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Down-syndrome-like acute megakaryoblastic leukemia in a patient with Cornelia de Lange syndrome.
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Down-syndrome-like acute megakaryoblastic leukemia in a patient with Cornelia de Lange syndrome.

Haematologica. 2017 Dec 07;:

Authors: Vial Y, Lachenaud J, Verloes A, Besnard M, Fenneteau O, Lainey E, Marceau-Renaut A, Preudhomme C, Baruchel A, Cavé H, Drunat S

PMID: 29217785 [PubMed - as supplied by publisher]




Outcome and survival of myeloma patients diagnosed 2008-2015. Real world data on 4904 patients from the Swedish Myeloma Registry (SMR).
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Outcome and survival of myeloma patients diagnosed 2008-2015. Real world data on 4904 patients from the Swedish Myeloma Registry (SMR).

Haematologica. 2017 Dec 07;:

Authors: Blimark CH, Turesson I, Genell A, Ahlberg L, Björkstrand B, Carlson K, Forsberg K, Juliusson G, Linder O, Mellqvist UH, Nahi H, Kristinsson SY, Swedish Myeloma Registry

Abstract
Epidemiology and outcome of myeloma is mainly reported from large university centers and collaborative groups and do not represent real world patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatments and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose to improve the management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first line treatment up to 2014, with a follow-up until December 2016. We present age-adjusted incidence, patient characteristics at baseline, treatment, response, and survival. Baseline data was available with a 97% coverage in 4,904 patients (median age 71 years, males 70 years, females 73 years, 72% were 65 years or older), and one-year follow-up of 3,558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100 000 inhabitants and year. Among initially symptomatic patients (n=3,988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients up to 66 years, and to 22% of patients 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first line treatment, rising from 31% in 2008 to 81% 2014. In MM, the median relative survival of patients 65 years or younger was 7.7 years, and 3.4 years in 66 years and older. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (p<0.05), and with a significant higher overall survival with a HR of 0.84 (95% CI 0.77-0.92; p< 0.05). There was small, but significant survival benefit in patients treated in university hospitals (HR 0.93; 95% CI 0.87-0.99, p<0.05). Analysis of progression-free survival has to await collection of additional follow-up data. We here report on a near complete real world population of myeloma patients during an 8-year period, when newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden compare to other large registry studies and responses and survival improved during the study period.

PMID: 29217784 [PubMed - as supplied by publisher]




Somatic STAT3 mutations in the Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.
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Somatic STAT3 mutations in the Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia.

Haematologica. 2017 Dec 07;:

Authors: Savola P, Brück O, Olson T, Kelkka T, Kauppi MJ, Kovanen PE, Kytölä S, Sokka-Isler T, Loughran TP, Leirisalo-Repo M, Mustjoki S

Abstract
Felty syndrome is a rare disease defined by neutropenia, splenomegaly, and rheumatoid arthritis. Sometimes the differential diagnosis between Felty syndrome and large granular lymphocyte leukemia is problematic. Recently, somatic STAT3 and STAT5B mutations were discovered in 30-40% of patients with large granular lymphocyte leukemia. We now aimed to study whether these mutations can also be detected in Felty syndrome, which would imply for a common pathogenic mechanism between these two disease entities. We collected samples and clinical information from 14 Felty syndrome patients who were monitored at the rheumatology outpatient clinic for Felty syndrome. Somatic STAT3 mutations were discovered in 43% (6/14) of Felty syndrome patients with deep amplicon sequencing targeting all STAT3 exons. Mutations were located in the SH2 domain of STAT3 which is a known mutational hotspot. No STAT5B mutations were found. In blood smears, overrepresentation of large granular lymphocytes was observed, and in the majority of cases the CD8+ T-cell receptor repertoire was skewed when analyzed by flow cytometry. In bone marrow biopsies, an increased amount of phospho-STAT3 positive cells was discovered. Plasma cytokine profiling showed that 10 of the 92 assayed cytokines were elevated both in Felty syndrome and large granular lymphocyte leukemia, and three of these cytokines were also increased in patients with uncomplicated rheumatoid arthritis. In conclusion, somatic STAT3 mutations and STAT3 activation are as frequent in Felty syndrome as in large granular lymphocyte leukemia. Considering that the symptoms and treatment modalities are also similar, unified re-classification of these two syndromes is warranted.

PMID: 29217783 [PubMed - as supplied by publisher]




Rational management approach to pure red cell aplasia.
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Rational management approach to pure red cell aplasia.

