Diagnostic clues in a stem cell transplant patient manifested with chronic central nervous system GVHD and IRIS.

Transplant physicians should be aware of the immune deviation-related clinical conditions as allogeneic hematopoietic stem cell transplantation is widely used for the treatment of patients with malignant and non-malignant disorders. Neurological manifestations and graft-versus-host disease (GVHD) may commonly develop in transplant recipients. However, overlapping clinical immunological conditions may lead to diagnostic challenges. Herein, we discussed the differential diagnosis of a patient with immune reconstitution inflammatory syndrome (IRIS) developing on the basis of chronic GVHD.

Spontaneous Tumour Lysis Syndrome in a Multiple Myeloma.

The tumor lysis syndrome (TLS) is a collection of metabolic abnormalities that occur in consequence of the release of intracellular contents following lysis of tumor cells. TLS occurs spontaneously or after chemotherapy. Spontaneous TLS is uncommon occurrence in multiple myeloma (MM). We define a case of a 70-year-old woman patient who was found to have MM with spontaneous TLS, following a compression fracture of the T-12 vertebrae. While serum uric acid and phosphorous levels were high, low calcium levels were identified. There were also acute kidney injury and metabolic acidosis. Upon the diagnosis of TLS, she was treated with hydration, allopurinol, sodium bicarbonate, and calcium gluconate. The improvement of her laboratory data was observed. We submitted this case in order to draw attention to the presentation of MM with spontaneous TLS.

Treatment of pyoderma gangrenosum with thalidomide in a myelodysplastic syndrome case.

Thalidomide may be used as a treatment option for pyoderma gangrenosum (PG) and myelodysplastic syndrome (MDS). Herein, we aimed to report a patient who was treated well with thalidomide and whose diagnosis was PG with MDS. A 61-year-old man with painless ecchymotic lesions in his right upper extremity was admitted to the hospital in Isparta, Turkey, in January 2015. The lesions were diagnosed as PG. In his anamnesis, it was found that he was diagnosed with MDS 6 years ago and had been treated with cyclosporine at 2×100 mg for 5 years, which was stopped in January 2015. Aspiration from liver lesion revealed the presence of Mycobacterium tuberculosis, so antituberculosis treatment was started. Bone marrow investigation revealed MDS-refractory anemia with excess blasts (7%). For lesions in bilateral upper extremities, thalidomide treatment was started at 50 mg/d. After 1 month from the initiation of thalidomide treatment, the lesions in upper extremities had disappeared. In the literature, there are some reports of patients with PG who were successfully treated with thalidomide. Our patient is a complicated case who simultaneously has MDS, PG, and tuberculosis infection. The reason for thalidomide usage in our patient was the need of immune modulation without immune suppression. Our patient has tolerated the drug well, and excellent response was obtained after 1 month of initiation of thalidomide treatment. To conclude, thalidomide is a very effective drug acting as an immune modulator, which is useful in the clinical management of both MDS and PG.

The Prognosis of Adult Burkitt's Cell Leukemia in Real-Life Clinical Practice.

OBJECTIVE: Many studies reported an improved prognosis in patients with Burkitt's lymphoma obviating the need of stem cell transplantation. However, prognosis of the advanced disease [i.e. Burkitt's cell leukemia (BCL)] has not been reported with current treatment modalities except for a few prospective trials. The aim of this study is to compare the prognoses of BCL patients with similarly treated and nontransplanted patients with other types of acute lymphoblastic leukemia (ALL) and with ALL patients that underwent allogeneic stem cell transplantation (ASCT) in their first remissions. MATERIALS AND METHODS: In this retrospective analysis, BCL patients aged between 16 and 63 who were admitted between 2000 and 2014 to the hospitals of Hacettepe or Gazi University and were treated with intensive therapies aimed at cure were included. All ALL patients who were treated with a similar protocol not including transplantation during the same period (NT-ALL group) and all ALL patients who underwent ASCT in the first complete remission during the same period (T-ALL group) served as control groups. RESULTS: The central nervous system or extramedullary involvement rates, lactate dehydrogenase levels, and white blood cell counts at diagnosis were higher in the BCL group than the NT-ALL group and these differences were significant. BCL patients had disease-free survival (DFS) durations comparable with the T-ALL cohort but NT-ALL patients had significantly shorter DFS durations. Both cumulative relapse incidence and cumulative nonrelapse mortality were higher in NT-ALL patients compared to the T-ALL group and BCL patients. CONCLUSION: DFS in BCL patients treated with a widely accepted modern regimen, R-HyperCVAD, is comparable to results in other ALL patients receiving allogeneic transplantation. Our results are in agreement with a few prospective noncomparative studies suggesting no further need for stem cell transplantation in BCL.

