The Philadelphia Chromosome, from Negative to Positive: A Case Report of Relapsed Acute Lymphoblastic Leukemia Following Allogeneic Stem Cell Transplantation.

Relapsed acute lymphoblastic leukemia (ALL) represents a continuous challenge for the clinician. Despite recent advances in treatment, the risk of relapse remains significant. The clinical, biological, cytogenetic, and molecular characteristics may be different at the time of relapse. Current comprehensive genome sequencing studies suggest that most relapsed patients, especially those with late relapses, acquire new genetic abnormalities, usually within a minor clone that emerges after ALL diagnosis. We report the case of a 23-year-old young woman diagnosed with Philadelphia chromosome-negative B cell acute lymphoblastic leukemia. The patient underwent allogeneic stem cell transplantation (allo-HSCT) after complete remission. Despite having favorable prognostic factors at diagnosis, the disease relapsed early after allo-HSCT. The cytogenetic and molecular exams at relapse were positive for the Philadelphia chromosome, respectively for the Bcr-Abl transcript. What exactly led to the recurrence of this disease in a more aggressive cytogenetic and molecular form, although there were no predictive elements at diagnosis?

Primary, secondary or less frequent causes of immune thrombocytopenia: A case report.

Primary immune thrombocytopenia (ITP) is characterized by isolated low platelet count and it is a diagnosis of exclusion, contrasting to secondary ITP. Therefore, a positive diagnosis is difficult and requires extensive investigation. Some of the underlying conditions that are associated with ITP are lymphoproliferative disorders and infections, especially viral ones. In the present study, the case of a patient diagnosed with diffuse large B-cell lymphoma, who received chemotherapy and autologous hematopoietic stem cell transplantation is presented. After a complete remission of four years, the patient presented with sudden intense hemorrhagic syndrome and severely decreased platelet count. The most frequent causes of secondary ITP were excluded, including lymphoma relapse, and intravenous corticosteroids were started. However, shortly after hospital admission, the patient developed neuro-psychiatric anomalies, fever and pancytopenia, and West-Nile encephalitis was diagnosed. Although the initial development was favorable, he started to complain of progressive severe muscle weakness and eventually succumbed to infectious complications in the setting of prolonged hospitalization, corticotherapy, and immobilization.

Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies.

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the NPM1 gene, followed by DNMT3A, FLT3 and NRAS. An unexpected co-occurrence of KMT2A translocation and DNMT3A-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.

Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?

Checkpoint inhibitors were a major breakthrough in the field of oncology. In September 2014, based on the KEYNOTE-001 study, the Food and Drug Administration (FDA) approved pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced or unresectable melanoma. Up until now, seven PD-1/PD-ligand(L)-1 inhibitors are approved in various solid cancers and hundreds of clinical studies are currently ongoing. In hematology, PD-1 inhibitors nivolumab and pembrolizumab were approved for the treatment of relapsed/refractory (R/R) classic Hodgkin lymphoma, and later pembrolizumab was approved for R/R primary mediastinal large B-cell lymphoma. In acute myeloid leukemia (AML), the combination of hypomethylating agents and PD-1/PD-L1 inhibitors has shown promising results, worth of further investigation, while other combinations or single agent therapy have disappointing results. On the other hand, rather than in first line, these therapies could be useful in the consolidation or maintenance setting, for achieving minimal residual disease negativity. Furthermore, an interesting application could be the use of PD-1/PD-L1 inhibitors in the post allogeneic hematopoietic stem cell transplantation relapse. There are several reasons why checkpoint inhibitors are not very effective in treating AML, including the characteristics of the disease (systemic, rapidly progressive, and high tumor burden disease), low mutational burden, and dysregulation of the immune system. We here review the results of PD-1/PD-L1 inhibition in AML and discuss their potential future in the management of this disease.

MicroRNAs Associated With a Good Prognosis of Acute Myeloid Leukemia and Their Effect on Macrophage Polarization.

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with poor outcomes despite very intensive therapeutic approaches. For the majority of patients which are unfit and treated less intensively, the prognosis is even worse. There has been unspectacular progress in outcome improvement over the last decades and the development of new approaches is of tremendous interest. The tumor microenvironment is credited with an important role in supporting cancer growth, including leukemogenesis. Macrophages are part of the tumor microenvironment and their contribution in this setting is increasingly being deciphered, these cells being credited with a tumor supporting role. Data on macrophage role and polarization in leukemia is scarce. MicroRNAs (miRNAs) have a role in the post-transcriptional regulation of gene expression, by impending translation and promoting degradation of messenger RNAs. They are important modulators of cellular pathways, playing major roles in normal hematopoietic differentiation. miRNA expression is significantly correlated with the prognosis of hematopoietic malignancies, including AML. Oncogenic miRNAs correlate with poor prognosis, while tumor suppressor miRNAs, which inhibit the expression of proto-oncogenes, are correlated with a favorable prognosis. miRNAs are proposed as biomarkers for diagnosis and prognosis and are regarded as therapeutic approaches in many cancers, including AML. miRNAs with epigenetic or modulatory activity, as well as with synergistic activity with chemotherapeutic agents, proved to be promising therapeutic targets in experimental, pre-clinical approaches. The clinical availability of emerging compounds with mimicking or suppressor activity provides the opportunity for future therapeutic targeting of miRNAs. The present paper is focusing on miRNAs which, according to current knowledge, favorably impact on AML outcomes, being regarded as tumor suppressors, and reviews their role in macrophage polarization. We are focusing on miRNA expression in the setting of AML, but data on correlations between miRNA expression and macrophage polarization is mostly coming from studies involving normal tissue.

