Leukemia Research

Editorial Board

2012-03-01

What do kinase inhibition profiles tell us about tyrosine kinase inhibitors used for the treatment of CML?

Michael W. Deininger, Paul Manley — 2011-10-13

Abstract: Cancer treatment has long been based upon cytotoxic therapies that affect all rapidly dividing cells, and as such, is necessarily associated with significant toxicity. More recently, drugs targeted toward pathways critical for tumor cell survival have been developed. With limited off-target activity, such therapies are expected to be better tolerated than broad-acting cytotoxic chemotherapies. BCR-ABL inhibitors in chronic myeloid leukemia are reviewed as a model to investigate the concept of targeted cancer therapies and evaluate how the kinase inhibition profiles of these agents may contribute to their toxicity profiles.

Imatinib does not impair gonadal function

Charles Chuah — 2011-12-02

The Bcr-Abl tyrosine kinase inhibitor, imatinib, was introduced into the armamentarium for the treatment of chronic myeloid leukemia (CML) and has revolutionized the management and significantly improved the long term prognosis of the disease. Durable clinical responses are now achievable in a significant number of chronic phase CML patients and their projected survival is expected to be more than 10–15 years . Imatinib is generally well tolerated and many patients can expect to have a normal quality of life. A recent report has also suggested that imatinib can possibly be interrupted safely in patients who have had sustained complete molecular responses . This positive outlook has raised the expectations of many patients in the childbearing age group who may want to parent children.

Update on developments in the diagnosis and prognostic evaluation of patients with myelodysplastic syndromes (MDS): Consensus statements and report from an expert workshop

2011-12-05

Abstract: Several new treatments for myelodysplastic syndromes (MDS) have recently become available, or are in development. Patients who could benefit from active treatment must be effectively identified and followed up. Therefore, guidelines for the diagnosis and prognostic evaluation of MDS need to be kept up to date with technological and scientific advances. An expert workshop was convened to review currently available and emerging diagnostic technologies and developments in prognostic classification systems, to ensure appropriate management of individual patients. The panel also provided suggestions to ensure adherence to guidelines and highlighted the mandatory requirement for cytogenetic evaluation in patients with MDS.

Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model

Beate Schultheis, Bart A. Nijmeijer, H. Yin, Roger G. Gosden, Junia V. Melo — 2011-10-24

Abstract: Imatinib should be avoided in women planning to become pregnant or during pregnancy, due to a higher risk of congenital malformations. However, it is not known whether imatinib affects future potential for fertility. Here we analysed ovaries and testes from adult mice receiving imatinib, focusing on testicular and ovarian functions. Seven male and 7 female mice were orally treated with 150mg/kg body weight/day imatinib for two months. No effects on folliculogenesis or spermatogenesis could be observed postmortem by histological examinations, suggesting that, at least in two mouse models of imatinib treatment this tyrosine kinase inhibitor does not reduce fertility.

Elevated Fas/FasL system and endothelial cell microparticles are involved in endothelial damage in acute graft-versus-host disease: A clinical analysis

Qiuling Wu, Huixin Chen, Jun Fang, Wei Xie, Mei Hong, Linghui Xia — 2011-09-15

Abstract: Acute graft-versus-host disease (aGVHD) is the major cause of early morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, but its mechanism remains not well understood. This study firstly compared dynamic change of Fas/Fas ligand (FasL) system in plasma and also in the surface of endothelial cell microparticles (EMPs) in aGVHD patients, pre-aGVHD patients (7, 14, 21 and 28 days after transplantation), non-aGVHD patients and normal controls. Plasma soluble FasL (sFasL) was detected by ELISA. Fas, FasL and EMPs were evaluated by Confocal microscopy and flow cytometric analysis respectively. Significantly higher levels of sFasL and EMPs were detected in the patients at the time of aGVHD attack. In addition, sFasL exhibited significant elevation but EMPs exhibited simultaneously decrease within the early phase (+21d) after allo-HSCT in pre-aGVHD group compared with non-aGVHD group. At +21d, there was a significant difference of sFasL and EMPs between pre-aGVHD group and non-aGVHD group. Moreover our present study firstly reported that EMPs expressed higher Fas antigen (Fas+-EMPs) in the patients with aGVHD. Therefore it can be inferred that EMPs may play protective roles through Fas in endothelial cell damage of aGVHD after allo-HSCT. This suggested monitoring EMPs and sFasL in the early phase after HSCT may be useful for the early diagnosis and forecast of aGVHD and it also provided new clues in understanding the pathogenesis of endothelial cell injury during aGVHD after allo-HSCT and meanwhile help identifying new drugs to circumvent it in clinic.

