Thanawat Rattanathammethee

Clinical Manifestations and Risk Factors for Complications of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

BACKGROUND Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid lineages. Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical Philadelphia chromosome (Ph)-negative MPN that have a Janus Kinase 2 (JAK2) mutation, especially JAK2V617F in the majority of patients. The major complications of Ph-negative MPNs are thrombosis, hemorrhage, and leukemic transformation. OBJECTIVE To study clinical manifestations including symptoms, signs, laboratory findings, and JAK2V617F mutations of Ph-negative MPN (PV, ET and PMF) as well as their complications. MATERIALS AND METHODS All Ph-negative MPN (PV, ET and PMF) patients who attended the Hematology Clinic at Maharaj Nakorn Chiang Mai Hospital from January, 1 2003 through December, 31 2013 were retrospectively reviewed for demographic data, clinical characteristics, complete blood count, JAK2V617F mutation analysis, treatment, and complications. RESULTS One hundred and fifty seven patients were included in the study. They were classified as PV, ET and PMF for 68, 83 and 6 with median ages of 60, 61, and 68 years, respectively. JAK2V617F mutations were detected in 88%, 69%, and 100% of PV, ET and PMF patients. PV had the highest incidence of thrombosis (PV 29%, ET 14%, and PMF 0%) that occurred in both arterial and venous sites whereas PMF had the highest incidence of bleeding (PMF 17%, ET 11%, and PV 7%). During follow up, there was one ET patient that transformed to acute leukemia and five cases that developed thrombosis (three ET and two PV patients). No secondary myelofibrosis and death cases were encountered. CONCLUSIONS Ph-negative MPNs have various clinical manifestations. JAK2V617F mutations are present in the majority of PV, ET, and PMF patients. This study confirmed that thrombosis and bleeding are the most significant complications in patients with Ph-negative MPN.

Clinical characteristics and long-term outcomes of warm-type autoimmune hemolytic anemia

Objectives: To study the clinical manifestations, outcomes, and survival of warm-type autoimmune hemolytic anemia (AIHA) patients. Methods: This study was a retrospective single-center study from 2002 to 2013. Clinical data of AIHA patients were reviewed and analyzed. Results: One hundred and one patients were included, of whom 77% were female with a median age of 43 years. Primary AIHA was found in 61% of the patients. The secondary causes were systemic lupus erythematosus (SLE) (64%), solid malignancies (13%), lymphomas (10%), drugs (8%), and infections (5%). Most patients (96%) responded to steroids, which were not different between primary and secondary AIHA. Second-line treatments were required in 33 patients (33%). The indications were steroid dependence (58%), relapse (30%), and others (12%). The most common second-line treatment was cyclophosphamide (52%). The response rate for second-line treatments was 93%. Relapse occurred in 50 patients (50%) in which 58% occurred more than 3 years after diagnosis. The SLE patients relapsed and received second-line therapy more than the non-SLE group (P < 0.001). At the median 53-month follow-up, the overall survival (OS) was 84%. The independent risk factors for OS were age more than 50 years and malignancy. Sepsis was the most common cause of death. Discussion and conclusion: AIHA has a good prognosis and long-term survival especially in young patients without malignancy. Most patients have responded initially to steroids and have a high response rate to second-line therapy. Carefully adjusted and rapid taper of immunosuppressant is necessary to avoid sepsis complications.

Acute Non-Atherosclerotic ST-Segment Elevation Myocardial Infarction in an Adolescent with Concurrent Hemoglobin H-Constant Spring Disease and Polycythemia Vera.

Thrombosis is a major complication of polycythemia vera (PV) and also a well-known complication of thalassemia. We reported a case of non-atherosclerotic ST-segment elevation myocardial infarction (STEMI) in a 17-year-old man with concurrent post-splenectomized hemoglobin H-Constant Spring disease and JAK2 V617F mutation-positive PV. The patient initially presented with extreme thrombocytosis (platelet counts greater than 1,000,000/µL) and three months later developed an acute STEMI. Coronary artery angiography revealed an acute clot in the right coronary artery without atherosclerotic plaque. He was treated with plateletpheresis, hydroxyurea and antiplatelet agents. The platelet count decreased and his symptoms improved. This case represents the importance of early diagnosis, awareness of the increased risk for thrombotic complications, and early treatment of PV in patients who have underlying thalassemia with marked thrombocytosis.

