Prognostic Value of the Expression of Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR-1) in Chronic Lymphocytic Leukemia.

Background: The transmembrane receptor tyrosine kinase-like orphan receptor 1 (ROR1) has acted on the causation and sustentation of mature B-cell lymphomagenesis for chronic lymphocytic leukemia (CLL) cells. The study attempted to show whether there is a relationship between the level of ROR1 surface expression in CLL cells and disease findings. Materials and Methods: The level of ROR1 cell surface expression was determined in accordance with the flow cytometric analysis of CLL patients at the first diagnosis time.  Two groups were formed according to the high and low ROR1 levels. The cut-off point for the ROR1 level was calculated for advanced-stage disease using receiver operating characteristic (ROC) curves. A two-sided p-value <0,05 was considered statistically significant. Results: 108 CLL cases with a median age of 60 were enrolled. The median percentage of ROR1 cell surface marker positivity in the CD5/CD19 positive leukemic cell was 62%. The CLL cases with high ROR1 levels have thrombocytopenia (p=0.042), anemia (p=0.028), and high beta-2 microglobulin value ≥3 mg/dL (p=0.002) and the need for first-line treatment (p=0.043). Conclusion: The poor prognostic parameters such as splenomegaly, anemia, higher beta-2 microglobulin levels, intermediate/advanced RAI stage disease, and need for first-line treatment had associated high-level ROR 1 expression of our CLL patients. It needs to be investigated for its effect on predicting disease burden and aggressiveness with more comprehensive studies on ROR1 expression levels in CLL cases.

Predictive Factors for Molecular Response in Chronic Myeloid Leukemia: Reduction Ratio and Halving Time of BCR::ABL1 IS Transcript Levels

Objective: Achieving an early molecular response (EMR) is crucial for improving the prognosis of patients with chronic myeloid leukemia (CML). The halving time (HT) and reduction ratio (RR) of BCR::ABL1 transcript levels have recently emerged as additional prognostic indexes besides the BCR::ABL1 International Scale (IS). We aimed to investigate the prognostic role of BCR::ABL1 transcript levels, HT, and RR on molecular response kinetics at 3 months in patients with newly diagnosed chronic-phase (CP)-CML. Materials and Methods: Forty patients with CP-CML who received first-line imatinib treatment were included in this study. BCR::ABL1 transcript levels and molecular responses at baseline and at 3, 6, 12, and 24 months of treatment were evaluated retrospectively. Major molecular response (MMR) at 12 months and event-free survival (EFS) were determined as primary endpoints and the effects of treatment kinetics on these parameters were examined. Results: Of the 40 patients, BCR::ABL1 IS was ≤10% at 3 months in 72.5%, representing EMR. The rate of event occurrence was 45.5% in patients with BCR::ABL1 IS of >10%, whereas it was 6.9% in those with BCR::ABL1 IS of ≤10% (p=0.004). MMR was detected in 62.1% of the patients with EMR and in 9.1% of those without EMR (p=0.003). The cut-off value for achieving MMR was 24 days for HT and 0.04 for RR. Deep molecular response (DMR) at 24 months was associated with HT of ≤24 days and RR of ≤0.04. EFS was found to be significantly better in the group with BCR::ABL1 IS of ≤10% and HT of ≤24 days (p=0.001) and in the group with BCR::ABL1 IS of ≤10% and RR of ≤0.04 (p=0.007) compared to others. Conclusion: Our findings revealed that MMR could be predicted via EMR as well as by HT and RR. Additionally, HT of ≤24 days and RR of ≤0.04 were more important than BCR::ABL1 IS of ≤10% in achieving DMR at 24 months, and the combination of BCR::ABL1 IS of ≤10% with both HT of ≤24 days and RR of ≤0.04 has the best predictive value for EFS.

