamycin on Gli in AML cells also has been assessed. Gli inhibitor GANT61 caused growth arrest and apoptosis in AML cells. Rapamycin decreased not only the Gli protein and mRNA expressions but also expression of the Gli-luciferase reporter in AML cells. Synergism effect between GANT61 and rapamycin was found in Kasumi-1, HL-60 and U937 cell lines. The results suggest that aberrant Gli activation is a feature of some myeloid leukemic cells and Gli activiation can be down-regulated by rapamycin.

Combined effect of histone deacetylase inhibitor suberoylanilide hydroxamic acid and anti-CD20 monoclonal antibody rituximab on mantle cell lymphoma cells apoptosis

Wei Shi, Xiaohong Han, Jiarui Yao, Jianliang Yang, Yuankai Shi — 2012-04-05

Abstract: Interactions between histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and anti-CD20 monoclonal antibody rituximab in mantle cell lymphoma have been examined both in vitro and in vivo. The combination of SAHA and rituximab synergistically induced apoptosis, concomitant with caspase activation and Bcl-2 downregulation. These events were associated with multiple perturbations in signal transduction pathways, including inactivation of cyto-protective nuclear factor (NF)-κB, Akt, extracellular signal-regulating kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) pathways, and activation of c-jun N-terminal kinase (JNK) when pretreated with the pan-caspase inhibitor. Moreover, the combination of SAHA and rituximab significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, SAHA had no apparent effect on the CD20 expression in the two MCL cell lines. Taken together, our results demonstrate the synergistic anti-MCL activity of SAHA and rituximab, and build the framework for clinical trials using SAHA-rituximab combining regimen in the treatment of MCL.

Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML

2012-01-04

Abstract: In this study, we show that conditioned media (CM) generated from bone marrow (BM)-derived mesenchymal stromal cells lead to BCR-ABL independent STAT3 activation. Activation of STAT3 is important not only for survival of CML cells but also for its protection against Nilotinib (NI), within the BM microenvironment. Reducing the expression of both JAK2 and TYK2 or utilizing a pan-JAK inhibitor blocked CM-mediated STAT3 activation and sensitized CML cells to NI-mediated cell death. Finally, we demonstrate that in patient-derived primitive leukemic cells, co-cultured with BM stromal cells, inhibition of BCR-ABL and JAK activity was a successful strategy to potentiate their elimination.

Interleukin-6, osteopontin and Raf/MEK/ERK signaling modulate the sensitivity of human myeloma cells to alkylphosphocholines

Deyan Y. Yosifov, Christina Reufsteck, Spiro M. Konstantinov, Martin R. Berger — 2012-03-16

Abstract: Alkylphosphocholines are highly active against multiple myeloma (MM) cells in vitro and are devoid of myelotoxicity. Little is known about the determinants of MM cell responsiveness or resistance to these drugs. In this study we investigated the effects of disease-relevant cytokines, such as interleukin-6 (IL-6) and osteopontin (OPN), on the in vitro antimyeloma activity of erufosine and perifosine. The role of the Raf/MEK/ERK pathway was also studied. Exogenous IL-6 reduced the cytotoxicity of erufosine against OPM-2 cells and, to a smaller extent, against U-266 cells. This was accompanied by inhibition of apoptosis in OPM-2 cells. The efficacy of perifosine was similarly affected, but to a greater extent. IL-6 slightly enhanced the sensitivity of RPMI-8226 cells to erufosine, thus emphasizing the heterogeneity of MM. Induced overexpression of OPN isoforms made OPM-2 cells less sensitive to erufosine. In all cases of IL-6- or OPN-induced resistance, the effective concentrations of erufosine were still within the clinically achievable range. Like other alkylphosphocholines, erufosine enhanced Raf/MEK/ERK signaling in MM cells but in some cases this contributed to cytotoxicity.

Histone deacetylase inhibition restores cisplatin sensitivity of Hodgkin's lymphoma cells

Stefanie Kewitz, Toralf Bernig, Martin S. Staege — 2012-03-19

Abstract: Increasing evidence suggest that epigenetic mechanisms (e.g. histone modification by histone deacetylases) play a major role in the pathogenesis of Hodgkin's lymphoma (HL). We treated HL cell lines with the histone deacetylase inhibitor vorinostat and investigated the gene expression profile of these cells by using DNA microarrays. Vorinostat inhibited cell proliferation and induced chances in the gene expression profile of HL cells, including down regulation of interleukin-26 and CD30. Vorinostat also increased sensitivity for cisplatin. Our data suggest that the combination of vorinostat and chemotherapy might be an interesting option for patients with chemoresistant HL.