SDF-1/CXCR4 axis in myelodysplastic syndromes: Correlation with angiogenesis and apoptosis

2011-07-29

Abstract: To study the role of SDF-1/CXCR4 axis in MDS, the expression of SDF-1 and CXCR4, VEGF, MVD and apoptosis were measured in MDS. The results showed that the expression of SDF-1 of the low-grade MDS is higher than that of the high-grade MDS and the control. The high-grade MDS had a significantly higher CXCR4 expression on CD34+ cell than low-grade MDS and the control. It was suggested that the SDF-1/CXCR4 axis play an important role in MDS. Apoptosis was significantly increased in low-grade MDS, compared with high-grade MDS. The expression of VEGF and MVD were higher in the high-grade MDS than in the low-grade MDS. There are positive correlations between SDF-1 and apoptosis in the low-grade MDS. For the high-grade MDS, there were positive correlations between CXCR4 and VEGF, and between SDF-1 concentration and MVD. The apoptosis is one of the hallmarks for low-grade MDS and the angiogenesis for high-grade MDS. A refined understanding of the roles that SDF-1/CXCR4 axis and its correlation with angiogenesis and apoptosis play in MDS will fuel the development of therapies that can be targeted to the SDF-1/CXCR4 axis.

The degree of neutropenia has a prognostic impact in low risk myelodysplastic syndrome

2011-12-02

Abstract: The severity of neutropenia in myelodysplastic syndrome (MDS) has not been completely studied. We analyzed the prognostic significance of severe neutropenia (neutrophils count<0.5×109/L) at diagnosis in 1109 patients with de novo MDS and low/intermediate-1 IPSS included in the Spanish MDS Registry. Severe neutropenia was present at diagnosis in 48 of 1109 (4%). Patients with severe neutropenia were most strongly represented within the groups of refractory cytopenia with multilineage dysplasia (40%) and refractory anemia with excess of blast type 1 (29%). Severe neutropenia had negative effects on the low/intermediate-1 risk group. A significant difference in overall survival was observed between patients with severe neutropenia (28months) and patients with a neutrophil count higher than 0.5×109/L (66months) (p<0.0001). Also, severe neutropenia predicted a significantly reduced on leukemia-free survival (p<0.0001). In the multivariate analysis, severe neutropenia retained its independent prognostic influence on overall survival [HR: 2.19, 95% CI (1.41–3.10), p<0.0001] and leukemia free survival [HR: 3.51, 95% CI (1.97–6.26), p<0.0001]. The degree of neutropenia should be considered as additional prognostic factor in low/intermediate-1 IPSS MDS.

Differential MiRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features

2011-11-18

Abstract: The present study aimed to analyze the expression profile of the microRNAs previously described as associated with childhood ALL, miR-92a, miR-100, miR-125a-5p, miR-128a, miR-181b, miR-196b and let-7e, and their association with biological/prognostic features in 128 consecutive samples of childhood acute lymphoblastic leukemia (ALL) by quantitative real-time PCR. A significant association was observed between higher expression levels of miR-196b and T-ALL, miR-100 and patients with low white blood cell count at diagnosis and t(12;21) positive ALL. These findings suggest a potential activity of these microRNAs in pediatric ALL biology.

Interactions between acute lymphoblastic leukemia and bone marrow stromal cells influence response to therapy

2011-09-05

Abstract: The cure rate for pediatric patients with B precursor acute lymphoblastic leukemia (pre-B ALL) is steadily improving, however relapses do occur despite initial response to therapy. To identify links between drug resistance and gene deregulation we used oligonucleotide microarray technology and determined in 184 pre-B ALL specimen genes differentially expressed compared to normal CD34+ specimens. We identified 20 signature genes including CTGF, BMP-2, CXCR4 and IL7R, documented to regulate interactions in the bone marrow. We recorded remarkably similar levels of expression in three independent patient cohorts, and found distinct patterns in cytogenetically defined subgroups of pre-B ALL. The canonical pathways that were affected are involved in inter- and intra-cellular communication, regulating signaling within the microenvironment. We tested experimentally whether interaction with stromal cells conferred protection to four drugs used in current ALL therapy, and demonstrated that bone marrow stromal cells significantly influenced resistance to vincristine and cytosine arabinoside. Compounds designed to block the identified cellular interactions within the bone marrow microenvironment are expected to mobilise the leukemic cells and make them more accessible to contemporary antileukemic agents. The data provide novel insight into the pathobiology of ALL and indicate new therapeutic targets for patients with ALL.