A Rare Lymphoproliferative Disease: Castleman Disease

Castleman disease is a rare lymphoproliferative disease also known as angiofollicular lymph node hyperplasia. It is classified as hyaline vascular and plasmacytic variants histologically but characteristics of both types can coexist. Most unicentric cases of the disease are hyaline vascular while most multicentric cases are of the plasmacytic type. Although the pathogenesis is not completely understood, the role of interleukin (IL)-6 in unicentric disease and the roles of IL-6 and human herpes virus-8 in multicentric disease are well defined. Unicentric disease is typically localized and symptoms are minimal and treated locally. Multicentric disease is systemic and clinically characterized by generalized lymphadenopathy, splenomegaly, anemia, and systemic inflammatory symptoms. Systemic therapies are primarily given. Several malignant diseases including lymphomas, POEMS syndrome, follicular dendritic cell sarcomas, paraneoplastic pemphigus, Kaposi sarcoma, and amyloidosis can be associated with Castleman disease. In this paper, recent information about Castleman disease, which is a rare disease, is summarized.

The Triple Positivity for EBV, PD-1, and PD-L1 Identifies a Very High Risk Classical Hodgkin Lymphoma.

BACKGROUND: The programmed death receptor (PD-1) and ligand (PD-L1) pathway act by suppressing the antitumor response in chronic Hodgkin lymphoma (cHL). In this study, we aimed to investigate the effect of PD-1, PD-L1, and Epstein-Barr virus (EBV) positivity on prognosis at the initial diagnosis of cHL. MATERIAL AND METHODS: Thirty-six patients with cHL were retrospectively analyzed. PD-L1 staining was performed for RS cells and tumor microenvironment in the biopsy materials of cases. The presence of EBV was investigated by EBER (EBV-encoded RNA) method in tumor cell. P < .05 was accepted as significant. RESULTS: The presence of advanced-stage disease, B symptoms, intermediate or high-risk international prognostic index (IPS), and extranodal involvement were found to be related to both PD-L1 positivity and EBV positivity in RS cells. PD-L1 positivity in RS cells was also associated with EBV positivity. There were 6 (16.7%) triple-positive (EBV+, RS-PD-L1+, mic-PD-1+) patients. All of these patients had advanced-stage disease, B symptoms at the time of diagnosis, and intermediate-high IPS score, and 4 of 6 patients had extranodal involvement. This group also had significantly shortened overall survival compared with others (38.4 months vs. 67.9 months P = .024). CONCLUSION: Our data suggest that there is correlation between PD-L1 positivity and EBV positivity in tumor RS cells that are also associated with extranodal involvement, intermediate and high IPS score, presence of B symptoms, and advanced-stage disease. In addition, we identified a group of triple-positive (EBV+, RS-PD-L1+, mic-PD-1+) cHL patients who have a very high-risk disease.

Is Cd11c and Fmc7 Negativity in Chronic Lymphocytic Leukemia Poor Prognostic?

Chronic lymphocytic leukemia (CLL) is a common hematological malignancy. This study is aimed to investigate the prognostic effect of clinic, laboratory and flow cytometric analysis in CLL patients. Newly diagnosed 55 CLL cases were divided into two groups, as stable disease (Group 1) and progressive disease (Group 2). Group 1 included those who did not require any treatment since diagnosis and those who did not progress after receiving the first step anti CLL treatment. Group 2 included the patients who received ≥ 2 steps treatment. The relation between the two groups was analyzed statistically in terms of clinical, laboratory and flow cytometric findings. Twenty patients (36.3%) required treatment at the time of diagnosis, four patients (3.8%) received first-line treatment during follow-up and 31 (56.3%) patients were followed without any treatment. Thirteen patients required second step treatment after a median of 26.3 months. The risk of progression was found to be increased 5-fold (p = 0.015) in the CD38 positive patient group, 4.2-fold (p = 0.0147) in the FMC7 negative patient group and 2.8-fold in the CD11c negative patient group. FMC 7 negativity decreased total survival 5.9-fold (p = 0.051). Unlike similar publications, we found that patients with CD11c or FMC7 negativity were in a higher need for ≥ 2 step treatment. This suggests that CD11c or FMC7 negativity may be used as a poor prognostic marker in CLL.

