Leukemia Research - Articles in Press

Src, Akt, NF-κB, BCL-2 and c-IAP1 may be involved in an anti-apoptotic effect in patients with BCR-ABL positive and BCR-ABL negative acute lymphoblastic leukemia - Corrected Proof

2012-05-16

Abstract: BCR-ABL kinase has been observed to be potentially related to leukemic cell development. Adult patients with acute lymphoblastic leukemia (ALL) were evaluated to determine whether presence/absence of BCR-ABL induced differences in activation of Src, PI3K/Akt and NF-κB or in the expression of anti-apoptotic proteins such as BCL-2 and c-IAP1. BCR-ABL positive patients showed a significantly higher activation of Src and Akt compared with BCR-ABL negative patients and healthy donors. BCR-ABL negative patients also showed a significant activation of Src and low levels of Akt activation compared with healthy donors. Both patient groups had increased NF-κB activation and overexpression of BCL-2 and c-IAP1. This is the first study to evaluate concurrently in ALL patients presence/absence of BCR-ABL in relation to activation of Src, Akt and NF-κB and the expression of anti-apoptotic proteins. Results suggest that these proteins may be involved in an anti-apoptotic signaling pathway.

ALK-positive anaplastic large cell lymphoma with TPM3-ALK translocation - Corrected Proof

Saeam Shin, Juwon Kim, Sun Och Yoon, Yu Ri Kim, Kyung-A. Lee — 2012-05-16

Anaplastic large cell lymphoma (ALCL) is a T cell lymphoma consisting of large cells that express CD30 . Anaplastic lymphoma kinase (ALK) is expressed in 50–80% of ALCLs, with a higher frequency of ALK-positive than ALK-negative ALCL in younger patients . ALK-positive ALCL is associated with various translocations involving the ALK gene and partner genes on chromosomes 1, 2, 3, 17, 19, 22, and X . The most frequent of these (84% of translocations) is t(2;6)(p23;q35), leading to the formation of a fusion protein between nucleophosmin and anaplastic lymphoma kinase (NPM-ALK) . This fusion results in aberrant expression of receptor tyrosine kinase ALK and seems to be associated with cell transformation . ALK positivity has been considered a favorable prognostic factor ; however, since ALCL involving fusion of ALK with proteins other than NPM is uncommon, the clinical features of these cases are not well known. Translocation between ALK and non-muscular tropomyosin3 (TPM3) gene on chromosome 1 has been reported very rarely . Here, we report a case of ALK-positive ALCL with t(1;2)(q25;p23).

Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia - Corrected Proof

2012-05-16

Abstract: Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL.

Thalidomide maintenance therapy for patients with multiple myeloma: Meta-analysis - Corrected Proof

Yuki Kagoya, Yasuhito Nannya, Mineo Kurokawa — 2012-05-14

Abstract: We performed a meta-analysis of randomized controlled trials comparing thalidomide maintenance with other regimens after induction chemotherapy for multiple myeloma. Overall, 6 trials including 2786 patients were identified. Patients treated with thalidomide maintenance had marginally better overall survival (hazard ratio HR 0.83, P=0.07). The improvement was especially prominent in a subgroup of studies using corticosteroids with thalidomide (HR 0.70, P=0.02). Thalidomide improved progression-free survival (HR 0.65, P<0.01), but had more frequent venous thrombosis (risk difference 0.024, P<0.05) and peripheral neuropathy (risk difference 0.072, P<0.01). These results suggest that thalidomide maintenance with corticosteroids is effective in prolonging survival for multiple myeloma.

Synergistic effect of Toll-like receptor 4 and 7/8 agonists is necessary to generate potent blast-derived dendritic cells in Acute Myeloid Leukemia - Corrected Proof

2012-05-14

Abstract: Leukemic cells from AML patients can be differentiated to dendritic cells (DCs). Such DCs have potential for immunotherapy of patients. Blasts from 15 AML patients were differentiated into DCs and matured by different TLR agonists. We could generate AML-DCs from 73% of patients mostly with M4 or M5 subtypes. The DC recoveries ranged from 28% to 50%. The results showed that concomitant use of TLR4 and TLR7/8 agonists induced proficient DCs. Therefore, a combination of TLR4 and 7/8 agonists can be considered as an appropriate maturation cocktail for AML-DC production in order to use in the immunotherapy of AML patients.

Erythroblastic sarcoma - Corrected Proof

Andrew Riddle, Brian Olsen — 2012-05-14

Myeloid sarcoma is a rare entity associated with acute myeloid leukemia (AML)/myelodysplasia (MDS) or myeloproliferative neoplasia (MPN). It can precede, occur concurrently or appear after the diagnosis of AML/MDS/MPN. Myeloid sarcoma is defined by the WHO 2008 classification scheme as a tumor mass consisting of myeloid blasts with or without maturation occurring at a site outside of the bone marrow. We report a very rare variant of myeloid sarcoma with predominant erythroid differentiation, to which the term “erythroblastic sarcoma” may be best applied.

ETV6 fusion genes in hematological malignancies: A review - Corrected Proof

2012-05-14

Abstract: Translocations involving band 12p13 are one of the most commonly observed chromosomal abnormalities in human leukemia and myelodysplastic syndrome. Their frequently result in rearrangements of the ETV6 gene. At present, 48 chromosomal bands have been identified to be involved in ETV6 translocations, insertions or inversions and 30 ETV6 partner genes have been molecularly characterized. The ETV6 protein contains two major domains, the HLH (helix-loop-helix) domain, encoded by exons 3 and 4, and the ETS domain, encoded by exons 6 through 8, with in between the internal domain encoded by exon 5. ETV6 is a strong transcriptional repressor, acting through its HLH and internal domains. Five potential mechanisms of ETV6-mediated leukemogenesis have been identified: constitutive activation of the kinase activity of the partner protein, modification of the original functions of a transcription factor, loss of function of the fusion gene, affecting ETV6 and the partner gene, activation of a proto-oncogene in the vicinity of a chromosomal translocation and dominant negative effect of the fusion protein over transcriptional repression mediated by wild-type ETV6. It is likely that ETV6 is frequently involved in leukemogenesis because of the large number of partners with which it can rearrange and the several pathogenic mechanisms by which it can lead to cell transformation.