Haematologica. 2017 Dec 07;:

Authors: Balasubramanian SK, Sadaps M, Thota S, Aly M, Przychodzen BP, Hirsch CM, Visconte V, Radivoyevitch T, Maciejewski JP

Abstract
Pure red cell aplasia is an orphan disease without rationally established standard therapies. Most cases are idiopathic; a subset is antibody-mediated. There is overlap between idiopathic cases and those with T-large granular lymphocytic leukemia, hypogammaglobulinemia, and low-grade lymphomas. In all these, the pathogenetic mechanisms may involve autoreactive cytotoxic responses. We selected 62 uniformly diagnosed pure red cell aplasia patients and analyzed their pathophysiologic features and responsiveness to rationally applied first-line and salvage therapies to propose diagnostic and therapeutic algorithms that may help guide management of prospective patients. Of these, 52% were idiopathic; others involved large granular lymphocytic leukemia, thymoma, and B-cell dyscrasia. T-cell mediated responses ranged between a continuum from polyclonal to monoclonal (as seen in large granular lymphocytic leukemia). During a median observation period of 40mo., patients received on average 3 different therapies to achieve remission. Frequently used therapy included calcineurin-inhibitors with a steroid taper yielding a first-line overall RR (response rate) of 76% (53/70). Oral cyclophosphamide showed activity albeit lower than cyclosporine. Intravenous immunoglobulins were efficacious in parvovirus patients but also effective in hypogammaglobulinemia cases. In salvage settings, alemtuzumab is active, particularly in large granular lymphocytic leukemia associated cases. Other potentially useful salvage options include rituximab, anti-thymocyte globulin and bortezomib. The workup of acquired pure red cell aplasia should include investigations of common pathological associations. Most effective therapies are directed against T cell-mediated immunity and therapeutic choices need to account for associated conditions that may help in choosing alternative salvage agents such as intravenous immunoglobulin, alemtuzumab and bortezomib.

PMID: 29217782 [PubMed - as supplied by publisher]




Benefits and pitfalls of Peg-Interferon-α2a therapy in patients with myeloproliferative neoplasm-associated myelofibrosis, a French Intergroup of Myeloproliferative neoplasms (FIM) study.
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Benefits and pitfalls of Peg-Interferon-α2a therapy in patients with myeloproliferative neoplasm-associated myelofibrosis, a French Intergroup of Myeloproliferative neoplasms (FIM) study.

Haematologica. 2017 Dec 07;:

Authors: Ianotto JC, Chauveau A, Boyer-Perrard F, Gyan E, Laribi K, Cony-Makhoul P, Demory JL, de Renzis B, Dosquet C, Rey J, Roy L, Dupriez B, Knoops L, Legros L, Malou M, Hutin P, Ranta D, Benbrahim O, Ugo V, Lippert E, Kiladjian JJ

Abstract
We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of sixty-two patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years-old, the median follow-up since pegylated interferon initiation was 58 months. At time of analysis, 30 (48.4%) patients were alive including 16 still treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and DIPSS scores treated with pegylated interferon was increased in comparison to historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70 vs. 30 months after two years of treatment, p<10-12). JAK2V617F allele burden was decreased by more than 50% in 58.8% of patients and 2 patients even achieved complete molecular response. Next generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survivals. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for intermediate or high-risk Lille and DIPSS score patients. It also reduced the JAK2V617F allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.(Clinicaltrials.gov #NCT02910258 and #NCT02897297).

PMID: 29217781 [PubMed - as supplied by publisher]




From transplant to novel cellular therapies in multiple myeloma: EMN guidelines and future perspectives.
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From transplant to novel cellular therapies in multiple myeloma: EMN guidelines and future perspectives.

Haematologica. 2017 Dec 07;:

Authors: Gay F, Engelhardt M, Terpos E, Wäsch R, Giaccone L, Auner HW, Caers J, Gramatzki M, van de Donk N, Oliva S, Zamagni E, Garderet L, Straka C, Hajek R, Ludwig H, Einsele H, Dimopoulos M, Boccadoro M, Kröger N, Cavo M, Goldschmidt H, Bruno B, Sonneveld P

Abstract
Survival of myeloma patients has greatly improved with the use of autologous stem cell transplantation and novel agents, such as proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. Compared to bortezomib- and lenalidomide-based regimens alone, the addition of high-dose melphalan followed by autologous transplantation significantly improves progression-free survival; although an overall survival benefit was not observed in all trials. Moreover, follow-up of recent trials is still too short to show any difference in survival. In the light of these findings, novel agent-based induction followed by autologous transplantation is considered the standard upfront treatment for eligible patients (level of evidence: 1A). Post-transplant consolidation and maintenance treatment can further improve patient outcome (1A). The availability of several novel agents has led to the development of multiple combination regimens as salvage treatment options. In this context, the role of salvage autologous transplantation and allotransplant have not been extensively evaluated. In case of prolonged remission after upfront autologous transplantation, another autologous transplantation at relapse can be considered (2B). Patients who experience early relapse and/or have high-risk features have a poor prognosis and may be considered as candidates for clinical trials that - in young and fit patients - may also include an allograft in combination with novel agents (2B). Ongoing studies are evaluating the role of novel cellular therapies, such as inclusion of antibody-based triplets and quadruplets and Chimeric Antigen Receptor-T cells: despite preliminary encouraging results, longer follow-up and larger patient numbers are needed before their clinical use can be widely recommended.