A new minimal deleted region at 11q22.3 reveals the importance of interpretation of diminished FISH signals and the choice of probe for ATM deletion screening in chronic lymphocytic leukemia

2011-09-28

Abstract: Deletion of ATM detected by fluorescent in situ hybridization (FISH) in chronic lymphocytic leukemia predicts short treatment free survival and poor outcome following alkylator/purine analogue therapy. We describe five cases, with a diminished ATM FISH signal, investigated by TP53 mutation/dysfunction studies and single nucleotide polymorphism (SNP) array. The diminished signal represented loss of the ATM gene, which could have been missed were the cases not further investigated. These rare cases highlight the need for careful consideration of the choice of probe and interpretation of unusual signal patterns in FISH screening. We define a new minimal region of deletion at 11q22.3.

Rituximab for the treatment of adult relapsed/refractory CD20 positive B-ALL patients: A pilot series

2011-12-15

Abstract: No series have reported the results of the use of the therapeutic anti-CD20 monoclonal antibody (Rituximab) in the setting of adult refractory/relapsed B-ALL. We report here the outcomes of such nine patients treated at two french institutions by a combination of Rituximab+chemotherapy. We showed that four patients could achieve complete response while four other patients were documented with blast clearance superior to 50% from the baseline in bone marrow. We conclude that our results suggested some efficacy for the use of Rituximab in combination with chemotherapy in the setting of refractory/relapsed adult B-ALL. Larger series within prospective trials are needed to confirm these results.

Minimal residual disease monitoring based on FLT3 internal tandem duplication in adult acute myeloid leukemia

2011-12-02

Abstract: FLT3 internal tandem duplication (FLT3-ITD) is usually considered as a bad marker for minimal residual disease (MRD) follow-up in acute myeloid leukemia (AML). Our objective was to evaluate the suitability of FLT3-ITD as a target for MRD detection by real-time quantitative PCR, in comparison with two other molecular MRD markers, NPM1 mutation and WT1 overexpression, in 20 adult AML patients treated in Acute Leukemia French Association (ALFA) trials. Overall, these 3 MRD markers showed comparable kinetics in 17/20 (85%) cases. Furthermore, we found that FLT3-ITD MRD levels after induction chemotherapy are predictive of complete remission duration.

Influence of JAK2 46/1 haplotype in the natural evolution of JAK2V617F allele burden in patients with myeloproliferative neoplasms

2011-10-17

Abstract: JAK2V617F allele burden was prospectively measured in untreated patients with polycythaemia vera (PV, n=26) or essential thrombocythaemia (ET, n=36) and compared according to JAK2 46/1 haplotype status. The mean increase in JAK2V617F allele burden per year was 1%, 0.8% and 6% for PV patients with the JAK2 46/1 haplotype in negative, heterozygous and homozygous status, respectively (p<0.001). The JAK2 46/1 haplotype had no influence in JAK2V617 allele burden in ET. In conclusion, untreated PV patients homozygous for the JAK2 46/1 haplotype show a progressive increase in the JAK2V617F allele burden during the evolution of the disease.

The long term risk of myelodysplastic syndromes among anemia patients: A population-based study

D. Meytes, G. Chodick, V. Shalev, A. Porath — 2011-12-06

Abstract: We have utilized the computerized data of a nationwide health plan to elucidate several epidemiologic aspects and risk factor of myelodysplastic syndromes (MDS) in Israel. The annual incidence rate (IR) of reported MDS was of 3.32 per 100,000. Among anemic patients aged 40+, the risk of reported MDS was 56.7 per 100,000. Only 44% of the reported MDS cases had an indication of bone marrow examination. In a multivariable model, older age, hemoglobin level <9g/dl, white blood cell count of less than 3500/mm3, and platelet count of less than 100×109/L were associated with a significantly higher risk of MDS. The mean lag period from the first demonstration of anemia to the final diagnosis of MDS was 3.5 years. Our study results could be helpful for improving the detection of patients with high MDS risk, therapeutic decision-making, and designing interventional trials in the future.