A novel prognosis of acute myeloid leukemia: AML-M2 complicate with thrombocythemia after complete remission - Corrected Proof

Yi-xin Chen, Ying Li, Ling-yan Zhang, Bin Liu — 2012-05-14

In February 2008, a 79-year-old man was admitted into the hospital with a 3-month history of smothered cough and fatigue. The patient had obvious tender pain in the middle and lower sternum and crude breathing sounds in both lungs. However, a physical examination revealed no other positive findings. A blood test showed the patient's white blood cell (WBC) count was 144.3×109L−1, the hemoglobin (Hb) was 115g/L, and the platelet (PLT) count was 236×109L−1. A peripheral blood smear revealed that the white blood cells were significantly increased. The myeloblasts and promyelocytes accounted for 31% of all the peripheral blood cells and neutrophilic metamyelocytes were visible. The results of a bone marrow analysis showed hyperplasia in the myeloid lineage. Myeloblasts within the bone marrow accounted for 34% hyperplastic cells, and promyelocytes accounted for 12% of hyperplastic cells. Cells with a band-shaped nucleus were the most common cell type observed. The cell sizes varied and the nuclei were round. The cells exhibited compacted chromatin, visible nucleoli, and light blue-stained cytoplasm, which contained Auer bodies; moreover, these cells were also POX (+). Red line hyperplasia was suppressed, and mature erythrocytes varied in cell size. Moreover, the lymphocyte compartment accounted for 1.5% of cells. There were 130 megakaryocytes and platelets scattered in small clusters (). An analysis of common fusion genes was conducted. However, the examination showed that the patient was JAK2V617F mutation (−) and BCR-ABL translocation (−). Analysis of the patient's blood by immunophenotyping with flow cytometry showed that R3 accounted for 21.88% of cells. The cells expressed CD15, CD33 and cMP0. The cells expressed varying levels of CD117, CD11b, CD34, CD64, CD19, HLA-DR and CD13. The cells did not express CD14, CD5, CD7, CD56, CD138, CD3, CD22, CD20 and cCD79a.

A patient with acute megakaryoblastic leukaemia who achieved CRi after decitabine treatment - Corrected Proof

2012-05-14

Acute megakaryoblastic leukaemia (AML-M7) is a rare subtype of acute myeloid leukaemia (<5%), which was first described in 1931 by Von Boros and Koreny . It can occur in both adults and children. AML-M7 patients present with cytopenias and frequently thrombocytopenia, although some may have thrombocytosis. AML-M7 is also a clinical subtype of refractory AML due to its poor response to conventional induction therapy and poor prognosis. Effective treatment regimens have not been explored, as the disease is so uncommon. Here, we report a patient with AML-M7 who achieved complete remission after eight days of decitabine induction therapy.

Proliferative monocyte frequency is associated with circulating monocyte prevalence - Corrected Proof

Felix I.L. Clanchy, John A. Hamilton — 2012-05-14

Monocytes and macrophages are often described as having limited potential for proliferation, although a significant proportion of human monocyte-derived cells enter the cell cycle and divide in vitro . The circulating monocyte subset that proliferates in culture has been termed the proliferative monocyte (PM) and possesses greater osteoclastic potential . Phenotyping of the PM subset indicates that these circulating cells have a CD14hi (CD13loCD64hiCD11bloCD33loCD16−) FACS profile . The capacity to proliferate and the increased differentiation potential suggest that the PM is less mature than the majority of peripheral blood monocytes. Despite significant research, homeostatic processes for the maintenance of peripheral blood leukocyte numbers and mechanisms for trafficking and re-circulation of leukocytes are still far from well characterised . During disease the numbers and proportions of leukocytes change due in part to the modulation of haematopoiesis and leukocyte mobilisation; the prevalence of immature circulating cells is also increased in haematological malignancy.

PAX5-AUTS2: A recurrent fusion gene in childhood B-cell precursor acute lymphoblastic leukemia - Corrected Proof

2012-05-14

Abstract: PAX5 rearrangements resulting in the expression of fusion transcripts account for 2–3% of childhood B-cell precursor acute lymphoblastic leukemia. Most PAX5 fusions are rare and many of them have only been described in a couple of, or even only in single, cases. We have identified the third case with a PAX5-AUTS2 fusion, which results from unbalanced t(7;9)(q11.2;p13.2) rearrangements. Our findings substantiate that PAX5-AUTS2 is a recurrent fusion gene in pediatric B-cell precursor acute lymphoblastic leukemia, and we summarize the clinical characteristics of such patients.

Paraneoplastic pemphigus associated with chronic lymphocytic leukaemia: Treatment with alemtuzumab - Corrected Proof

Maria Ekbäck, Bertil Uggla — 2012-05-14

Paraneoplastic pemphigus (PNP) is a rare autoimmune mucocutaneous disease associated with neoplasia , most commonly B-cell lymphoproliferative diseases. The mechanism behind the general propensity for autoimmunity in CLL is unknown; however a few theories have been presented. One theory is that CLL cells act as atypical antigen-presenting cells. Another possibility is that the immunoglobulin produced by the CLL cells act as auto antibodies. A third postulated mechanism is the suppression of regulatory T-cells, especially after treatment with fludarabine . It is suggested that PNP is the skin manifestation of a paraneoplastic autoimmune multiorgan syndrome, as auto antibodies could also be detected in the kidney, bladder and smooth and striated muscle. The involvement of the mouth, the pharynx, the larynx, the oesophagus and the lungs are examples of epithelial target antigen depositions . In one-third of the cases, PNP precedes the malignancy. PNP is characterized by painful mucosal erosions and ulcers, often involving the lateral borders of the tongue and the vermillion of the lips. The mucosal lesions in PNP are commonly more extensive than the mucosal lesions seen in pemphigus vulgaris and usually an early sign of the disease. Similar changes can also be found in other mucosal areas . Skin eruptions are polymorphous, if seen, but not mandatory for diagnosis .

Erythropoietin: The swinging pendulum - Corrected Proof

Howard S. Oster, Drorit Neumann, Michael Hoffman, Moshe Mittelman — 2012-05-14

Abstract: Erythropoiesis stimulating agents (ESAs) have been used widely for anemic patients, especially those on dialysis and with cancer. However, reports have suggested shorter survival in erythropoietin (EPO)-treated cancer patients. The purpose of this review is to summarize and evaluate critically the current information about ESA treatment and its possible association with mortality in cancer patients. The pendulum that initially swung in the direction of widespread ESA treatment, and then in the direction of no treatment, is swinging back toward a stable position. This review also provides tools to decide how and when to use ESAs safely, according to accepted guidelines.

A novel I293MP mutation within BCR-ABL kinase domain in a Ph-positive acute lymphoblastic leukemia patient presenting resistant to imatinib but sensitive to nilotinib - Corrected Proof

2012-05-14

Combination of BCR-ABL specific tyrosine kinase inhibitors (TKIs) with chemotherapy has demonstrated superior responses resulting in higher complete remission (CR) rates and lower toxicity in Ph-positive acute lymphoblastic leukemia (Ph+ALL). However, the high disease relapse and rapid evolution of drug resistance weaken the treatment effects . More than 40 mutations within the BCR-ABL kinase domain (KD) have been identified, carrying different degrees of resistance to TKIs . We report a novel mutation (I293MP) identified in a relapsed Ph+ALL patient who presented resistant to imatinib but sensitive to nilotinib. Molecular dynamic simulation study suggests that this mutation confers resistance by disrupting binding of imatinib but not nilotinib with ABL KD.

Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase - Corrected Proof

2012-05-14

Abstract: The prognosis for patients with Philadelphia-negative myeloproliferative neoplasms (MPN) who evolve into acute myeloid leukemia (AML) or blast phase (MPN-BP) is extremely poor. Although allogeneic stem cell transplantation (allo-SCT) is considered potentially curative, very few patients have been reported who have undergone allo-SCT for MPN-BP; therefore the success rate remains unknown. In a retrospective review, we identified 13 patients with an MPN transformation to blast phase after a median 9 years (range 5 months to 30 years); 8 (median age 55) continued to allo-SCT within 6 months. Induction chemotherapy cleared blood/marrow blasts in 60% (6/10) (2 declined therapy, 1 had early death). At the time of allo-SCT, 5/8 patients were in complete remission (CR) of their leukemia or had returned to MPN chronic phase (CP), 2 had residual blood blasts and 1 was refractory with >5% marrow blasts. At follow-up (median 20.3 months), 6 patients are alive in CR of both their leukemia/MPN. All 5 patients in CR/CP at pre-allo-SCT remain alive in remission, while 2/3 with persistent blood/marrow blasts relapsed and expired. We conclude that MPN-BP can be cured by allo-SCT in a significant percentage of patients, but that adequate leukemic clearance prior to allo-SCT offers an optimal outcome.

Improved survival in MDS patients receiving iron chelation therapy – A matched pair analysis of 188 patients from the Düsseldorf MDS registry - Corrected Proof

2012-05-08

Abstract: MDS patients are prone to develop transfusional iron overload. Iron overload may partly explain why transfusion dependency is associated with a decreased likelihood of survival. Our matched-pair analysis included 94 patients on long-term chelation therapy and 94 matched patients without it. All patients had iron overload, defined as serum ferritin (SF) above 1000ng/ml or a history of multiple transfusions and SF≥500ng/ml. Median SF was 1954ng/ml in chelated and 875ng/ml in non-chelated patients. The difference in median survival (74 vs. 49 months, respectively; p=0.002) supports the idea that iron chelation therapy is beneficial for MDS patients.

The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells - Corrected Proof

2012-05-07

Abstract: Mantle cell lymphoma (MCL) is one of the most difficult B-cell lymphomas to be treated. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is constitutively activated in MCL and plays a critical role in tumor growth and survival. However, single targeted agent mTOR has limited efficacy in treating MCL. Here, we investigate for the first time potential efficacy of NVP-BEZ235 (BEZ235) in treating MCL by simultaneously targeting Akt and mTOR.In this study, phosphorylated Akt and mTOR level were elevated in tissue samples from MCL patients and in MCL cell lines. We also generated bortezomib-resistant MCL cell lines and found increased phosphorylation of Akt and mTOR. Individual inhibition of PI3K or mTOR had limited anti-proliferative effects, whereas dual inhibition with BEZ235 effectively inhibited cell growth. The effect of BEZ235 was synergistic and sensitized the cells to the cytotoxic effects of conventional agents. Furthermore, BEZ235 could overcome acquired resistance to bortezomib in MCL cells and suppress the activated Akt/mTOR pathway. Therefore, these data suggest that the Akt/mTOR pathway plays a key role in the growth and survival of MCL cells and that these proteins may need to be simultaneously targeted for effective treatment of the disease. Our findings suggest that BEZ235 may be an effective agent for the treatment of MCL.

Mycosis fungoides with testicular involvement: A rare phenomenon - Corrected Proof

2012-05-07

A 76-year-old Caucasian male was referred to Indiana University Melvin and Bren Simon Cancer Center (IUSCC) in July 2009 after a skin biopsy demonstrated mycosis fungoides. The histopathology was reviewed at IUSCC () which confirmed perivascular lymphocytic infiltrate with marked cytologic atypia including hyperchromatic convoluted nuclei and occasional Pautrier microabscesses. Immunostains were positive for CD2, CD3 and CD4 and weakly positive for CD5 and CD7. Immunostains for CD56, CD57, TIA, TdT and CD68 were negative. These findings were determined to be consistent with mycosis fungoides. There was no evidence of extra-cutaneous involvement on physical examination, bone marrow biopsy or positron emission and computed tomography (PET/CT). The patient was treated for Stage IB (T2, N0, M0, B0) mycosis fungoides with betamethasone 0.05% followed by combination clobestesol 0.05%, bexarotene 1% and then single agent topical nitrogen mustard 20mg% ointment. Improvement in skin lesions was observed; however, complete resolution was not achieved.

The place of sideroblastic erythropoiesis in WHO 2008 classification of MDS; RCMD versus RCMD-RD as combined or a separate entity? - Corrected Proof

Yataro Yoshida — 2012-05-04

The 2001 WHO classification of myeloid neoplasms divided refractory anemia (RA) of the myelodysplastic syndromes (MDS) to two types; those with dysplasia restricted to the erythroid lineage and those with dysplasia in two or more myeloid cell lines . The latter, called refractory cytopenia with multilineage dysplasia (RCMD), generally have worse prognosis than the former (RA). The reported median overall survival (OS) is approximately 40 months and the frequency of acute leukemia evolution at 2 years is ∼10% . Likewise, RA with ringed sideroblasts (RARS) was divided into pure erythroid dysplastic type with ringed sideroblasts comprising 15% of more of the marrow erythroid cells and sideroblastic type associated with dysplasia in two or more myeloid cell lines (RCMD-RS). These subdivision was based on the findings that multilineage dysplasia imparts a worse prognosis than if only erythroid dysplasia is present . The RCMD-RS category was, however, incorporated into RCMD in the 2008 WHO classification, thus no longer has place as an MDS subtype . The rationale appears that although morphologically distinct, RCMD and RCMD-RS do not have a different outcome. This means that ringed sideroblastosis bears little prognostic significance in the settings of multilineage dysplasia. Nonetheless, we still keep the two favorable subtypes, RA and RARS, within WHO 2008 system. Both RA and RARS have a comparable prognosis with a median OS of 66–75 months and less than 5% frequency of AML transformation .