Prevalence and Risk Factors for Complications in Patients with Nontransfusion Dependent Alpha- and Beta-Thalassemia

Background. Nontransfusion dependent thalassemia (NTDT) is a milder form of thalassemia that does not require regular transfusion. It is associated with many complications, which differ from that found in transfusion-dependent thalassemia (TDT). Currently available information is mostly derived from beta-NTDT; consequently, more data is needed to describe complications found in the alpha-NTDT form of this disease. Methods. We retrospectively reviewed the medical records of NTDT patients from January 2012 to December 2013. Complications related to thalassemia were reviewed and compared. Results. One hundred patients included 60 females with a median age of 38 years. The majority (54 patients) had alpha-thalassemia. Overall, 83 patients had one or more complications. The three most common complications were cholelithiasis (35%), abnormal liver function (29%), and extramedullary hematopoiesis (EMH) (25%). EMH, cardiomyopathy, cholelithiasis, and pulmonary hypertension were more commonly seen in beta-thalassemia. Osteoporosis was the only complication that was more common in alpha-thalassemia. The risk factors significantly related to EMH were beta-thalassemia type and hemoglobin < 8 g/dL. The risk factors related to osteoporosis were female gender and age > 40 years. Iron overload (ferritin > 800 ng/mL) was the only risk factor for abnormal liver function. Conclusion. The prevalence of alpha-NTDT complications was lower and different from beta-thalassemia.

Diagnosis and Monitoring of Chronic Myeloid Leukemia: Chiang Mai University Experience

BACKGROUND A diagnosis of chronic myeloid leukemia (CML) is made on discovery of the presence of a Philadelphia (Ph) chromosome. The success of the treatment of this form of leukemia with tyrosine kinase inhibitor (TKI) is monitored by reduction of the Ph chromosome. OBJECTIVE To compare the role of conventional cytogenetic (CC) methods with a real time quantitative polymerase chain reaction (RQ-PCR) and fluorescence in situ hybridization (FISH) for diagnosis and treatment monitoring of CML patients. The secondary outcome was to analyze the treatment responses to TKI in CML patients. MATERIALS AND METHODS This was a retrospective study of CML patients who attended the Hematology clinic at Chiang Mai University Hospital from 2005-2010. Medical records were reviewed for demographic data, risk score, treatment response and the results of CC methods, FISH and RQ-PCR. RESULTS One hundred and twenty three cases were included in the study, 57.7% of whom were male with a mean age of 46.9 years. Most of the patients registered as intermediate to high risk on the Sokal score. At diagnosis, 121 patients were tested using the CC method and 118 (95.9%) were identified as positive. Five patients failed to be diagnosed by CC methods but were positive for BCR-ABL1 using the FISH method. Imatinib was the first-line treatment used in 120 patients (97.6%). In most patients (108 out of 122, 88.5%), a complete cytogenetic response (CCyR) was achieved after TKI therapy and in 86 patients (70.5%) CCyR was achieved long term by the CC method. Five out of the 35 analyzed patients in which CCyR was achieved by the CC method had a positive FISH result. Out of the 76 patients in which CCyR was achieved, RQ-PCR classified patients to only CCyR in 17 patients (22.4%) with a deeper major molecular response (MMR) in 4 patients (5.3%) and complete molecular response (CMR) in 55 patients (72.4%). In the case of initial therapy, CCyR was achieved in 95 patients (79.1%) who received imatinib and in both patients who received dasatinib (100%). For the second line treatment, nilotinib were used in 30 patients and in 19 of them (63.3%) CCyR was achieved. In half of the 6 patients (50%) who received dasatinib as second line or third line treatment CCyR was also achieved. CONCLUSIONS CML patients had a good response to TKI treatment. FISH could be useful for diagnosis in cases where CC analysis failed to detect the Ph chromosome. RQ-PCR was helpful in detecting any residual disease and determining the depth of the treatment response at levels greater than the CC methods.

The role of red cell distribution width in the differential diagnosis of iron deficiency anemia and non-transfusion dependent thalassemia patients

This study aims to find the cut-off value and diagnostic accuracy of the use of RDW as initial investigation in enabling the differentiation between IDA and NTDT patients. Patients with microcytic anemia were enrolled in the training set and used to plot a receiving operating characteristics (ROC) curve to obtain the cut-off value of RDW. A second set of patients were included in the validation set and used to analyze the diagnostic accuracy. We recruited 94 IDA and 64 NTDT patients into the training set. The area under the curve of the ROC in the training set was 0.803. The best cut-off value of RDW in the diagnosis of NTDT was >21.0% with a sensitivity and specificity of 81.3% and 55.3% respectively. In the validation set, there were 34 IDA and 58 NTDT patients using the cut-off value of 21.0% to validate. The sensitivity, specificity, positive predictive value and negative predictive value were 84.5%, 70.6%, 83.1% and 72.7% respectively. We can therefore conclude that RDW >21.0% is useful in differentiating between IDA and NTDT patients with high diagnostic accuracy.