Impaired bactericidal and fungicidal activities of neutrophils in patients with myelodysplastic syndrome

2011-12-16

Abstract: Infections are a major cause of morbidity and mortality in patients with myelodysplastic syndrome (MDS) due to quantitative and qualitative granulocytic defects. We evaluated the in vitro bactericidal and fungicidal activities of neutrophils isolated from MDS. With comparison to those from healthy individuals, MDS neutrophils following infection showed a significantly reduced killing activity against Escherichia coli at 8 (p=0.002), 24 (p<0.0001), 48 (p=0.0005), and 72h (p=0.0264), against Lactococcus lactis at 24 (p=0.0002), 48 (p<0.0001), and 72h (p<0.0001), and more against Candida albicans at 8 (p=0.0003), 24 (p<0.0001), 48 (p<0.0001), and 72h (p<0.0001). Our data show that MDS neutrophils have an impaired microbicidal function, which might account for the high susceptibility to infections of MDS patients.

miR-590-5p, miR-219-5p, miR-15b and miR-628-5p are commonly regulated by IL-3, GM-CSF and G-CSF in acute myeloid leukemia

Amanda J. Favreau, Pradeep Sathyanarayana — 2011-10-24

Abstract: Aberrations in IL-3, GM-CSF and G-CSF induced signaling are frequently reported in acute myeloid leukemia (AML). Herein, we utilized a unique human myeloid leukemic cell line, AML-193, which responds to all three cytokines to analyze the regulation at microRNA level. Using real-time PCR-based miRNA expression profiling, we investigated miRNA signatures regulated by IL-3, GM-CSF and G-CSF for n=704 miRNAs. We discovered that in addition to regulating specific miRNAs, these cytokines also regulate common set of miRNAs, which includes miR-590-5p, miR-219-5p, miR-15b and miR-628-5p. Taken together, we have identified novel candidate miRNAs that may be instructive during leukemic and normal hematopoiesis.

Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis

2011-12-05

Abstract: Activation of the mTOR pathway subsequent to phosphatase and tensin homolog (PTEN) mutation may be associated with glucocorticoid (GC) resistance in acute lymphoblastic leukemia (ALL). The combination activity of rapamycin and dexamethasone in cell lines and xenograft models of ALL was determined. Compared with either drug alone, dexamethasone+rapamycin showed significantly greater apoptosis and cell cycle arrest in some cell lines, and was more frequently seen in T-lineage cell lines with PTEN mutation. The combination significantly extended the event-free survival of mice carrying PTEN mutated xenografts. Our data suggest that PI3K/mTOR pathway inhibitors could benefit patients with PTEN mutated T-ALL.

A combination of methotrexate and irradiation promotes cell death in NK/T-cell lymphoma cells via down-regulation of NF-κB signaling

2011-09-07

Abstract: Nasal NK/T-cell lymphoma (NKTL) is a highly aggressive disease. Although radiotherapy is the first-line of treatment for NKTL, the clinical outcome is poor. Thus, there is a need for an effective radiosensitizer to improve the survival rate of patients. NF-κB activation contributes to cell survival as well as chemo- and radio-resistance in various cancer cells. In NKTL, the constitutive activation of NF-κB is also a critical factor. In the present study, we used two EBV-expressing NKTL cell lines (Hank-1 and NK-92) to evaluate the radiosensitizing effect of methotrexate (MTX), highlighting the role of NF-κB. Combined treatment of MTX and IR significantly induced apoptosis and growth inhibition in both NKTL cells. The synergistic cytotoxicity was correlated with blocking nuclear NF-κB and suppressing expression of NF-κB-mediated anti-apoptotic proteins. These data suggest that the combined treatment with MTX and IR can inhibit IR-induced NF-κB activation in NKTL cells. Taken together, co-treatment with MTX and IR may provide a therapeutic advantage for patients with NKTL.