Vitamin D Deficiency and Janus kinase 2 V617F Mutation Status in Essential Thrombocythemia and Polycythemia Vera.

INTRODUCTION: Vitamin D, which is known for its effects on calcium and bone metabolism, has recently been associated with haematological malignancies. We aimed to investigate the relationship between disease findings and vitamin D deficiency in essential thrombocythemia (ET) and polycythemia vera (PV). MATERIAL AND METHODS: This retrospective cohort study conducted in Turkey included 73 patients diagnosed with PV or ET according to WHO criteria between 2012 and 2018. Vitamin D deficiency was defined as 25-OH vitamin D < 20 ng/mL. Polymerase chain reaction (PCR) was used to detect the Janus kinase 2 (JAK2) V617F mutation. RESULTS: Vitamin D deficiency was found in 66.7% of PV and 74.2% of ET patients. The median follow-up time of ET and PV patients was 48 months and 47 months, respectively. Patients with the JAK2 mutation had a higher prevalence of a history of thrombosis and age older than 65 years. There was a significant relationship between JAK2 positivity and vitamin D deficiency. CONCLUSION: There was a remarkably higher prevalence of vitamin D deficiency in JAK2 mutation-positive ET and PV patients. These patients should be carefully evaluated for vitamin D deficiency. More studies are required to further investigate the association between JAK2 and vitamin D.

VAD Chemotherapy versus Bortezomib Containing Regimens as Remission Induction For ASCT in Multiple Myeloma: A Single Center Experience.

Background: Complete response (CR) and very good partial response (VGPR) are targeted with pre-ASCT induction regimens in patients by diagnosed multiple myeloma (MM), who are candidates for ASCT. In this study, it was aimed to compare the response and survival evaluations of cases who underwent induction treatment by vincristine-doxorubicin-dexamethasone (VAD) protocol versus bortezomib containing regimens. Materials and Methods: The data of 96 ASCT eligible patients, retrospectively analyzed. P value> 0.05 was considered statistically significant. Results: While 66 cases had received bortezomib containing regimens as induction regimen, 30 cases had received VAD protocol. The total survival was 91.3 (st.s 6) months and 43 (st.s 7.9) months, respectively, when we compared the cases without ASCT and with ASCT (p = 0.001). The OS of patients who underwent ASCT after reaching at least VGPR was longer than the underwent ASCT without reaching VGPR (p=0.019). Post-ASCT PFS (p=0.717) and OS (p = 0.126) analyzes were performed in 74 cases undergoing ASCT treatment, there was no significant statistical difference when patients with treated by VAD protochol and treated by bortezomib containing regimens as pre-ASCT induction regimens was compared to each other. Conclusion: Whatever the type of induction regimen is, the level of response achieved before ASCT is important. The survival of the myeloma patients are much more influenced with HDT-ASCT as well as post-transplantation strategies to keep the patients in remission. Even though it is outdated, we think that the VAD protocol may be an option in patients who are not responding with the new generation of agents in the following days.

Lupus-like symptoms with anti-RNP/Sm and anti-nuclear antibodies positivity: An extremely rare adverse event of dasatinib.