Prognoses of MDS subtypes RARS, RCMD and RCMD-RS are comparable but cytogenetics separates a subgroup with inferior clinical course - Corrected Proof

2012-05-03

Abstract: In 2008, the WHO combined the former categories RCMD (refractory cytopenia with multilineage dysplasia) and RCMD-RS (ring sideroblasts ≥15%). We studied the clinical impact and genetic background of RARS, RCMD, and RCMD-RS in 1082 patients. Good karyotypes (IPSS) were similarly frequent in RARS, RCMD, and RCMD-RS. 2-year overall survival (OS) rates were similar in RARS, RCMD, and RCMD-RS (85.9%/89.0%/91.7%; n.s.). The 2-year OS rate was better in good than intermediate or poor karyotypes (p<0.001). These results support to combine RCMD and RCMD-RS as performed by WHO and emphasize the prognostic power of cytogenetic criteria for these MDS subtypes.

Cytogenetics in myelodysplastic syndromes: Old methods, new clues - Corrected Proof

Gian Matteo Rigolin, Antonio Cuneo — 2012-05-01

The identification of non-random chromosomal abnormalities by metaphase karyotyping is a cornerstone in the diagnostic work-up of patients affected by myelodysplastic syndromes (MDS). The demonstration of chromosomal abnormalities was included as one of the decisive criteria for the diagnosis of MDS while the presence of recurring chromosomal abnormalities was considered by the WHO as a presumptive evidence of MDS in the setting of persistent cytopenia of undetermined origin in the absence of definitive morphologic features of MDS. Chromosomal abnormalities are also part of several prognostic indexes and specific treatments may be considered in the presence of some cytogenetic aberrations .

Clinical significance of minimal residual disease detected by multidimensional flow cytometry: Serial monitoring after allogeneic stem cell transplantation for acute leukemia - Corrected Proof

2012-05-01

Abstract: We analyzed minimal residual disease (MRD) by multidimensional flow cytometry (MFC) after allogeneic stem cell transplantation in 41 patients with acute myeloid leukemia (AML) (n=31) or acute lymphoblastic leukemia (ALL) (n=10). Aberrant antigen expression was compared with the results of quantitative PCR for WT1 mRNA (n=41) and leukemia-specific fusion transcripts (n=12; AML in seven, ALL in five). There was a significant correlation between detection of MRD by MFC and WT1 mRNA, as well as between MFC and fusion transcripts. Serial monitoring of MRD by the three techniques correlated in parallel to the clinical course in most of the patients, but three patients were only positive for WT1 during hematological remission. The overall survival time of patients with complete remission was significantly associated with the appearance of aberrant expression after transplantation. In conclusion, MFC is valuable for clinical management decisions after transplantation.

The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells - Corrected Proof

2012-04-30

Abstract: Caspase function is known to be essential for cell death by apoptosis, but it is now increasingly recognized that these proteases also play important roles in other cellular events. Here we report for the first time that inhibition of cellular caspase activity can induce differentiation of AML blasts, and can enhance vitamin D-induced cell differentiation of these cells. This was studied in blasts obtained from nine patients with AML and one patient with CML by ex vivo culture in the presence of Q-VD-OPh (QVD), a pan caspase inhibitor. Cell differentiation was manifested by the expression of markers of monocytic differentiation CD11b and CD14. Differentiation induced by 1α,25-dihydroxyvitamin D3 (1,25D) or its analogs PRI-1906 and PRI-2191 was enhanced by QVD to a varying degree, depending on the subtype of the leukemia. QVD and 1,25D-induced differentiation was accompanied by increased signaling by Hematopoietic Progenitor Kinase 1(HPK1), and the expression of transcription factors known to be involved in monocytic differentiation was increased. Although the magnitude and nature of these changes were not invariable, it is clear that caspase inhibitors warrant attention as components of differentiation therapy of leukemia, perhaps in combination with derivatives of vitamin D.

Will a peripheral blood (PB) sample yield the same diagnostic and prognostic cytogenetic data as the concomitant bone marrow (BM) in myelodysplasia? - Corrected Proof

2012-04-26

Abstract: In patients with myelodysplastic syndromes (MDS), chromosome anomalies are detected by conventional cytogenetic studies (CCS) and/or interphase fluorescence in situ hybridization (FISH) of bone marrow (BM) samples and provide prognostic and diagnostic information, which can direct therapy. Whether peripheral blood (PB) can be substituted for bone marrow in these cases and can provide the same information remains unknown. Concurrent BM and PB specimens collected from 100 patients with recently diagnosed MDS were studied using both CCS and FISH. While 68% of BM samples showed an abnormal karyotype by CCS, only 31% of PB samples were abnormal by CCS. In 12% of patients, FISH and CCS were discordant due to the inability of the FISH panel to detect all possible abnormalities. However, only one case (1%) had a cryptic abnormality detected by FISH. BM and PB FISH were discordant in 3% of cases, most likely due to the smaller clone size in PB vs. BM. While PB should not be substituted for BM at diagnosis, it is a viable alternative for monitoring patients using the appropriate FISH probe(s).

Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks - Corrected Proof

2012-04-25

Abstract: To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate±6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early-death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p=0.393) and the low-risk and high-risk group (p=0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors.

A role for caspase inhibitors in differentiation therapy of myeloid leukaemia - Corrected Proof

Geoffrey Brown, Philip J. Hughes — 2012-04-25

The paper by Chen-Deutch et al. in this issue describes an interesting way forward to the possible use of 1α,25-dihydroxyvitamin D3 (D3) in differentiation therapy of acute myeloid leukaemia (AML) by the combined use of D3 and the pan-caspase inhibitor Q-VD-OPh (QVD).

Assessing signaling pathways associated with in vitro resistance to cytotoxic agents in AML - Corrected Proof

2012-04-23

Abstract: This study uses single cell network profiling (SCNP) to characterize biological pathways associated with in vitro resistance or sensitivity to chemotherapeutics commonly used in acute myeloid leukemia (AML) (i.e. cytarabine/daunorubicin, gemtuzumab ozogamicin (GO), decitabine, azacitidine, clofarabine). Simultaneous measurements at the single cell level of changes in DNA damage, apoptosis and signaling pathway responses in AML blasts incubated in vitro with the above drugs showed distinct profiles for each sample and mechanistically different profiles between distinct classes of agents. Studies are ongoing to assess the clinical predictive value of these findings.

Adverse impact of IDH1 and IDH2 mutations in primary AML: Experience of the Spanish CETLAM group - Corrected Proof

2012-04-23

Abstract: The study of genetic lesions in AML cells is helpful to define the prognosis of patients with this disease. This study analyzed the frequency and clinical impact of recently described gene alterations, isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations, in a series of homogeneously treated patients with primary (de novo) AML.Two-hundred and seventy-five patients enrolled in the CETLAM 2003 protocol were analyzed. IDH1 and IDH2 mutations were investigated by well-established melting curve-analysis and direct sequencing (R140 IDH2 mutations). To establish the percentage of the mutated allele a pyrosequencing method was used. Patients were also studied for NPM, FLT3, MLL, CEBPA, TET2 and WT1 mutations.IDH1 or IDH2 mutations were identified in 23.3% AML cases and in 22.5% of those with a normal karyotype. In this latter group, mutations were associated with short overall survival. This adverse effect was even more evident in patients with the NPM or CEBPA mutated/FLT3 wt genotype. In all the cases analyzed, the normal allele was detected, suggesting that both mutations act as dominant oncogenes. No adverse clinical impact was observed in cases with TET2 mutations.IDH1 and IDH2 mutations are common genetic alterations in normal karyotype AML. Favourable genotype NPM or CEBPA mutated/FLT3 wt can be further categorized according to the IDH1 and IDH2 mutational status.

Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol - Corrected Proof

2012-04-23

The ETV6/RUNX1 fusion, which is the molecular consequence of the cytogenetically cryptic t(12;21)(p13;q22), is present in approximately 25% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL) cases in the Nordic countries. ETV6/RUNX1-positive BCP ALL is generally considered to have an excellent prognosis; however, reports of frequent late relapses as well as similar incidences of t(12;21) in newly diagnosed and relapsed cases have cast doubts on its favourable prognostic impact . Furthermore, the clinical consequences of additional aberrations involving the ETV6 and RUNX1 genes, e.g., deletions of wild-type ETV6 and trisomy 21, harbouring either a non-rearranged RUNX1 gene or an additional ETV6/RUNX1 chimaera, have also been debated. For example, 12p deletions, involving the non-rearranged ETV6 allele, have been suggested to influence adversely the outcome . In addition, Stams et al. reported that the subgroups with either an additional ETV6/RUNX1 fusion gene, located on an extra der(21)t(12;21), or without any secondary aberration involving the ETV6 and RUNX1 genes did worse in terms of disease-free survival . Furthermore, the frequencies of additional aberrations of these genes, with the exception of ETV6 deletions, have been shown to be higher in relapsed than in diagnostic samples . On the other hand, in a large study comprising 245 t(12;21)-positive cases, the presence of secondary aberrations of 12p and 21q did not predict a higher risk of relapse , and, recently, cases with ETV6 deletions were actually shown to have a more favourable prognosis than cases without deletions . In order to address this potentially clinically important issue we have ascertained and reviewed all ETV6/RUNX1-positive cases treated according to the NOPHO-ALL-2000 protocol.

Gadd45a transcriptional induction elicited by the Aurora kinase inhibitor MK-0457 in Bcr-Abl-expressing cells is driven by Oct-1 transcription factor - Corrected Proof

2012-04-23

Abstract: The advantage of Aurora kinase (AK) inhibitors in chronic myeloid leukemia (CML) therapy mostly arises from “off-target” effects on tyrosine kinase (TK) activity of wild type (wt) or mutated Bcr-Abl proteins which drive the disease resistance to imatinib (IM). We proved that the AK inhibitor MK-0457 induces the growth arrest DNA damage-inducible (Gadd) 45a through recruitment of octamer-binding (Oct)-1 transcription factor at a critical promoter region for gene transcription and covalent modifications of histone H3 (lysine 14 acetylation, lysine 9 de-methylation). Such epigenetic chromatin modifications may depict a general mechanism promoting the re-activation of tumor suppressor genes silenced by Bcr-Abl.

Directed therapy for patients with myelodysplastic syndromes (MDS) by suppression of cyclin D1 with ON 01910.Na - Corrected Proof

2012-04-23

Abstract: Background: We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). “Knockdown” of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS.Experimental design: We performed preclinical studies using BMMNCs from patients with MDS and AML to examine the effects of the styryl sulfone ON 01910.Na on cyclin D1 accumulation, aneuploidy, and CD34+ blast percentage. We next treated twelve patients with higher risk MDS and two trisomy 8 AML patients with ON 01910.Na on a phase I clinical protocol (NCT00533416).Results: ON 01910.Na inhibited cyclin D1 expression, and was selectively toxic to trisomy 8 cells in vitro. Flow cytometry studies demonstrated increased mature CD15+ myeloid cells and decreased CD34+ blasts. Three patients treated with ON 01910.Na on a clinical had decreased bone marrow blasts by ≥50%, and three patients had hematologic improvements, one of which was sustained for 33 months. Patients with hematologic responses to ON 01910.Na had decreased cyclin D1 expression in their CD34+ cells.Conclusions: The preclinical results and responses of patients on a clinical trial warrant further investigation of ON 01910.Na as a potential novel targeted therapy for higher risk MDS patients.

Extranodal marginal zone lymphoma of the CNS arising after a long-standing history of atypical white matter disease - Corrected Proof

2012-04-20

In February 2009 a 39 year old female patient with a long standing history of atypical white matter lesions mimicking multiple sclerosis was admitted to the Department of Neurology, Budapest, due to disease progression.

Epigenetic regulation of PRAME in acute myeloid leukemia is different compared to CD34+ cells from healthy donors: Effect of 5-AZA treatment - Corrected Proof

2012-04-16

Abstract: PRAME is a tumor associated antigen (TAA) of particular interest since it is widely expressed by lymphoid and myeloid malignancies. Several studies have associated high PRAME RNA levels with good prognosis in acute myeloid leukemia (AML). PRAME expression is regulated at the epigenetic level. For this reason inhibitors of DNA methylation, such as 5-azacytidine, can modulate the expression of this TAAs. In the current study we analyzed the effect of 5-azaC on the expression of PRAME in blasts versus CD34+ cells from healthy donors in an attempt to increase its expression, thus inducing a potential target for therapeutic strategies.

Deferasirox exposure induces reactive oxygen species and reduces growth and viability of myelodysplastic hematopoietic progenitors - Corrected Proof

2012-04-16

Abstract: We examined the effect of deferasirox (DFX) on CD34+ hematopoietic progenitors from MDS patients. Progressive, dose-dependent suppression of MDS progenitor proliferation in culture was observed with DFX concentrations ranging from 5μM to 20μM. This effect was more pronounced in MDS compared to CD34+ progenitors isolated from umbilical cord blood or normal peripheral blood. There was reduced viability of MDS progenitors but not normal progenitors at 20μM DFX which increased with duration of exposure. Exposure to 20μM DFX for 14days markedly suppressed colony growth of MDS progenitors. Reactive oxygen species levels were elevated above control at concentrations of DFX above 5μM. We conclude that exposure to DFX results in dose-dependent inhibition of proliferation, and survival in MDS progenitors.