CD44 activation enhances acute monoblastic leukemia cell survival via Mcl-1 upregulation

2011-10-13

Abstract: Survival of acute myeloid leukemia (AML) cells is regulated by their adherence to bone marrow stromal environment. Several adhesion molecules mediate interactions between AML cells and stroma, but their specific role in AML cell survival is still poorly understood. Here, we show that CD44 activation with the Hermes-3 monoclonal antibody enhances primary AML5 blast survival and increases apoptosis resistance of THP-1 monoblastic leukemia cells. Moreover, we show that CD44 activation upregulates the anti-apoptotic Mcl-1 protein and that Mcl-1 is essential for apoptosis resistance of THP-1 cells. These results suggest that Mcl-1 inhibitors might be required to block pro-survival activity of CD44 in AML5.

Combination of atiprimod and the proteasome inhibitor bortezomib induces apoptosis of mantle cell lymphoma in vitro and in vivo

2011-10-14

Abstract: The proteasome inhibitor bortezomib (BTZ) is known to be chemotherapeutic in relapsed or refractory mantle cell lymphoma (MCL). Atiprimod (ATI), a novel cationic amphophilic compound, has been tested in clinical trials in multiple myeloma (MM). We sought to evaluate the effect of an ATI–BTZ combination on MCL and to elucidate its therapeutic mechanisms. The ATI and BTZ combination significantly inhibited growth and induced apoptosis of both cultured MCL cell lines and freshly isolated tumor cells from patients with refractory or relapsed MCL. However, the combination yielded lower cytotoxicity in normal peripheral blood mononuclear cells (PBMC). Furthermore, ATI and BTZ induced apoptosis via two different signaling pathways. More significantly, ATI and BTZ markedly delayed tumor growth and prolonged survival in MCL-bearing NOD–SCID mice. Our results demonstrate that ATI and BTZ confer significant therapeutic effects in MCL in vitro and in vivo and should therefore be investigated in a clinical trial in patients with relapsed or refractory MCL.

Retrovirus-transformed erythroleukemia cells induce central nervous system failure in a new syngeneic mouse model of meningeal leukemia

2011-09-19

Abstract: Lack of suitable mouse models for central nervous system (CNS)-associated leukemias has hindered mechanism-guided development of therapeutics. By transplanting retrovirus-transformed mouse erythroleukemia cells into syngeneic mice, we developed a new animal model of meningeal leukemia associated with rapid paralysis. Necropsy revealed massive proliferation of the leukemic cells in the bone marrow (BM) followed by pathological angiogenesis and invasion of the leukemic cells into the meninges of the CNS. Further analysis demonstrated that the erythroleukemia cells secreted high levels of VEGF and preferentially adhered in vitro to fibronectin. This unique animal model for meningeal leukemia should facilitate studies of engraftment and proliferation of leukemic cells in the BM and their invasion of the CNS as well as pre-clinical evaluation of experimental therapeutics for CNS-associated leukemias.

Unique association of systemic mastocytosis and myeloid/lymphoid neoplasm in blast crisis with abnormality of FGFR1 gene

2011-10-26

Mastocytosis is a heterogeneous group of diseases characterized by abnormal growth and accumulation of mast cells . It is now classified as a myeloproliferative neoplasm or MPN in the 2008 World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues . Based on the previous 2001 WHO classification, two major variants of mastocytosis are defined: cutaneous mastocytosis and systemic mastocytosis (SM) . SM is further divided into six subtypes: indolent SM, SM with associated clonal haematological non-mast cell lineage disease (SM-AHNMD), aggressive SM, mast cell leukaemia, mast cell sarcoma and extracutaneous mastocytoma. The 2008 WHO classification has recently individualized a new subgroup of MPN defined as myeloid and lymphoid neoplasms with eosinophilia and abnormalities of FGFR1. We describe here a rare SM-AHNMD associating a systemic mastocytosis and a myeloid neoplasm in blast crisis, with a ZNF198–FGFR1 molecular rearrangement.