INTRODUCTION: Dasatinib is a potent tyrosine-kinase inhibitor which is used for chronic myeloid leukemia treatment. Pleural effusion is a frequent side effect in patients during dasatinib treatment. Pulmonary arterial hypertension is a rare and life-threatening adverse event of dasatinib. The relationship between dasatinib and autoimmune disorders is unclear, but there are reports of possible mechanisms that have triggered autoimmunity by dasatinib. CASE REPORT: A 53-year-old male was diagnosed with chronic myeloid leukemia and initiated imatinib mesylate as a treatment. Imatinib was changed to dasatinib as the patient was unresponsive in the first year of treatment. In the fourth year of dasatinib when chronic myeloid leukemia was in both hematological and cytogenetical remission, the patient presented with bilateral massive exudative pleural effusion. Echocardiography was consistent with pericardial effusion with right ventricle enlargement and normal left-side cardiac function. Pulmonary arterial hypertension was diagnosed with high systolic pulmonary arterial pressure. When he had fever and arthralgia, further investigation showed positivity of anti-nuclear antibodies (1/160 titer) and anti-RNP/Sm, which have high specificity for the diagnosis of Systemic Lupus Erythematosus (SLE). MANAGEMENT AND OUTCOME: Dasatinib was discontinued and nilotinib was initiated. As the pleural effusion persisted despite diuretics and methylprednisolone, mycophenolate mofetil was initiated as a steroid-sparing immune-suppressive agent. The lupus-like symptoms disappeared, and antibodies became undetectable after dasatinib discontinuation. Pericardial effusion improved and pleural effusion did not relapse. DISCUSSION: Screening for auto-antibodies may be recommended for patients with a history or symptoms of autoimmune disease before starting dasatinib. All patients who develop pleural effusion while on dasatinib treatment should be investigated for antibodies for lupus.

Thiol-disulphide Homeostasis in Essential Thrombocythemia Patients.

BACKGROUND: This study aimed to show the status of thioldisulphide homeostasis in essential thrombocytosis patients, which is known to play a role in platelet function. METHODS: The study included 27 ET patients and a control group of 36 healthy subjects. Serum total (-SH + -S-S-) and native (-SH) thiol levels were measured in all subjects using an automatic method. RESULTS: Age and gender distribution were similar in both groups. Compared with the control group, in the ET group, there were increased native thiol and total thiol levels (p = 0.001, p = 0.046). There was no correlation between thiol, total thiol and disulphide ratios with Jak2 mutation, hemorrhage and thrombosis. A positive correlation was determined between thrombosis and thiol disulphide homeostasis (p = 0.058). The study results showed that thiol-disulphide homeostasis shifted to the proliferative side in ET, in which ineffective erythropoiesis was predominant. It is also known that platelets are more active in ET cases and thiol disulphide balance is important in platelet function. CONCLUSIONS: This result suggests that thrombotic complications may be reduced if the formation is achieved of mechanisms (oxidation mechanisms) that will trigger the increase of disulphide groups. However, more extensive research is needed on this subject.

Development of plasma cell leukemia in a patient with chronic myeloid leukemia while on treatment with imatinib mesylate.

Plasma cell leukemia (PCL) is a rare and an aggressive form of plasma cell dyscrasias. We report a 67-year-old male with PCL which developed while on imatinib mesylate (IM) therapy 38 months after diagnosis of chronic myeloid leukemia (CML). The patient has been treated successfully with bortezomib, melphalan and prednisolone. To our knowledge, only one case of PCL superimposed on Philadelphia positive CML has been reported in the literature and this was before the IM era.

Acquired hemophilia with thrombosis in a cancer patient: an unusual presentation.

: Acquired hemophilia A (AHA) which presents with spontaneous severe intramuscular, mucosal and/or subcutaneous bleeding is a rare bleeding disorder. Even 50% of AHA patients are defined as idiopathic; 10% of cases are related with malignancy. Here, we present a case of AHA in a 43-year-old lady who was diagnosed with malignancy and venous thromboembolism on vena cava 2 years ago. To the best of our knowledge, this is the first report in literature presented with both acquired hemophilia and thrombosis associated with malignancy. A routine workup for malignancy like solid tumors, lymphoproliferative, or myeloproliferative diseases should be performed and followed up for a long time despite clinical improvement for individuals presented with AHA. Moreover, because of warfarin treatment, the diagnosis may be difficult and delayed. Clinicans should rule out AHA in patients who are on warfarin treatment and have abnormal coagulation tests.

Evaluation of Inflammation Parameters in Philadelphia Negative Chronic Myeloproliferative Neoplasia Patients.