Isolation of siRNA target by biotinylated siRNA reveals that human CCDC12 promotes early erythroid differentiation

2012-01-24

Abstract: Erythroid differentiation is a tightly regulated multi-step process that has not been fully elucidated. We previously reported that a siRNA screened from random siRNA library, siRNA clone-67, induced erythroid differentiation in human erythroleukemia K-562cell line. Here we identified that human CCDC12 (coiled-coil domain containing 12) is a target of siRNA clone-67, by target capture with biotinylated siRNA. Over-expression of CCDC12 in K-562cell up-regulated the expression of CD235, ɛ-globin and γ-globin, accelerated cell growth, and slightly down-regulated the expression of GATA-2. Knockdown of CCDC12 slowed down the cell growth. These data indicate that CCDC12 is a new participant that promotes early erythroid differentiation.

The Smac mimetic RMT5265.2HCL induces apoptosis in EBV and HTLV-I associated lymphoma cells by inhibiting XIAP and promoting the mitochondrial release of cytochrome C and Smac

2012-02-13

Abstract: The inhibitors of apoptosis (IAP) are important regulators of apoptosis. However, little is known about the capacity of Smac mimetics (IAP inhibitor) to overcome virally associated-lymphoma's (VAL) resistance to apoptosis. Here, we explored the pro-apoptotic effect of a novel Smac mimetic, RMT5265.2HCL (RMT) in VAL cells. RMT improved the sensitivity to apoptosis in EBV- and to some extend in HTLV-1- but not in HHV-8-VAL. Furthermore, we identified that RMT promotes caspase 3 and 9 cleavage by inhibiting XIAP and inducing the mitochondrial efflux of Smac and cytochrome C. This investigation further support exploring the use of Smac inhibitors in VAL.

Adriamycin dose and time effects on cell cycle, cell death, and reactive oxygen species generation in leukaemia cells

2012-03-15

Abstract: We investigate the relative importance of the different mechanisms of Adriamycin, an anthracycline, and their interrelations, in particular the link between cell cycle arrest, cell death, and generation of reactive oxygen species (ROS) that is suspected to be the origin of cardiotoxic side-effects. We introduced a lifetime fluorescence based technology and used videomicrofluorometry, two efficient analytical methods. We show that depending on the doses and time after incubation, ADR will not reach the same compartments (nucleus, mitochondria, cytosol) in the cells, having consequences on the production of ROS, growth arrest pathways and cell death pathways.

Advanced systemic mastocytosis as a mimicker of metastatic clear cell renal cell carcinoma

2012-03-30

A 63-year-old male patient with a history of a right-sided renal cell carcinoma eight years ago presented with palpable splenomegaly, flush, diarrhea, vertigo and fatigue. Blood counts revealed thrombocytopenia (88×109/L) and transfusion-dependent anemia (8.4g/dL). In addition to hepato-/splenomegaly, ascites and marked lymphadenopathy of the mesenteric, paraaortal and gastral regions was found. Ultrasound revealed a tumor of 2.3cm in maximum diameter in the left kidney which was removed by partial left-sided nephrectomy. Histopathologic analysis revealed a clear cell renal cell carcinoma (CCRCC; pT1a, G2, Nx, R0; A).

Long-term remission in a case of acute promyelocytic leukemia patient with marked myelofibrosis treated with arsenic trioxide, all-trans retinoic acid and consolidation therapy with daunorubicin plus cytarabine

Quanyi Lu, Yamei Chen, Zhipeng Li — 2012-03-05

Myelofibrosis (MF) is a frequent complication of hematological malignancy. It has been reported that any French-American-British (FAB) subtype of acute myelogenous leukemia (AML) may be complicated by fibrosis, and the severity of fibrosis has been associated with poor prognosis . Acute promyelocytic leukemia (APL), a subtype FAB-M3, has a good prognosis with all-trans retinoic acid (ATRA), and a few cases of severe marrow fibrosis in APL patients have been reported to date and all achieved molecular remission . However, as far as we know, its prognostic significance has not yet been established and it is uncertain whether MF can affect the response to arsenic trioxide (ATO) treatment on patients with APL.