Calreticulin mutation analysis in non-mutated Janus kinase 2 essential thrombocythemia patients in Chiang Mai University: analysis of three methods and clinical correlations

ABSTRACT Objectives: The primary objective was to determine the prevalence of calreticulin (CALR) mutation in patients with non-JAK2V617F mutated essential thrombocythemia (ET). The secondary objectives were to evaluate the accuracy of CALR mutation analysis by high-resolution melting (HRM) analysis and real-time polymerase chain reaction (PCR) compared with DNA sequencing and to compare clinical characteristics of CALR mutated and JAK2V617F mutated ET. Methods: This was a prospective cohort study involving ET patients registered at Chiang Mai University in the period September 2015–September 2017 who were aged more than 2 years, and did not harbor JAK2V617F mutation. The presence of CALR mutation was established by DNA sequencing, HRM, and real-time PCR for type 1 and type 2 mutation. Clinical data were compared with that from ET patients with mutated JAK2V617F. Results: Twenty-eight patients were enrolled onto the study. CALR mutations were found in 10 patients (35.7%). Three patients had type 1 mutation, 5 patients had type 2 mutation, 1 patient had type 18 mutation, and 1 patients had novel mutations (c.1093 C–G, c.1098_1131 del, c.1135 G–A). HRM could differentiate between the types of mutation in complete agreement with DNA sequencing. Patients with a CALR mutation showed a significantly greater male predominance and had a higher platelet count when compared with 42 JAK2V617F patients. Discussion and Conclusions: The prevalence of CALR mutation in JAK2V617F-negative ET in this study is 35.7%. HRM is an effective method of detecting CALR mutation and is a more advantageous method of screening for CALR mutation.

The efficacy of colchicine and dapsone combination therapy in relapsed immune thrombocytopenia

The aim of the present paper is to evaluate the efficacy and safety of colchicine and dapsone combination therapy in cases of steroid-dependent, relapsed and refractory immune thrombocytopenia (ITP). This is a retrospective study of ITP patients who attended the Hematology Clinic at Chiang Mai University Hospital (Thailand) from 1 January 2008 to 30 September 2014. Medical records and clinical data were reviewed for efficacy and adverse effects. Sixty-four ITP patients received the combination therapy. The median age was 46 years and 70.3% were female. The majority (65.6%) were relapsed ITP patients. Median platelet count before starting treatment was 22.6×109/L. The response rate was 82.8%, with 75.0% of patients having a complete response. Median time to response was 8 weeks. The response rate was higher in relapsed patients (90.4%) compared to refractory (61.5%) and steroid-dependent patients (77.8%). Steroid treatment was discontinued in 30 patients (50%) following combination therapy. The most common side effect was hemolysis due to dapsone which was found in eight patients (12.5%). We can therefore conclude that combination therapy with colchicine and dapsone is an alternative second-line therapy option in relapsed ITP cases with acceptable side effects.

Peripheral Artery Occlusive Disease Among Patients With Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitors: A Cross-Sectional Case-Control Study

Background: There were some reports of peripheral artery occlusive disease (PAOD) associated with nilotinib usage in chronic myeloid leukemia (CML). These complications in other tyrosine kinase inhibitors are revealed as unknown. Materials and methods: We determined the prevalence of PAOD in patients with CML as compared with matched-control population by cross-sectional case-control study. Peripheral artery occlusive disease was screened by ankle-brachial index (ABI). Results: In total, 78 CML and 156 matched-control patients were included. The median age was 55 years. In all, 61 (78.2%) were on imatinib and 13 (16.7%) were on nilotinib, whereas 4 patients (5.2%) were on dasatinib. Prevalence of low ABI (<0.9) was 9.0%, and nilotinib users had the highest prevalence of low ABI of 30.7%. All cases with low ABI were not shown to be clinically overt of PAOD. There were well-balanced characteristics between cases of CML and matched control except in higher levels of hypercholesterolemia in the control. Interestingly, CML had more amounts of pathologic ABI than the control (odds ratio: 2.09, 95% confidence interval: 0.71-6.21), and diagnosis of diabetes found it to be independent of the risk of PAOD. Conclusions: Peripheral artery occlusive disease was higher among patients with CML than the control, especially in patients who had diabetes.

Acquired hemophilia A in the HIV-infected patient: a case report and literature review.

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Spontaneous bleeding in the various sites and severity is the most common clinical presentation. Here, we report a 74-year-old Thai woman with HIV infection who presented with spontaneous ecchymoses. The laboratory revealed isolated activated partial thromboplastin time prolongation with low FVIII activity and a presence of FVIII inhibitor. She was diagnosed with acquired hemophilia A. Corticosteroid monotherapy was the treatment regimen for inhibitor eradication. We demonstrate the clinical course of the rare condition and review the relevant literature.