BACKGROUND: Chronic myeloproliferative diseases are clonal stem cell diseases which occur as a result of uncontrollable growth and reproduction of hematopoietic stem cells, which are the myeloid series source in bone marrow. Recent studies have suggested that chronic inflammation can be a triggering factor in the clonal change in chronic myeloproliferative neoplasia (CMPN). In our study, we evaluated the existence of a chronic inflammation process in our Philadelphia negative (Ph-)CMPN patients using inflammation parameters in combination with demographic, laboratory and clinical characteristics of the patients. MATERIALS AND METHODS: Demographic characteristics, clinical and laboratorial data, and thrombosis histories of 99 Ph-CMPN patients, who were diagnosed at our outpatient clinic of hematology in accordance with WHO 2008 criteria, were analyzed retrospectively,with 80 healthy individuals of matching gender and age included as controls. Complete blood counts, sedimentation, C reactive protein (CRP), JAK V617F gene mutations, abdomen ultrasound images and previous thrombosis histories of these patients were retrospectively analyzed. RESULTS: Ph-CMPN and healthy control groups included 99 and 80 cases, respectively. PV, ET and MF diagnoses of patients were 43 (%43.4), 44 (44.4%) and 12 (12.1%), respectively. JAK V617F gene mutation was found to be positive in 64 (71.1%) of all cases and in 27(65.8%), 32 (82%), 5 (50%) of the cases in PV, ET and PMF groups, respectively. Thrombosis was determined as 12 (12%) in the entire group, 12.5% in the JAK V617F negative and 15.3% in the positive patients, with no statistical significance (p=0.758). No significant difference was observed between patients with and without previous thrombosis history in respect to hemogram parameters, sedimentation and CRP (p>0.05), neutrophil to lymphocyte ratio (NLR), erythrocyte distribution width (RDW), mean platelet volume (MPV) and sedimentation levels of the patient.

Epstein-barr virus-negative post-transplant lymphoproliferative diseases: three distinct cases from a single center.

Three cases of Epstein-Barr virus (EBV)-negative post-transplant lymphoproliferative disease that occurred 6 to 8 years after renal transplantation are reported. The patients respectively had gastric mucosa-associated lymphoid tissue lymphoma, gastric diffuse large B-cell lymphoma, and atypical Burkitt lymphoma. Absence of EBV in the tissue samples was demonstrated by both in situ hybridization for EBV early RNA and polymerase chain reaction for EBV DNA. Patients were treated with reduction in immunosuppression and combined chemotherapy plus an anti-CD20 monoclonal antibody, rituximab. Despite the reduction in immunosuppression, patients had stable renal functions without loss of graft functions. The patient with atypical Burkitt lymphoma had an abnormal karyotype, did not respond to treatment completely, and died due to disease progression. The other patients are still alive and in remission 5 and 3 years after diagnosis, respectively. EBV-negative post-transplant lymphoproliferative diseases are usually late-onset and are reported to have poor prognosis. Thus, reduction in immunosuppression is usually not sufficient for treatment and more aggressive approaches like rituximab with combined chemotherapy are required.

Vanishing bile duct syndrome after allogeneic bone marrow transplantation: is it the end of the road?

In this paper, we report the case of a 19-year-old male patient who presented with lymphoblastic phase of chronic myeloid leukemia and received an allogeneic bone marrow transplant from his cousin. The patient experienced severe, steroid-refractory acute graft versus-host disease of skin, gastrointestinal tract and liver that required further immunosuppression. However, hepatic graft-versus-host disease was complicated with vanishing bile duct syndrome, characterized by progressive destruction of small intrahepatic bile ducts, which was refractory to all available therapies and eventually led to end-stage liver disease. The pathogenesis and treatment of graft-versus-host disease after allogeneic hematopoietic cell transplantation is discussed with an emphasis on liver transplantation for intractable hepatic graft-versus-host disease.

Blood group genotyping in multi-transfused patients.