Retrospective analysis of adult patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation: A multicenter experience of daily practice.

Compared to pediatric age group, the prognosis of adult acute lymphoblastic leukemia (ALL) is still dismal even in patients receiving allogeneic hematopoietic cell transplantation (AHCT). We retrospectively analyzed 205 adults (male: 122; female: 83) with ALL who underwent AHCT. Median age of patients was 28 (18-59). Fifty-two patients had Ph(+) ALL. The estimated relapse-free and overall survival (OS) of the study cohort at 1, 2 and 3 years were 52.3%/63.9%, 42.9%/49.5% and 39.9%/45.6%, respectively. On multivariate analysis, first complete remission at the time of AHCT, TBI-based conditioning and development of chronic graft-versus-host disease were only factors, which were significantly associated with prolonged OS.

Comparison of Myelodysplastic Syndrome Prognostic Scoring Systems.

OBJECTIVE: Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease. Patients are at risk of developing cytopenias or progression to acute myeloid leukemia. Different classifications and prognostic scoring systems have been developed. The aim of this study was to compare the different prognostic scoring systems. MATERIALS AND METHODS: One hundred and one patients who were diagnosed with primary MDS in 2003-2011 in a tertiary care university hospital's hematology department were included in the study. RESULTS: As the International Prognostic Scoring System (IPSS), World Health Organization Classification-Based Prognostic Scoring System (WPSS), MD Anderson Prognostic Scoring System (MPSS), and revised IPSS (IPSS-R) risk categories increased, leukemia-free survival and overall survival decreased (p<0.001). When the IPSS, WPSS, MPSS, and IPSS-R prognostic systems were compared by Cox regression analysis, the WPSS was the best in predicting leukemia-free survival (p<0.001), and the WPSS (p<0.001) and IPSS-R (p=0.037) were better in predicting overall survival. CONCLUSION: All 4 prognostic systems were successful in predicting overall survival and leukemia-free survival (p<0.001). The WPSS was found to be the best predictor for leukemia-free survival, while the WPSS and IPSS-R were found to be the best predictors for overall survival.

Can red cell distribution width be a marker of disease activity in ulcerative colitis?

AIM: The current study aimed to investigate the association between disease activity and red cell distribution width (RDW) levels in ulcerative colitis and to determine whether RDW can be used as a marker of disease activity in non-anemic ulcerative colitis. METHODS: The RDW levels of 310 ulcerative colitis patients who underwent colonoscopy were analyzed retrospectively. The patients were divided into two groups (active disease and remission) according to the endoscopic activity index. In addition, the accuracy of RDW in determining disease activity in non-anemic patients was assessed. The efficacy of RDW in determining disease activity was compared to that of white blood cell count, platelet count, C-reactive protein, and erythrocyte sedimentation rate. RESULTS: Two hundred and six (66.5%) patients had active disease, and 104 (33.5%) were in remission. The mean RDW levels in patients with active ulcerative colitis and in those in remission were 16.8±2.9 and 15.5±1.4, respectively (P<0.001). Ninety-six (46.6%) patients in the active disease group and 89 (85.6%) in the remission group were non-anemic, and their respective RDW levels were 15.4±1.2 and 15.3±1.1 (P=0.267). The sensitivity and specificity of RDW in determining inflammation were 41% and 91%, respectively (AUC 0.65, P<0.001). CONCLUSIONS: This study demonstrated that RDW can be used as a marker for disease activity in ulcerative colitis, but it did not have the same efficacy in the non-anemic group.