PMID: 29217780 [PubMed - as supplied by publisher]




Prognostic significance of tumor burden assessed by whole-body magnetic resonance imaging in multiple myeloma patients treated with allogeneic stem cell transplantation.
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Prognostic significance of tumor burden assessed by whole-body magnetic resonance imaging in multiple myeloma patients treated with allogeneic stem cell transplantation.

Haematologica. 2017 Dec 07;:

Authors: Mosebach J, Shah S, Delorme S, Hielscher T, Goldschmidt H, Schlemmer HP, Schönland SO, Hegenbart U, Hillengass J

Abstract
Allogeneic stem cell transplantation is a disputed but increasing therapeutic option in patients suffering from multiple myeloma in Europe. To study possible predictors of survival, 79 patients were investigated using whole-body magnetic resonance imaging to assess the visible tumor burden before and after allogeneic stem cell transplantation. Statistical analysis of clinical and imaging parameters included Cox regression models and distribution of survival time estimates (Kaplan-Meier method). Log rank test was used to determine the prognostic impact of the presence of focal lesions on survival. A higher tumor burden according to the lesion count was associated with a shorter overall survival (univariable/multivariable Cox regression: 1st magnetic resonance imaging p=0.028/ p=0.048; 2nd magnetic resonance imaging p=0.008/ p=0.024). Focal infiltration pattern itself seemed to be an additional adverse prognostic factor for overall survival (2nd MRI p=0.048), although no definite cut-off could be defined. Kaplan-Meier estimates at 60 months of follow-up show a significant difference (Log rank p=0.04) for overall survival rates between patients with focal infiltration (32%) and those without (75%). Since this subgroup of patients may benefit from maintenance therapy, adoptive immunotherapy, or local interventions, whole-body imaging is an appropriate and highly recommendable diagnostic approach for detection of prognostically relevant lesions before and after treatment.

PMID: 29217779 [PubMed - as supplied by publisher]




Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.
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Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7.

Haematologica. 2017 Dec 07;:

Authors: Pastor VB, Sahoo S, Boklan J, Schwabe GC, Saribeyoglu E, Strahm B, Lebrecht D, Voss M, Bryceson YT, Erlacher M, Ehninger G, Niewisch M, Schlegelberger B, Baumann I, Achermann JC, Shimamura A, Hochrein J, Tedgård U, Nilsson L, Hasle H, Boerries M, Busch H, Niemeyer CM, Wlodarski MW

Abstract
Familial myelodysplastic syndromes arise from haploinsufficiency of genes involved in hematopoiesis and are primarily associated with early-onset disease. Here we describe a familial syndrome in 7 patients from 4 unrelated pedigrees presenting with myelodisplastic syndrome and loss of chromosome 7/7q. Median age at diagnosis was 2.1 (1-42) years, all patients presented with thrombocytopenia with or without additional cytopenias and a hypocellular marrow without increase of blasts. Genomic studies identified constitutional mutations (p.H880Q, p.R986H, p.R986C and p.V1512M) in SAMD9L gene on 7q21, with decreased allele frequency in hematopoiesis. The nonrandom loss of mutated SAMD9L alleles was attained via monosomy 7, deletion 7q, UPD7q, or acquired truncating SAMD9L variants p.R1188X and p.S1317RfsX21. Incomplete penetrance was noted in 30% (3/10) of mutation carriers. Long-term observation revealed divergent outcomes with either leukemic progression and/or accumulation of driver mutations (n=2), persistent monosomy 7 (n=4), and transient monosomy 7 followed by spontaneous recovery with SAMD9L-wildtype UPD7q (n=2). Dysmorphic features or neurological symptoms were absent in our patients, pointing to the notion that myelodisplasia with monosomy 7 can be a sole manifestation of SAMD9L disease. Collectively, our results define a new subtype of familial myelodisplastic syndrome and provide an explanation for the phenomenon of transient monosomy 7. www.clinicaltrials.gov; #NCT00047268.

PMID: 29217778 [PubMed - as supplied by publisher]




High throughput sequencing in acute lymphoblastic leukemia reveals clonal architecture of central nervous system and bone marrow compartments.
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High throughput sequencing in acute lymphoblastic leukemia reveals clonal architecture of central nervous system and bone marrow compartments.