Idiopathic thrombocytopenic purpura (ITP) - new era for an old disease.

Immune thrombocytopenia is an autoimmune hematological disorder characterized by severely decreased platelet count of peripheral cause: platelet destruction via antiplatelet antibodies which may also affect marrow megakaryocytes. Patients may present in critical situations, with cutaneous and/or mucous bleeding and possibly life-threatening organ hemorrhages (cerebral, digestive, etc.) Therefore, rapid diagnosis and therapeutic intervention are mandatory. Corticotherapy represents the first treatment option, but as in any autoimmune disorder, there is a high risk of relapse. Second line therapy options include: intravenous immunoglobulins, thrombopoietin receptor agonists, rituximab or immunosuppression, but their benefit is usually temporary. Moreover, the disease generally affects young people who need repeated and prolonged treatment and hospitalization and therefore, it is preferred to choose a long term effect therapy. Splenectomy - removal of the site of platelet destruction - represents an effective and stable treatment, with 70-80% response rate and low complications incidence. A challenging situation is the association of ITP with pregnancy, which further increases the risk due to the immunodeficiency of pregnancy, major dangers of bleeding, vital risks for mother and fetus, potential risks of medication, necessity of prompt intervention in the setting of specific obstetrical situations - delivery, pregnancy loss, obstetrical complications, etc. We present an updated review of the current clinical and laboratory data, as well as a detailed analysis of the available therapeutic options with their benefits and risks, and also particular associations (pregnancy, relapsed and refractory disease, emergency treatment).

A Review of Macrophage MicroRNAs' Role in Human Asthma.

There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 macrophage polarization, thereby controlling immune responses. Here we review the current published data concerning miRNAs with known correlation to a specific human macrophage phenotype and polarization, and their association with adult asthma. MiRNA-targeted therapy is still in the initial stages, but clinical trials are under recruitment or currently running for some miRNAs in other diseases. Regulating miRNA expression via their upregulation or downregulation could show potential as a novel therapy for improving treatment efficacy in asthma.

Splenectomy in Lymphoproliferative Disorders: A Single Eastern European Center Experience.

Background and Objectives: Hematological malignancies are usually systemic diseases of life-threatening impact, and frequently require prompt and energetic therapeutic intervention. Due to systemic involvement, the role of surgery is generally limited to diagnostic approaches, and it is very rarely employed as a therapeutic modality. Splenectomy represents an exception to this paradigm, being used both as a diagnostic and tumor debulking procedure, notably in splenic lymphomas. Materials and Methods: We investigated the role of splenectomy in a single center prospective study of splenectomy outcome in patients with splenic involvement in the course of lymphoproliferative disorders. In the present study, we included all patients treated in our department for lymphoid malignancies over a period of six years, who underwent splenectomy as a diagnostic or debulking procedure after referral and workup, or had been referred to our department after first being splenectomized and diagnosed with splenic lymphoma. Patient characteristics and treatment outcome were investigated. Results: We enrolled 54 patients, with 34 (63%) splenectomized patients: 12 splenectomies (22.2%) for diagnostic purposes and 22 (40.7%) for treatment. Special attention was given to the 28 (51.85%) patients diagnosed with splenic marginal zone lymphoma (SMZL), a subtype with a clear therapeutic indication for splenectomy. Average age of patients was 57.5 (±13.1) years with a higher prevalence of feminine gender (66.67%). Age above 60 years old (p = 0.0295), ECOG (Eastern Cooperative Oncology Group) > 2 (p = 0.0402) and B-signs (p nonsignificant (NS)) were most frequently found in SMZL patients. Anemia, and notably autoimmune anemia, was more frequent in SMZL versus other small-cell lymphomas and also in splenectomized patients, as was leukocytosis and lymphocytosis. Treatment of patients with lymphoproliferative disorders consisted of chemotherapy and/or splenectomy. Most SMZL patients received chemotherapy as first line treatment (61.5%) and had only partial response (57.7%). Second treatment line was splenectomy in 80% of patients who required treatment, followed by a 60% rate of complete response (CR). Splenectomy offered a higher complete response rate (twice as high than in non-splenectomized, regardless of histology type, p = NS), followed by a survival advantage (Overall Survival (OS)~64 versus 59 months, p = NS). Particularly, SMZL patients had a 4.8 times higher rate of CR than other non-Hodgkin lymphoma (NHL) patients (p = 0.04), a longer progression free survival (73 months vs. 31 months for other small-cell NHLs p = NS) and a 1.5fold lower death rate (p = NS). The procedure was rather safe, with a 38.5% frequency of adverse reactions, mostly minor and manageable. Conclusions: Our data suggest that splenectomy is an effective and safe therapeutic option in patients with lymphoid malignancies and splenic involvement, particularly splenic marginal zone lymphoma.