Late Onset and Protracted Course of Steroid Refractory Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is one of the most important causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT). Occurring in 30% to 70% of patients, cGVHD has a median time to onset of 4 to 6 months and most cases present within 2 years after aHSCT. Here, we present a patient transplanted at the age of 55 who developed refractory cutaneous cGVHD more than 5.5 years after aHSCT.

Melanonychia Secondary to Long-Term Treatment with Hydroxycarbamide: An Essential Thrombocytosis Case.

Hydroxycarbamide is used in the treatment of essential thrombocytosis and other myeloproliferative disorders. We report the case of a 63-year-old woman with essential thrombocytosis who had melanonychia after the long-term use of the hydroxycarbamide with a dose of 1000 mg/day. Two years after the initiation of the hydroxycarbamide, our patient had pain on her toes and melanonychia on her nails. Hydroxycarbamide treatment was discontinued because of pain and she was given anagrelide treatment. The pathogenesis of melanonychia secondary to long-term hydroxycarbamide treatment is not yet well understood. Some investigators suggested that genetic factors, induction of melanocytes, and some changes in nail matrix could be the reason of hydroxycarbamide related melanonychia. Our patient has suffered color changes in her nails as well as pain that made us doubtful for a beginning of ulceration besides melanonychia. Maybe early clinical reaction of discontinuation of the drug has prevented more severe side effect like ulceration in our patient. Also side effect of hydroxycarbamide has developed more slowly in our patient compared to other patients in the mentioned study. To conclude, long-term hydroxycarbamide treatment can cause mucocutaneous side effects and more studies should be done in future in order to reveal the underlying mechanism.

Pharmacobiological Approach for the Clinical Development of Ruxolitinib in Myeloproliferative Neoplasms.

Ruxolitinib, a JAK1 and JAK2 inhibitor drug, has recently been approved for the treatment of patients with high- or intermediate-risk myelofibrosis with symptomatic splenomegaly. Ruxolitinib is the first clinically useful targeted therapy in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The aim of this paper is to indicate pharmacobiological aspects of ruxolitinib within the potential context of MPNs. Pharmacobiological assessments, in addition to knowledge of the risk profile for ruxolitinib in MPNs, are required. We propose hypotheses based on our experience in a splenectomized MPN patient with hyperproliferative bone marrow and moderate fibrosis receiving ruxolitinib. We believe that a true clinical development approach for this drug should include pharmacobiological assessments for ruxolitinib in addition to the disease risk profile of MPNs.

High frequency of autonomous T-cell proliferation compatible with T-cell large granular lymphocytic leukemia in patients with cytopenia of unknown etiology.

Large granular lymphocytic leukemia/lymphoproliferative disorder (LGL-L/LPD) is a heterogeneous neoplastic disease of large granular lymphocytes and is a well-known cause of cytopenias. We aimed to reveal the incidence of LGL-L/LPD in patients with cytopenia(s) of unknown etiology (CUE). Twenty-eight patients with CUE were investigated for LGL-L/LPD. T-cell LGL leukemia (LGL-L) was diagnosed in 12 (42.9 %) patients. The frequencies of LGL-L in patients who had anemia, neutropenia, and thrombocytopenia were 9/14 (64.2 %), 11/23 (47.8 %), and 3/10 (30 %), respectively. Seventeen of the 28 patients met the criteria of idiopathic cytopenia of undetermined significance (ICUS), and LGL-L was found in six (35.3 %) of them. We conclude that LGL-L is a rather common disease in patients with CUE and ICUS. It should be considered in this patient group and investigated thoroughly.