Haematologica. 2017 Dec 07;:

Authors: Bartram J, Goulden N, Wright G, Adams S, Brooks T, Edwards D, Inglott S, Yousafzai Y, Hubank M, Halsey C

PMID: 29217777 [PubMed - as supplied by publisher]




Melphalan 140mg/m2 or 200mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.
Related Articles

Melphalan 140mg/m2 or 200mg/m2 for autologous transplantation in myeloma: results from the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study. A report by the EBMT Chronic Malignancies Working Party.

Haematologica. 2017 Dec 07;:

Authors: Auner HW, Iacobelli S, Sbianchi G, Knol-Bout C, Blaise D, Russell NH, Apperley JF, Pohlreich D, Browne P, Kobbe G, Isaksson C, Lenhoff S, Scheid C, Touzeau C, Jantunen E, Anagnostopoulos A, Yakoub-Agha I, Tanase A, Schaap N, Wiktor-Jedrzejczak W, Krejci M, Schönland SO, Morris C, Garderet L, Kröger N

Abstract
Melphalan at a dose of 200mg/m2 is standard conditioning prior to autologous haematopoietic stem cell transplantation for multiple myeloma, but a dose of 140mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine if melphalan 200 and melphalan 140 are equally effective and tolerable in clinically relevant patient subgroups we analysed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, haematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 (n=245) and melphalan 200 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 versus melphalan 140: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favoured melphalan 140 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 and melphalan 140 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favour melphalan 200 or melphalan 140 for key transplant outcomes (NCT01362972).

PMID: 29217776 [PubMed - as supplied by publisher]




Chemotherapy-induced differential cell cycle arrest in B cell lymphomas affects their sensitivity to Wee1 inhibition.
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Chemotherapy-induced differential cell cycle arrest in B cell lymphomas affects their sensitivity to Wee1 inhibition.

Haematologica. 2017 Dec 07;:

Authors: Wang X, Chen Z, Mishra AK, Silva A, Ren W, Pan Z, Wang JH

Abstract
Chemotherapeutic agents, e.g., cytarabine or doxorubicin cause DNA damages. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B cell lymphomas, and whether this phenotype can be exploited for developing new therapies. Here, we treated various types of B cells including primary and B lymphoma cells, with cytarabine or doxorubicin, and determined DNA damage responses, cell cycle regulation and sensitivity to Wee1 inhibitor. We found that cyclin A2/B1 upregulation appear to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of cell cycle. Wee1 inhibitor significantly enhanced the apoptosis of G2 phase-arrested B cell lymphomas via inducing premature mitotic entry and mitotic catastrophe, whereas, it did not affect G1/S-phase-arrested lymphomas. Cytarabine-induced G1-arrest can be converted to G2-arrest by doxorubicin treatment in certain B cell lymphomas, which correlates with newly acquired sensitivity to Wee1 inhibitor. Consequently, Wee1 inhibitor together with cytarabine or doxorubicin more effectively inhibited tumor growth in vitro and in vivo, providing a new therapeutic potential for treating B cell lymphomas. We propose that the differential cell cycle arrest can be exploited to enhance chemo-sensitivity of B cell lymphomas.

PMID: 29217775 [PubMed - as supplied by publisher]




MicroRNA-155 is a direct target of Meis1, but not a driver in acute myeloid leukemia.
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MicroRNA-155 is a direct target of Meis1, but not a driver in acute myeloid leukemia.

Haematologica. 2017 Dec 07;:

Authors: Schneider E, Staffas A, Röhner L, Malmberg ED, Ashouri A, Krowiorz K, Pochert N, Miller C, Wei SY, Arabanian L, Buske C, Döhner H, Bullinger L, Fogelstrand L, Heuser M, Döhner K, Xiang P, Ruschmann J, Petriv OI, Heravi-Moussavi A, Hansen CL, Hirst M, Humphries RK, Rouhi A, Palmqvist L, Kuchenbauer F

Abstract
MicroRNA-155 (miR-155) is one of the first described oncogenic miRNAs. Although multiple direct targets of miR-155 have been identified, it is not clear how it contributes to the pathogenesis of acute myeloid leukemia. We found miR-155 to be a direct target of Meis1 in murine Hoxa9/Meis1 induced acute myeloid leukemia. The additional overexpression of miR 155 accelerated the formation of acute myeloid leukemia in Hoxa9 as well as in Hoxa9/Meis1 cells in vivo. However, in the absence or after the removal of miR-155, leukemia onset and progression were unaffected. Although, miR-155 accelerated growth and homing as well as impaired differentiation, our data underscore the pathophysiological relevance of miR 155 as an accelerator rather than a driver of leukemogenesis. This further highlights the complexity of the oncogenic program of Meis1 to compensate for the loss of a potent oncogene such as miR-155. These findings are highly relevant to current and developing approaches for targeting miR-155 in acute myeloid leukemia.

PMID: 29217774 [PubMed - as supplied by publisher]