Deletion of the long arm but not the 5q31 region of chromosome 5 in myeloid malignancies

2011-12-08

Deletion of the long arm of chromosome 5 is a recurrent cytogenetic abnormality that is frequently found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The commonly deleted region (CDR) has been identified by various investigators (review in ). The proximal CDR in the 5q31.2 region has been detected in MDS, AML and therapy-related MDS/AML. The distal CDR in the 5q32-q33 region is involved in the pathogenesis of MDS with isolated deletion 5q . Mutational analyses of the residual intact allele have not identified tumor suppressor genes. Haploinsufficiency of multiple genes in the proximal and distal CDRs may cooperate in MDS initiation and/or progression .

Erythroleukemia presenting with myeloid sarcoma of the lung as detected by immunophenotypic analysis of bronchoalveolar lavage fluid

2011-12-15

Myeloid sarcoma (MS) is an extramedullary tumor mass composed by immature myeloid cells, that may develop concurrently with acute myeloid leukemia (AML). Although MS can occur in any site, lung involvement is rare . Acute erythroid leukemia (AEL) represents less than 5% of AML cases . Its extramedullary presentation as a MS is extremely rare, and pulmonary involvement has never been described so far . Although flow cytometry analysis of bronchoalveolar lavage fluid (BALF) is effective to detect lymphomatous pulmonary involvement, whether this method discloses lung MS is unknown . We report an erythroid/myeloid AEL subtype presenting with pulmonary MS, as detected by BALF immunophenotype.

Absence of mutations in the activation loop and juxtamembrane domains of VEGFR-1 and VEGFR-2 gene in chronic myelomonocytic leukemia (CMML)

2011-12-07

Angiogenesis is recognized as a main feature of many human neoplasms. Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with exerts its biologic effects by interaction with either of 2 high-affinity tyrosine kinase receptors, VEGFR-1 (FLT1) and VEGFR-2 (KDR). Several studies have shown that both monocytes and myeloid precursors are able to produce and secreted VEGF and, commonly, co-express one or both VEGF receptors. On the other hand, overexpression and secretion of VEGF have been observed in 72% of patients with acute myeloid leukemia (AML), with the corresponding mRNA of the genes FLT1 or KDR being expressed in 60% and 19% of AML patients, respectively .

Atraumatic splenic rupture in patients with myelodysplastic syndromes: Report of a case occurred during treatment with 5-azacitidine and review of the literature