Clinical and pathological correlations of marrow PUMA and P53 expressions in myelodysplastic syndromes.

p53 is a key regulator of apoptosis. p53 upregulated modulator of apoptosis (PUMA) is a critical mediator of p53-dependent and independent apoptosis. The objective of this study was to evaluate the relationship of p53 and PUMA to the prognosis of MDS. Bone marrow biopsies of MDS patients at the time of diagnosis (n = 76) and at the time of transformation (n = 19) were included in the study group. The expression of p53 and PUMA was evaluated using immunohistochemistry. When compared to the control group, both p53 (p < 0.001) and PUMA (p = 0.012) expression levels were significantly higher in MDS group. In MDS group, there was a moderate positive correlation between p53 and PUMA expressions. PUMA expression was not correlated with event free and overall survival. However, overall survival was significantly lower in cases with p53 expression in more than 50% of the cells. There was an increase in PUMA expression in cases that showed transformation as compared to the initial diagnostic bone marrows but was not statistically significant. The correlation that existed between p53 and PUMA was lost in transformed cases. Our results showed that PUMA and p53 expressions are increased in MDS marrows compared to normal marrows. PUMA expression increases further during transformation while the expression of p53 is not significantly altered which suggests that PUMA alterations might be a late event during the evolution of MDS.

Rebound Thrombocytosis following Induction Chemotherapy is an Independent Predictor of a Good Prognosis in Acute Myeloid Leukemia Patients Attaining First Complete Remission.

There are very few data about the relationship between acute myeloid leukemia (AML) prognosis and bone marrow recovery kinetics following chemotherapy. In this study, we aimed to assess the prognostic importance and clinical associations of neutrophil and platelet recovery rates and rebound thrombocytosis (RT) or neutrophilia (RN) in the postchemotherapy period for newly diagnosed AML patients. De novo AML patients diagnosed between October 2002 and December 2013 were evaluated retrospectively. One hundred patients were suitable for inclusion. Cox regression analysis using need for reinduction chemotherapy as a stratification parameter revealed RT as the only parameter predictive of OS, with borderline statistical significance (p = 0.06, OR = 7; 95% CI 0.92-53), and it was the only parameter predictive of DFS (p = 0.024, OR = 10; 95% CI 1.3-75). In order to understand whether RT or RN was related to a better marrow capacity or late consolidation, we considered neutrophil recovery time and platelet recovery time and nadir-first consolidation durations in all patients in the cohort. Both the marrow recovery duration and the time between marrow aplasia and first consolidation were shorter in RT and RN patients. To our knowledge, this is the first study to report a correlation between RT/RN and prognosis in AML.

Potassium abnormalities in current clinical practice: frequency, causes, severity and management.

OBJECTIVE: We aimed to investigate the prevalence and etiology of potassium abnormalities (hypokalemia and hyperkalemia) and management approaches for hospitalized patients. SUBJECTS AND METHODS: Over a 4-month period, all hospitalized patients at Hacettepe University Medical Faculty Hospitals who underwent at least one measurement of serum potassium during hospitalization were included. Data on serum levels of electrolytes, demographic characteristics, cause(s) of hospitalization, medications, etiology of potassium abnormality and treatment approaches were obtained from the hospital records. RESULTS: Of the 9,045 hospitalized patients, 1,265 (14.0%) had a serum potassium abnormality; 604 (6.7%) patients had hypokalemia and 661 (7.30%) had hyperkalemia. In the hypokalemic patients, the most important reasons were gastrointestinal losses in 555 (91.8%) patients and renal losses in 252 (41.7%) patients. The most frequent treatment strategies were correcting the underlying cause and replacing the potassium deficit. Of the 604 hypokalemic patients, 319 (52.8%) were normokalemic at hospital discharge. The most common reason for hyperkalemia was treatment with renin-angiotensin-aldosterone system blockers in 228 (34.4%) patients, followed by renal failure in 191 (28.8%). Two hundred and ninety-eight (45.0%) patients were followed without any specific treatment. Of the 661 hyperkalemic patients, 324 (49.0%) were normokalemic at hospital discharge. CONCLUSION: This study showed a high prevalence of potassium imbalance among hospitalized patients. Although most of the potassium abnormalities were mild/moderate, approximately half of the patients treated for hypokalemia or hyperkalemia were discharged from the hospital with ongoing dyskalemia.

Clinicopathological associations of acquired erythroblastopenia.