POEMS syndrome complicated with multiple ischemic vascular events: case report and review of literature.

POEMS syndrome (acronym consisting of: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is an uncommon disorder associated with an underlying plasma cell dyscrasia. There is no single specific test for POEMS, and due to its rarity and heterogeneity, patients are often mis- or underdiagnosed. Castleman disease (CD) is a rare lymphoproliferative disorder, closely related to POEMS syndrome; ~11%-30% of POEMS patients are associated with concomitant CD. In contrast to frequently published reports on vascular events in POEMS syndrome affecting coronary arteries or lower limbs, cases of cerebrovascular events are rarely mentioned in literature. We hereby report a patient with POEMS syndrome accompanied by CD who presented recurrent strokes and splenic infarction.

A Challenging Case of Kikuchi-Fujimoto Disease Associated with Systemic Lupus Erythematosus and Review of the Literature.

Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare disease that is frequently underdiagnosed due to clinical features that are similar to those of non-Hodgkin lymphomas, systemic lupus erythematosus (SLE), or infectious reactive lymphadenopathy. An excisional biopsy is required. We report a young Caucasian female diagnosed with KFD with skin lesions, complicating with SLE. The clinical course, laboratory, and CT findings are described, as are histopathologic features, for a better recognition of this rare disorder in clinical practice.

MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.

Early severe preeclampsia with marked platelet dysfunction in association with essential thrombocytemia: case report and discussion.

Essential thrombocytemia--a classic myeloproliferative neoplasm characterized by persistent thrombocytosis--may associate both thrombotic and hemorrhagic events, as well as platelet dysfunction. Of all myeloproliferative neoplasms, essential thrombocytemia is more likely to be associated with pregnancy, because of a higher comparative incidence in younger patients. This association significantly increases the risk of pregnancy loss and of various pregnancy complications. We present a case of early severe preeclampsia with a critical and unusual evolution and life-threatening complications.

Refractory anemia with ring sideroblasts associated with marked thrombocytosis: case report and literature review.

"Refractory anemia with ring sideroblasts and thrombocytosis" (RARS-T) is a rare disease, a provisional entity, with a controversial status in the 2008 revised WHO classification. Even at present time, RARS-T is a matter of debate whether it is a distinct clinicopathological entity or more likely a constellation of clinical and pathological features of two well-defined myeloid neoplasms, myelodysplastic syndrome and myeloproliferative neoplasm. Perhaps none of the clonal disorders illustrates better the challenges presented by the current classification of myeloid neoplasms, than this clinical entity with overlapping features of both refractory anemia with ring sideroblasts and essential thrombocythemia. The purpose of this study is to present the evolution of such a case, with difficulties in establishing not only the correct diagnosis, but also the appropriate therapeutic approach. For this reported case, we present documented details regarding persistent thrombocytosis, slightly increased number of leukocytes and analysis of Janus kinase 2 (JAK2) genes that revealed a V617F mutation, confirming the presence of an underlying myeloproliferative neoplasm, followed later in the evolution by occurrence of myelodysplastic features as ring sideroblasts. This case might interest pathologists, but especially clinicians, for at least two reasons: the rarity of this disease and the lack of data on prognosis of these patients, probably because of relatively recent established diagnosis criteria and existence of few studies with small number of patients. The third interesting aspect for practitioners would be the absence of consensus on optimal clinical treatment for this disorder, because there are few cases that meet the rigorous diagnostic criteria.

The implications of revised WHO classification (2008) of chronic myeloid neoplasms.

Myeloid disorders constitute a subgroup of hematological malignancies of myeloid lineage. In the revised 2008 WHO classification system, the nomenclature for myeloproliferative entities has been changed from "chronic myeloproliferative diseases" to "myeloproliferative neoplasms", the definition criteria has changed, and and the MDS/MPN has emerged as a well defined entity the subgroup formerly known as "myelodysplastic/myeloproliferative diseases" has changed to "myelodysplastic/myeloproliferative neoplasms". The World Health Organization classification of myeloid neoplasms relies on the association of clinical, morphologic, immunophenotypic and genetic diagnostic features. The current review highlights these changes and also provides diagnostic algorithms that are tailored to routine clinical practice.

Double transformation of a hematopoietic malignancy and severe associated thrombopathy. Case presentation and review of the literature.

We present the case of a patient with a double transformation during the evolution of chronic hematopoietic malignancy - JAK2 positive chronic myeloproliferative neoplasm; the first transformation had occurred previous to the presentation in our Department, but the second transformation was observed in evolution and it was into a rapidly evolving disease, followed by survival of less than one month. We underline the very poor prognosis -- overall survival of 2.5 years from initial presentation -- a much reduced survival for a chronic myeloproliferative neoplasm, probably due also to multiple associated pathology. Also, the other interesting element of the case is related to the dysfunctional platelets -- hemorrhagic complication at increased platelet count, respectively thrombosis at platelet count under 20000/mmc.