Elevated HIF-1α expression of acute myelogenous leukemia stem cells in the endosteal hypoxic zone may be a cause of minimal residual disease in bone marrow after chemotherapy

2012-03-23

Acute myelogenous leukemia (AML) cells are generally chemosensitive, and 70–80% of AML patients undergo complete remission after chemotherapy . However, long-term disease-free survival remains as low as 30–50% , mainly because of relapse after chemotherapy. The relapse has been ascribed to minimal residual disease (MRD) in the bone marrow (BM) .

Recurrent chromosomal breakpoints in patients with myelodysplastic syndromes and complex karyotype versus fragile sites

2012-03-06

The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders characterized by a maturation defect in hematopoietic stem cells. Ineffective hematopoiesis leads to cytopenia, clonal instability and an increased risk of transformation to acute myeloid leukemia (AML). Biologic and genetic tests, in addition to cytogenetic and molecular cytogenetic analyses of bone marrow cells, are needed to confirm an MDS diagnosis to place the patient in the correct predictive risk group and to select the most effective therapy. The MDS karyotype has been established as an independent prognostic factor for survival, for response to therapy and for estimating the probability of AML evolution . Clonal chromosomal aberrations are detected in the bone marrow (BM) in ∼50% of newly diagnosed cases of MDS, and up to 30% of cases have complex chromosomal aberrations (CCA). CCA are defined as numerical or structural changes involving three or more chromosomes and/or rearrangements with three or more chromosomal breaks that are strongly associated with a very poor prognosis. Recurrent chromosomal aberrations (del(5)(q), monosomy 7, del(20)(q) and trisomy 8) have been described in BM from ∼50% of newly diagnosed MDS patients, frequently as a part of CCA. Recently, there have been several published reports of chromosomal breakpoints that are associated with cancer genesis and progression that have confirmed the co-localization of these chromosomal breakpoints to known fragile sites (FS). Breakpoints associated with structural changes that are localized to the FS (common or rare) may play a significant role in inactivation of tumor suppressor genes or activation of oncogenes. FS can be defined as heritable-specific loci on human chromosomes that exhibit non-random gaps or breaks when chromosomes are exposed to specific cell culture conditions. Rare fragile sites (RFS) are identifiable in less than 5% of the population, while common fragile sites (CFS) are intrinsic parts of normal chromosome structure that are present in all individuals. We applied microarray technology to analyze genomic structural aberrations in MDS patients with complex karyotypes to identify recurrent chromosomal breakpoints and to evaluate and compare their potential associations with FS.

Bortezomib and panobinostat combination is effective against PTCL

Colin Phipps, Swee Jin Mok, Ai Leen Ang, Yeow Tee Goh, Daryl Tan — 2012-03-23

A 51-year-old gentleman presented with eosinophilia of 3.87×109L−1 associated with itchy, confluent erythematous and edematous papules over his periorbital region, forehead, centre of his face and scalp with scattered papules and pustules over his chest wall and back. Initial CT-scans of the neck, thorax, abdomen and pelvis were unremarkable for lymphadenopathy and hepatosplenomegaly. A skin biopsy done on two occasions showed a non-specific chronic deep dermatitis with non-necrotising granulomatous and eosinophilic components. However, PCR amplification done on paraffin sections showed a prominent, reproducible monoclonal rearrangement of the T-cell receptor-gamma gene locus. Bone marrow aspirate and trephine biopsy was unremarkable except for flow cytometry revealing a small population (5%) of abnormal T-cells with aberrant loss of surface CD3.

Extramedullary blastic crisis in abdominal lymph nodes in a patient with chronic myelogenous leukemia on imatinib

Leyla Shune, Zuzan Cayci, John Rogosheske, Claudio Brunstein, Celalettin Ustun — 2012-03-23

Imatinib controls CML in the vast majority of patients; however approximately 5–15% of CML patients do not tolerate or do not respond to imatinib at initiation of imatinib (primary resistance). Some patients may progress following initial response to imatinib (secondary resistance). Although not all causes of imatinib resistance are identified, the resistance mechanisms can be divided into two groups: BCR/ABL-dependent (e.g., point mutations in the kinase domain of BCR/ABL fusion gene and upregulation of BCR/ABL) and BCR/ABL-independent (e.g., emergence of chromosomal abnormalities in addition to Philadelphia chromosome (Ph) and resistance of CML stem cells) . Moreover, pharmacologic/pharmacokinetic features of imatinib are important in response. The serum levels of imatinib have been found to be correlated with responses . Second-line tyrosine kinase inhibitors can salvage most of imatinib-intolerant or -resistant patients .