Azacitidine differentially affects CD4pos T-cell polarization in vitro and in vivo in high risk myelodysplastic syndromes - Corrected Proof

2012-04-16

Abstract: CD4pos T-cell subsets play a role in myelodysplastic syndromes (MDS) pathogenesis and may be affected upon 5-azacitidine (Aza) treatment. Aza enhanced human TH1 frequencies in vitro but not in vivo. The proportion of functional FoxP3pos regulatory T cells (Treg) was enhanced by Aza in vitro (p<0.0002), and a modest, temporary increase was observed in vivo (p=0.08). The overall number of TH17 was reduced both in vitro (p<0.03) and in vivo (p<0.006), indicating that Aza directly affects CD4pos polarization during activation in vitro. Upon in vivo treatment in high risk MDS patients, particularly the TH17-Treg axis is affected.

New complex chromosome abnormalities in multiple myeloma associated with a poor prognosis: A case report - Corrected Proof

2012-04-13

Multiple myeloma (MM) is a malignant proliferation of monoclonal plasma cells characterized by its accumulation in the bone marrow, production of excessive monoclonal immunoglobulin (M protein) in serum or urine, and osteolytic bone lesions. These features lead to a wide range of common manifestations that include pathological bone fragility, nephropathy, immunodeficiency and hematopoietic disorders. Non-specific clinical manifestations of MM are challenges for accurate diagnosis .

Towards a need to a “biological Sokal risk” in the era of tyrosine kinase inhibitors in choosing front-line therapy in chronic myeloid leukemia - Corrected Proof

Fabio Stagno, Paolo Vigneri, Francesco Di Raimondo — 2012-04-13

The recent introduction and proven effectiveness of dasatinib (DAS) and nilotinib (NIL) in the front-line therapy of chronic myeloid leukemia (CML) together with the revolutionary results already given and maintained by imatinib mesylate (IM) treatment raise now a critical and challenging question. How should we move in the upfront treatment of chronic phase CML? Whilst CML patients showing both a suboptimal response and a failure to IM treatment have clear therapeutic indications , no guideline has been released addressing a choice for front-line therapy. DAS and NIL may be used in first line therapy aiming to both prevent and limit resistance upfront, however their clinical follow-up is still too much short to draw any definitive conclusion as compared to a decade of successful IM-therapy . Moreover, tyrosine kinase inhibitors (TKIs) therapy lack evaluation of any CML patient individualization strategy and no efforts have been produced to prevent patients’ exposure to ineffective or toxic drug doses . In this view, as the Sokal score helped us to stratify CML patients at risk of disease progression, there is now an emerging need to identify at CML diagnosis new prognostic markers which might guide drug choice in first line therapy. In a BCR-ABL-dependent disease, in the molecular era of TKIs which target BCR-ABL activity, where clinical response is effectively determined by measuring both Philadelphia chromosome rates and BCR-ABL transcript levels (according to the International Scale ), it seems reasonable to believe that the amount of BCR-ABL transcript at diagnosis might represent an appropriate biomarker of the disease. Since BCR-ABL transcript increases during disease progression and declines in clinical, cytogenetic and molecular response, it can be speculated that BCR-ABL levels at diagnosis might be indicative of the overall leukemic load . Hence a molecular score based on/composed by the BCR-ABL transcript value might be helpful in stratifying at diagnosis those CML patients at risk of disease progression and who might benefit of a more aggressive treatment with 2nd generation TKIs, whereas low risk CML patients could go on taking IM-therapy. We believe that future studies aiming to investigate on such a bio-molecular score are warranted in CML.

Serum BAFF levels are related to angiogenesis and prognosis in patients with multiple myeloma - Corrected Proof

2012-04-12

Abstract: B-cell activating factor (BAFF) is a B-cell growth factor. We measured its serum levels and correlated them with parameters of disease activity, as serum levels of tumor necrosis factor-α and lactate dehydrogenase, bone marrow microvascular density and proliferating cell nuclear antigen expression, in 50 myeloma patients, in 22 of them in plateau phase and in 20 controls. All of them were higher in patients and in advanced disease while reduced in plateau phase. BAFF correlated with all the above markers. Higher BAFF levels predicted a shorter survival, suggesting an important prognostic marker and a possible therapeutic target in myeloma.

CD105 and placental growth factor – Potent prognostic factors in childhood acute lymphoblastic leukaemia - Corrected Proof

2012-04-12

Abstract: The studies aimed at identifying a prognostic significance of angiogenesis-related factors: CD105 and placental growth factor (PlGF) in a course of acute lymphoblastic leukaemia (ALL). Research protocol was based on detection of RNA and protein expressions in bone marrow blasts using quantitative PCR and immunocytochemical assays respectively.Kaplan–Meier statistics revealed CD105 and PlGF expression as managed separately do not correlate with relapse-free time in ALL patients. On the other hand, an associated analysis of CD105 and PlGF demonstrated a significantly shorter progression-free time in children who were CD105+ and PlGF+ or CD105− and PlGF+ at the moment of ALL diagnosis.

A possible role for oxidation stress in lymphoid leukaemias and therapeutic failure - Corrected Proof

2012-04-10

Abstract: The aim of this study was to evaluate the role of oxidative stress in the pathobiology of lymphoid leukaemias and its involvement in leukaemic relapse. For this purpose the generation of peroxides by mononuclear cells, the erythrocyte activity of superoxide-dismutase (SOD) and glutathione peroxidase (GL-PX), and the plasma levels of reduced glutathione (GSH) and vitamin E (VIT E) were determined in 52 patients with two different types of lymphoid leukaemias, chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL), 36 prior to chemotherapy and 16 treated patients. A decrease in SOD and GL-PX activities was observed in ALL patients prior to therapy, while a decrease in GSH and VIT E plasma levels was observed in untreated CLL, as compared to age-matched controls. An increase in peroxides formation occurred in both types of leukaemia, as compared to age-matched controls. There are significant differences for GSH, VIT E and peroxides generation between the different types of leukaemias. In relapsed ALL patients a decrease in peroxides generation was observed which may be due to the increase of the non-enzymatic defences GSH and VIT E. These data suggest the involvement of oxidative stress in acute and chronic lymphoid leukaemias and leukaemic relapse.

Neutrophilic panniculitis following azacitidine treatment for myelodysplastic syndromes - Corrected Proof

2012-04-09

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell disorders. The clinical spectrum ranges from a stable condition to manifestation of entities with increased morbidity and mortality because of bone marrow failure or evolution to acute myelogenous leukemia (AML). Among various newer therapeutic options, azacitidine (AZA) is a first FDA-approved drug for the treatment of MDS that has demonstrated improvements in overall survival and success in delaying progression to AML . AZA appears to be well tolerated with the most common grade 3 or 4 adverse events being hematological complications of peripheral blood cytopenias. Injection site complications occur in about 13–43% of cases and are the most common non-hematological complications in subcutaneous administration of the drug . The majority of injection site complications are typically mild erythema, and grade 3 or 4 toxicities occurs in <1% of the treated patients. Although these adverse events are usually completely and spontaneously reversible, efforts should be given for differential diagnosis of other causes of skin lesions such as Sweet's syndrome, for which aggressive treatment should be considered .