INTRODUCTION: Acquired erythroblastopenia (AE) is a rare clinical situation. It is characterized by the reduction of erythroid precursors in the bone marrow together with the low reticulocyte counts in the peripheral blood. BACKGROUND: Main secondary causes of AE are drugs, Parvovirus B19 and other infectious reasons, lymphoid and myeloid neoplasia, autoimmune diseases, thymoma and pregnancy. The aim of this study is to assess the frequencies and clinical associations of AE via analyzing 12340 bone marrow samples in a retrospective manner. MATERIAL AND METHOD: Bone marrow aspirations which were obtained from patients who applied to Hacettepe University Hematology Clinic between 2002 and 2013, were analyzed retrospectively. RESULTS: Thirty four erythroblastopenia cases were found. Patients ranged in age from 16 to 80 years with a median of 38 years. Fifteen patients were men (44%) and nineteen were women (56%). In these patients, detected causes of erythroblastopenia were MDS, idiopathic pure red cell aplasia (PRCA), parvovirus infection, post chemotherapy aplasia, plasma proliferative diseases, copper deficiency due to secondary amyloidosis, fever of unknown origin, hemophagocytic syndrome, enteric fever and legionella pneumonia. We found that between those reasons the most common causes of erythroblastopenia are MDS (17.7%) and idiopathic PRCA (17.7%). DISCUSSION: As a result, erythroblastopenia in the bone marrow may be an early sign of MDS. In those AE cases possibility of being MDS must be kept in mind as it can be mistaken for PRCA. CONCLUSION: To conclude, in adults MDS without excess blast is one of the most common causes of erythroblastopenia in clinical practice and in case of erythroblastopenia the presence of MDS should be investigated.

The factors affecting early death after the initial therapy of acute myeloid leukemia.

There are some improvements in management of acute myeloid leukemia (AML). However, induction-induced deaths still remain as a major problem. The aim of this study is to assess clinical parameters affecting early death in patients with AML. 199 AML patients, who were treated with intensive, non-intensive or supportive treatment between 2002 and 2014 in Hacettepe Hematology Department, were analyzed retrospectively. In our study early death rate for elderly was found to be lower than previous reports whereas it was similar for those who were under age of 60. Better ECOG performance (ECOG performance score 0 and 1) and non-intensive treatment associated with lower early death rates, however APL-type disease associated with higher early death rates. ECOG performance score at diagnosis was found to be the most related independent factor with higher rate of early death in 15 days after treatment (P<0.001). Therefore we decided to understand the factors which were related with ECOG. WBC count at diagnosis was found to be the only related parameter with ECOG performance score. Leucocyte count at diagnosis appears like to have an indirect effect on early death in AML patients. It maybe suggested that in recent years there is an improvement in early death rates of elderly AML patients. The currently reported findings require prospective validation and would encourage the incorporation of other next generation genomics for the prediction of early death and overall risk status of AML.

Bone marrow fibrosis may be an effective independent predictor of the 'TKI drug response level' in chronic myeloid leukemia.

OBJECTIVES: The aim of this study was to assess bone marrow (BM) fibrosis and dysplasia in chronic myeloid leukemia (CML) patients receiving the first-generation tyrosine kinase inhibitor (TKI), imatinib, or second-generation TKIs, dasatinib, and nilotinib. We further investigated whether CML under TKI is associated with dysplastic BM changes during the clinicopathological course of the disease. METHODS: In total, pre-treatment BM paraffin blocks of biopsy specimens were available for 41 adult patients diagnosed with chronic phase CML. Post-treatment BM aspirate clot and core biopsy samples were reviewed for fibrosis and dyshematopoiesis. RESULTS: Overall, 13 (31.7%) patients achieved a complete cytogenetic response with imatinib treatment, with no events. In 25 patients, imatinib was discontinued owing to primary or secondary resistance. In patients with initial dysmyelopoiesis, the rate of BM fibrosis was 82.4 versus 47.6% for other patient groups (P = 0.02). Overall, 24 patients with newly diagnosed CML showed marrow fibrosis, among which 19 (79.1%) had imatinib resistance. However, only 5 out of 15 patients (33.5%) without marrow fibrosis had imatinib resistance (P = 0.08). Discussion Our findings indicate that BM fibrosis is an independent predictor of the 'TKI drug response level' in CML and support its inclusion as a critical pathobiological parameter for decision-making with regard to TKI drug selection de novo, calculation of prognosis at the onset of disease, and monitoring response to TKI in the long-term disease course of CML.

Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic hematopoietic stem cell transplantation for acute leukemia patients: a single center experience.

Due to the high transplant related morbidity and mortality (TRM), relatively younger acute leukemia patients that have a good performance status and no comorbidity are eligible for myeloablative conditioning (MAC) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcomes of 84 consecutive adult patients with ALL (n=38) or AML (n=46) who underwent allo-HSCT from their HLA-identical siblings were evaluated retrospectively. The median age at transplantation was 34 (17-58 years) for the whole patient population. Of these, 24 patients received a MAC and 60 patients received a fludarabine-based reduced intensity conditioning regimen (RIC). After a median follow-up of 32 months (range, 1-119), for the entire group, the 3-year estimated overall survival (OS) was 57.5% and the disease-free survival (DFS) was 51.5%. The OS for ALL and AML patients were 53.9% vs 62.1%: and DFS were 50.5% and 53.4%, respectively. The 3-year estimated OS for RIC and MAC patients were 63.2% and 41.7%; and DFS were 57.1% and 34.7%, respectively. In ALL patients, conditioning regimens (RIC vs MAC) led to similar OS and DFS; however, in AML patients both OS (70.1% vs 21.4%) and DFS (59.3% vs 42.9%) were found to be higher in RIC patients compared to MAC recipients. Overall, the TRM at day 100 was 1.7% and has increased up to 5.1% at 1st year. In multivariate analysis, the diagnosis (p=0.03) and RIC regimen (p=0.027) were the prognostic variables for prolonged OS in all patients; and RIC regimen (p=0.031) was the only prognostic factor for prolonged OS in AML patients. The first complete remission (CR1) was correlated with a prolonged DFS as an independent variable for all patients (p=0.09). Eleven of the RIC patients (18.3%) and 6 of the MAC patients (25%) developed acute graft-versus-host disease (GvHD). Seventeen of the RIC patients (33.3%) and 4 of the MAC patients (16.7%) developed chronic GvHD. In conclusion, RIC conditioning regimens may provide a longer OS and DFS, especially in patients with AML who are in first CR, not eligible for MAC conditioning.

EUTOS CML prognostic scoring system predicts ELN-based 'event-free survival' better than Euro/Hasford and Sokal systems in CML patients receiving front-line imatinib mesylate.

OBJECTIVES: The validity of the three currently used chronic myeloid leukemia (CML) scoring systems (Sokal CML prognostic scoring system, Euro/Hasford CML scoring system, and the EUTOS CML prognostic scoring system) were compared in the CML patients receiving frontline imatinib mesylate. PATIENTS AND METHODS: One hundred and fourty-three chronic phase CML patients (71 males, 72 females) taking imatinib as frontline treatment were included in the study. The median age was 44 (16-82) years. Median total and on-imatinib follow-up durations were 29 (3.8-130) months and 25 (3-125) months, respectively. RESULTS: The complete hematological response (CHR) rate at 3 months was 95%. The best cumulative complete cytogenetic response (CCyR) rate at 24 months was 79.6%. Euro/Hasford scoring system was well-correlated with both Sokal and EUTOS scores (r = 0.6, P < 0.001 and r = 0.455, P < 0.001). However, there was only a weak correlation between Sokal and EUTOS scores (r = 0.2, P = 0.03). The 5-year median estimated event-free survival for low and high EUTOS risk patients were 62.6 (25.7-99.5) and 15.3 (7.4-23.2) months, respectively (P < 0.001). This performance was better than Sokal (P = 0.3) and Euro/Hasford (P = 0.04) scoring systems. Overall survival and CCyR rates were also better predicted by the EUTOS score. DISCUSSION: EUTOS CML prognostic scoring system, which is the only prognostic system developed during the imatinib era, predicts European LeukemiaNet (ELN)-based event-free survival better than Euro/Hasford and Sokal systems in CML patients receiving frontline imatinib mesylate. This observation might have important clinical implications.