2011-12-15

A 62-year old Caucasian woman with a previous history of arterial hypertension, dilative cardiomyopathy and cerebral transient ischemic attack, was admitted to our Department because of marked fatigue, in the absence of fever or hemorrhage. The complete blood count (CBC) revealed pancytopenia, with white blood cell (WBC) count 0.8×109/L in the absence of circulating blasts, hemoglobin (Hb) level 5.4g/dl and platelet (Plt) count 78×109/L, without signs of coagulopathy. Neither hepatomegaly nor splenomegaly were observed on abdominal ultrasonography. The morphological, cytochemical and immunophenotypic analyses performed on peripheral blood and bone marrow aspirate and trephine biopsy documented features consistent with a myelodysplastic syndrome (MDS). Conventional G-banding showed a normal 46,XX karyotype, while neither recurring fusion transcripts, usually associated with acute myeloid leukemia and related neoplasms, nor Flt3-ITD, Flt3 D835V point mutation, NPM1 and c-Kit somatically acquired mutations were documented by molecular examinations. Refractory anemia with excess of blasts-2 (RAEB-2) according to the revised WHO classification, intermediate-2 risk IPSS and high risk WPSS, was thus diagnosed. The treatment with low-dose aspirin was withdrawn because of thrombocytopenia. The patient received packed red blood cell (RBC) transfusions and was started on treatment with the hypomethylating agent 5-azacitidine administered subcutaneously according to the schedule 5–2–2 (75mg/m2/day for 5 days, followed by a 2-day weekend break, then two further treatment days). She was discharged on day +10 of the first cycle, with WBC count 0.48×109/L, Hb level 8.5g/dl and Plt count 38×109/L. On day +12, the patient, while remaining completely asymptomatic, was admitted at 9.00 AM to our outpatient's Department for blood examinations, which documented WBC count 0.5×109/L, Hb level 9.0g/dl and Plt count 43×109/L. On the same day, at 4.00PM, she experienced severe fatigue, dizziness and sweating, while becoming hypotensive and tachycardic. The CBC showed severe anemia (Hb level 5.8g/dl), while WBC count and Plt count were 0.6×109/L and 35×109/L, respectively. The clinical picture was consistent with hemorrhagic shock. There was no history of trauma. The patient responded to resuscitation with crystalloids combined with RBC and Plt transfusional support. The abdomen was soft and diffusely tender without peritoneal signs. Liver and spleen were not palpable. The remainder of the physical examination was unremarkable. Both abdominal ultrasonography and Computerized Tomography (CT) scan revealed massive peritoneal effusion with high fluid density, consistent with hemoperitoneum secondary to rupture of the spleen. Of note, the ruptured spleen was normal in size, but presented abnormal enhancement of the parenchyma, with diffuse hypodense areas. Bilateral lung infiltrates and pleural effusions were concurrently observed on chest CT scan. Emergency lapatoromic splenectomy was performed, and approximately 2500ml of blood were drained from the peritoneal cavity. On gross examination, the spleen was ruptured, with capsular laceration and discontinuation, in the absence of areas of infarction. Of note, the spleen weighed 125g and measured 10.5cm×8.5cm×3.8cm. The histological examination of the splenic tissue revealed preserved architecture of red and white pulp, with expansion of the red pulp and relative decrease in the white pulp areas (a). Moreover, focal areas of extramedullary hematopoiesis (EMH) were documented by morphologic and immunohistochemical examinations. In details, immature myeloid elements, mature granulocytes and few megakaryocytes, were observed in the splenic cords and sinuses of the red pulp (b and c). The number of CD34+ hematopoietic cells was also moderately increased in the red pulp (d). The CBC, immediately performed post-operatively, showed WBC count 0.7×109/L, Hb level 11.7g/dl and Plt count 32×109/L. There were no intraoperative complications, but, postoperatively, the patient became febrile. Long-lasting broad-spectrum antibiotic therapy, directed to Pseudomonas aeruginosa and Acinetobacter baumannii, which were sequentially recovered from bronchoalveolar lavage culture, was administered, obtaining nearly complete resolution of bilateral pneumonia. Immunizations against Haemophilus influenzae, Pneumococcus and Meningococcus were also administered. Two weeks after splenectomy (day +26 from 5-azacitidine treatment) the CBC significantly improved (WBC count 4.7×109/L with a differential count showing 56% neutrophils, Hb level 10.2g/dl and Plt count 232×109/L). On day +29, the patient underwent the second cycle of 5-azacitidine-based therapy with unmodified dosage. Actually, the patient has received the sixth cycle of hypomethylating therapy, without further hemorrhagic complications. The latest CBC documented WBC count 2.4×109/L, Hb level 8.3g/dl and Plt count 435×109/L.

Spontaneous, transient regression of B lymphoblastic leukemia in an adult patient: A variant presentation of prodromal/pre-ALL

Chaiyaporn Boonchalermvichian, Yi Xie, Russell K. Brynes, Imran N. Siddiqi — 2011-12-02

Rarely, acute lymphoblastic leukemia (ALL) can present after a brief preleukemic phase of pancytopenia/bone marrow failure, followed by transient and spontaneous normalization of bone marrow cellularity and peripheral blood counts, with subsequent progression to overt leukemia . These uncommon cases have been well described in children and adolescents, and very rarely in adults, and are often referred to as prodromal ALL or pre-ALL . The pancytopenic episode lasts for a few days up to a few weeks, typically followed by complete and spontaneous recovery . The prognosis has been reported not to be different from patients with classic presentation of ALL .

Clinical profile and outcome of patients of acute myeloid leukemia with high hyperdiploidy

2011-12-05

Acute myeloid leukemia (AML) is rarely associated with hyperdiploidy. Hyperdiploidy is included under complex karyotype in AML. High hyperdiploidy, i.e. near triploidy and tetraploidy is even rare cytogenetic abnormality seen commonly in elderly male AML patients and is associated with poor prognosis. In the last 3 years we had 5 cases of de-novo AML with near triploidy and tetraploidy. The AML FAB subtypes of these cases included one case of AML-M2 and four cases of AML-M4. Hyperdiploidy was determined by conventional karyotyping. All of our five patients were young and four of them were females. The overall outcome was poor. Because of the rarity of high hyperdiploidy in AML, better understanding of this disease and newer treatment approaches need to be defined. The clinical presentation and response to standard treatment in these five patients of AML with high hyperdiploidy is described here.