Long term follow-up of Polycythemia Vera patients treated with imatinib mesylate - Corrected Proof

C. Michael Jones — 2012-04-09

Silver et al. recently described in this journal . Their study of the treatment of Polycythemia Vera with imatinib mesylate and kindly noted our earlier reports. The design of both studies was comparable, although, the median age of our patients was somewhat higher at 54 compared to 47 for their series. Our initial response rate was somewhat higher at 75% versus 49%. However, our initial treatment period included a 12-week induction with a rapid dose escalation period compared to a 12-month induction with dosing at investigator discretion. Perhaps of greater significance is that 15 out of 20 of our patients were treatment naïve compared to 14 of 37 of Dr. Silver's patients. Median platelet counts were higher in Dr. Silver's patients at 599,000 compared to 316,000 in our series, and beginning hematocrits were slightly higher in our patients at 50 versus 42%. Initial white counts were equivalent ().

Day 22 of induction therapy is important for minimal residual disease assessment by flow cytometry in childhood acute lymphoblastic leukemia - Corrected Proof

2012-04-09

Abstract: This study was aimed to illustrate the significance of minimal residual disease (MRD) assessment on day 22 in childhood acute lymphoblastic leukemia. MRD were measured on day 22, day 36, week 12, month 6 and month 12 by four-color flow cytometry. The 5-year cumulative incidence of relapse was significantly different for patients with MRD levels of <0.01%, 0.01–0.1%, 0.1–1.0% and ≥1.0% on day 22: 6.9±2.6%, 16.7±5.5%, 25.8±6.2% and 58.4±13.4% (P<0.001). MRD on day 22 was more powerful than other parameters including NCI risk. However, other time points after induction, although predictive as well, were not accurate enough due to false positivity.

Acute myeloid leukemia with minimal differentiation: Unusual cytogenetics, morphology, phenotype and clinical course - Corrected Proof

2012-04-06

The diagnosis of acute myeloid leukemia (AML) requires the identification of more than 20% of the blasts in the bone marrow or the peripheral blood, with the expression of myeloid markers, such as CD13 and CD33, and positivity for myeloperoxidase (MPO) and/or anti-MPO. AML with an unusual phenotype is seen in less than 10% of all cases , and AML with minimal differentiation (AML-NOS; not otherwise specified, WHO 2008) is a rare subtype of acute leukemia in which the blasts normally do not show morphological differentiation and the conventional cytochemical staining is negative. The prognosis of patients with this AML subtype is remarkably poor .

Progressive arterial occlusive disease (PAOD) and pulmonary arterial hypertension (PAH) as new adverse events of second generation TKIs in CML treatment: Who's afraid of the big bad wolf? - Corrected Proof

Massimo Breccia, Fabio Efficace, Giuliana Alimena — 2012-04-06

The occurrence of side effects in chronic myeloid leukaemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) seem to differ between agents and also the rate of haematologic and non-haematologic side effects is reported to be agent specific. Recently, new TKI potentially related side effects were described in patients treated with second generation drugs and alerted physicians for the possible use of these agents as first-line strategy: progressive arterial occlusive disease (PAOD), associated with nilotinib, and pulmonary arterial hypertension (PAH), associated with dasatinib. PAOD occurred in 10–20% of adults 50–70 year old and nearly 75% of episodes were asymptomatic . Until now, only small and selected series of patients treated with nilotinib who experienced PAOD have been reported. Aichberger et al. described 4 cases out of 24 who were treated with nilotinib as second line treatment. All patients had pre-existing risk factors, such as concomitant tumors, diabetes and neuropathy and all cases had PAOD progression. All patients were pre-treated with dose escalation of imatinib. The authors hypothesized a possible role for discoidin domain receptor-1 (DDR1) inhibition, or c-kit inhibition or a correlation with nilotinib-induced diabetes. le Coutre et al. reported a four-centre series of 175 patients treated with nilotinib as second line: PAOD was recorded in 11 patients (6.1%). Seven patients were elderly (>60 years) with pre-existing risk factors, such as smoking, diabetes, hypertension, obesity, and hypercholesterolemia. PAOD events were reported as late events (median time of occurrence 105 weeks), prevalently in lower limbs. Two patients received nilotinib as first-line treatment (1 hypereosinophilic syndrome and 1 newly diagnosed CML). All patients received surgery interventions. Although observed in a retrospective analysis, including patients with other disease or with CML treated with nilotinib in second or first-line, the authors suggested a careful monitoring of patients receiving nilotinib that are at risk of PAOD. At last 2011 ASH meeting, the Austrian group updated its analysis and reported 6 cases of PAOD (17.6%) occurring in 34 patients treated with nilotinib: one or more pre-existing risk factors for atherosclerosis were identified in all patients, but none of these had developed a vascular event during prior imatinib therapy. Again at last 2011 ASH meeting, a large retrospective analysis was presented , in which were included patients enrolled in the ENESTnd and IRIS trials and TOPS study (2393 patients). Three large cohorts of patients were generated: the first (533 patients) without TKI exposure, the second (556 patients) treated with nilotinib (both doses of 300 and 400mg BID) and the third (1304 patients) treated with imatinib 400mg or 800mg/day. PAOD was recorded in 3 patients in first cohort, in 6 patients in the second cohort and in 6 patients in the third cohort. When using cohort 1 as a control, the relative risk of PAOD was 1.9 for the second cohort and 0.9 for the third cohort: no statistical difference was observed, also when using exposed-adjusted ratio. Eighty-seven percentage of patients who had PAOD had pre-existing risk factors (hypertension, diabetes, smoking, nicotine abuse). After 2 years of follow-up of ENESTnd trial (nilotinib 300mg BID or 400mg BID compared to standard dose imatinib in newly diagnosed CML patients) the incidence of PAOD was 1%, i.e. three patients in both nilotinib arms. Occurrence of this side effect seems to be very low, when considered in large series of patients and in relation to pre-existing risk factors. The potential pathogenetic mechanisms are unknown, but it is unlikely that this phenomenon is associated with hyperglycaemia: older age, arterial hypertension and hypercholesterolemia are risk factors mentioned to overlap for both pleural effusions during dasatinib and PAOD during nilotinib. Dasatinib was instead associated to the occurrence of pulmonary arterial hypertension (PAH), but until now few cases were reported. PAH was defined as the elevation of the mean pulmonary artery pressure >25mmHg at rest or >30mmHg with exercise . PAH is suspected if right ventricular systolic pressure (RSVP) is >35mmHg when measured by Doppler transthoracic echocardiography: it is usually asymptomatic at early stage, but with progressive dyspnoea and angina at late stage. In a large retrospective analysis including more than 2800 dasatinib-treated patients enrolled in sponsored clinical trials, only 1 case was reported . Diagnosis is certain only through right-heart catheterization and all cases identified often were taking concomitant medications or had other comorbidities. A report by Quintas-Cardama et al. showed increased RSVP in 18 patients (from a median of 29mmHg to 42mmHg) with prompt return to baseline after discontinuation of dasatinib. In 3 out of 4 cases reported PAH was associated to pleural effusion, initial starting dose was 70mg BID and the onset of the complication was late. In all cases an improvement of haemodynamic and clinical parameters were reported after permanent discontinuation of the drug. Two patients were switched to nilotinib without recurrence of PAH. The pathogenesis of this adverse event is unclear, but it could be related to off-target kinase inhibition, leading to pulmonary vascular smooth muscle cell changes and subsequent pulmonary vascular resistance increase. In the DASISION trial (dasatinib 100mg QD compared to standard dose imatinib in newly diagnosed CML patients), PAH incidence was reported to be 1.2% (3 patients) and none of the patients discontinued therapy due to this side effect. Literature evidences for PAOD and for PAH suggested that new potential side effects are linked to second generation TKIs: the incidence of these side effects is however low in patients treated frontline and all cases reported had other concomitant comorbidities and pre-existing risk factors. Dasatinib and nilotinib are actually selected as second line or as frontline treatment according to individual comorbidities predisposing to the onset of typical side effects, such as biochemical abnormalities or pleural effusions; based on reported low incidence of PAOD and PAH, prospective studies are needed to clarify how negatively select patients candidate to these drugs.