BACKGROUND: In chronically transfused patients, the classical hemagglutination assays may be inaccurate in defining the RBC phenotypes of the patients due to previous transfusions. DESIGN: DNA samples from 39 multi-transfused patients including thalassemia and sickle cell disease were used for red blood cell genotyping. The Rh-Type and KKD-Type (BAGene, BAG Healthcare) were used to determine the polymorphisms associated with antigen expression for RHD, RHCE and Kell, Kidd, Duffy blood group systems, respectively. Results were compared with previously determined phenotyping results for RhD, RhCcEe and Kell by hemagglutination method. RESULTS: Nineteen out of the 37(51%) patients had discrepancies between genotyping and phenotyping results in a total of 25 alleles. In 12 patients, the discrepancies had the potential of alloimmunization. CONCLUSION: Blood group genotyping has vital importance in transfusion management of chronically transfused patients especially if the patients were not phenotyped before starting the initial transfusions.

Myeloma as a Second Malignancy following AML: Is a Second Allo Equivalent to Auto?

We report a young male patient who developed plasma cell myeloma/plasmacytoma 11 years after having received an allogeneic hematopoietic cell transplantation for AML. The patient received a second transplantation from the same donor without immunosuppression and developed graft-versus-host disease (GVHD). Our observation has two aspects that warrant attention: first, insufficiency of long-term tolerance to prevent GVHD in the absence of immunosuppression and second, a stromal or genetic susceptibility to develop hematologic malignancies despite of a complete donor-type chimerism.

Simultaneous occurrence of Kaposi's sarcoma and nodular lymphocyte predominant subtype of Hodgkin's lymphoma in the same lymph node.

Many cases have been established with coexisting Kaposi's sarcoma (KS) and classical Hodgkin's Lymphoma (C-HL) in the same lymph node. But composite presentation of KS and Nodular Lymphocyte Predominant subtype of Hodgkin's lymphoma (NLPHL) in the same lymph node has not been described yet. KS is related to immunodeficiency most frequently due to human immunodeficiency virus (HIV) infection or immunosupression by other reasons. Our case presented here was not related to any immunodeficiency status. Besides of being the first case of composite KS and NLPHL in the same lymph node, it was also unusual with the indolent behaviour of the NLPHL without any therapy for 8 years follow up and primary lymph node presentation of KS without cutaneous involvement.

T-helper-1 (Th1) and Th2 cytokines after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Dysregulation of T-helper (Th)1 (IFN-g, IL-2, TNF-a) and Th2 (IL-4, IL-5, IL-10) type cytokines has been suggested in the pathogenesis of graft versus host disease (GvHD). We analyzed intracellular cytokine expression in Th (CD4+) lymphocytes in 23 patients undergoing allo-hematopoietic stem cell transplantation (HSCT) both in the week of neutrophil engraftment (S1) and on the posttransplant 100th day (S2). CD4+TNF-a+ cells increased from 22% at S1 to 26% at S2 in the allo-peripheral blood (PB) group. CD4+IL-2+ cells at S1 in the bone marrow (BM) group had a tendency to be higher than in the allo-PB group and also higher than at S2. IL-2 and TNF-a expressions at S1 were significantly higher and IL-2 expression at S2 was significantly lower in patients with grade II-IV acute GvHD compared with grade 0-I GvHD. IFN-g expression tended to be higher at S2 in the chronic GvHD group compared with the patient without GvHD. Consequently, the data in this study support the role of Th1 cytokines in GvHD.

Clonal evolution of monosomy 7 in acquired severe aplastic anemia: Two cases treated with allogeneic hematopoietic stem cell transplantation.

Aplastic anemia (AA) may evolve into clonal diseases like myelodysplastic syndrome (MDS) and acute myeloblastic leuke¬mia (AML). Monosomy 7 is a poor prognostic chromosomal abnormality commonly associated with therapy related MDS and secondary AML. It has also been associated with leukomogenic transformation in AA. We present here two adult ma¬le patients with acquired severe AA. Both patients had received immunosuppressive therapy (IST) as first line treatment and had monosomy 7 positive clone at transformation to MDS with refractory anemia and excess of blast (RAEB-II) and AML, respectively. Both patients have undergone allogeneic hematopoietic stem cell (HSC) transplantation from their HLA identical donors (unrelated and sibling).