Hypersensitivity to alkylation treatment of primary fibroblasts from patients with therapy-related myeloid neoplasms - Corrected Proof

2012-04-05

Therapy-related myeloid neoplasms (t-MNs) constitute a distinct clinical syndrome arising after cytotoxic treatments for a primary, often malignant disorder. In the majority of cases, previous treatment with alkylating agents was reported . The prognosis of patients with t-MNs is dismal which is in part due to a high non-relapse mortality rate in both, the conventional therapy and allogeneic hematopoietic stem cell transplantation (HSCT) setting . These data suggest that non-leukemia related factors contribute to an inferior outcome and prompted us to study whether non-malignant cells of patients with t-MNs exhibit increased sensitivity to cytotoxic treatment in vitro.

Stevens-Johnson syndrome after treatment with bendamustine - Corrected Proof

2012-04-05

Rituximab, the anti-CD20 monoclonal antibody, has changed the therapeutic landscape for patients with non-Hodgkin's lymphoma (NHL) either as a single agent or, particularly, in combination with chemotherapy, showing a low treatment-related toxicity. Bendamustine, a novel alkylating agent, has demonstrated consistent efficacy and acceptable tolerability in patients with indolent NHL and mantle cell lymphoma (MCL). It may be a particularly useful treatment option in patients with rituximab-refractory disease, but has also demonstrated efficacy as part of a first-line combination treatment with rituximab with a good tolerability profile . The major toxicities associated with bendamustine are reversible myelosuppression, gastrointestinal toxicity, and infection.

Therapy with the histone deacetylase inhibitor pracinostat for patients with myelofibrosis - Corrected Proof

2012-04-04

Abstract: Approximately half of the patients with myelofibrosis (MF) carry mutant JAK2V617F proteins. JAK2V617F has been recently shown to translocate to the nucleus and modify specific histones, thus regulating transcription. We report on a phase II study testing the activity and tolerability of the histone deacetylase inhibitor pracinostat given at 60mg every other day for three weeks per month in 22 patients with intermediate or high risk MF. Eight (36%) patients experienced clinical benefit, with 6 (27%) experiencing reductions in splenomegaly (median 3cm, range 1–4cm). According to International Working Group criteria, 2 (9%) patients had clinical improvement (anemia response in both cases). The most frequent side effect associated to pracinostat therapy was fatigue, which occurred in 20 (91%) patients (grade 2 in 3 patients). Grade 3–4 neutropenia, anemia, and thrombocytopenia occurred in 13%, 0%, and 21%, respectively. Twenty-one patients permanently discontinued pracinostat, mainly due to lack of efficacy. In conclusion, pracinostat at the dose tested is reasonably tolerated and has modest activity in patients with MF.

T-cell large granular lymphocytosis associated with malignant thymoma - Corrected Proof

2012-04-04

T-cell large granular lymphocytosis (T-LGL) is a proliferative disorder of CD3+ CD8+ T lymphocytes characterized by the clonal rearrangement of the T-cell receptor (TCR) and is consequently often termed a “leukemia” . While this rare disorder has a typically indolent course and is classically associated with cytopenias, a variety of other autoimmune disorders, Sjogrens syndrome and rheumatoid arthritis have been commonly associated with T-LGL. The clonal nature of the disorder has created controversy, with conflicting claims for describing the disorder as a leukemia versus immune dysregulation. Although the etiology has not been conclusively elucidated, chronic activation of T-cells by an auto-reactive or viral antigen and defects in apoptosis have been implicated in the pathogenesis.

Synergistic antileukemic action of a combination of inhibitors of DNA methylation and histone methylation - Corrected Proof

Richard L. Momparler, Youssef Idaghdour, Victor E. Marquez, Louise F. Momparler — 2012-04-03

Abstract: DNA methylation and histone methylation are both involved in epigenetic regulation of gene expression and their dysregulation can play an important role in leukemogenesis. Aberrant DNA methylation has been reported to silence the expression of tumor suppressor genes in leukemia. Overexpression of the histone methyltransferase, EZH2, a subunit of the polycomb group repressive complex 2 (PRC2), was observed to promote oncogenesis. This is due to aberrant gene silencing by the trimethylation of histone H3 lysine 27 (H3K27me3) by EZH2. Since both these epigenetic silencing events are reversible, they are interesting targets for chemotherapeutic intervention by using an inhibitor of DNA methylation, such as 5-aza-2′-deoxcytidine (5-AZA-CdR), and 3-deazaneplanocin-A (DZNep), an inhibitor of the EZH2. Human HL-60 and murine L1210 leukemic cells exposed in vitro to 5-AZA-CdR and DZNep in combination showed a synergistic loss of clonogenicity in a colony assay as compared to each agent alone. This positive chemotherapeutic interaction was also observed in mice with L1210 leukemia. Quantitative PCR showed that the combination also produced a remarkable synergistic activation of the tumor suppressor genes, CDKN1A and FBXO32. Microarray analysis showed that 5-AZA-CdR plus DZNep produced a synergistic activation of >150 genes. Our results indicate that 5-AZA-CdR plus DZNep can reactivate target genes that are silenced by two distinct epigenetic mechanisms leading to a loss of the proliferative potential of leukemic cells.