ABSTRACT
Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch's T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted.
Subject(s)
Janus Kinase 2 , Neutrophils , Polycythemia Vera , Thrombocythemia, Essential , Thrombosis , Humans , Thrombosis/etiology , Thrombosis/blood , Female , Male , Middle Aged , Janus Kinase 2/genetics , Aged , Retrospective Studies , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Polycythemia Vera/blood , Polycythemia Vera/complications , Polycythemia Vera/genetics , Adult , Myeloproliferative Disorders/blood , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/genetics , Leukocyte Count , Predictive Value of Tests , Aged, 80 and overABSTRACT
Chronic neutrophilic leukemia (CNL) is a clonal disorder that is characterized by increasing mature neutrophils. Colony stimulating factor 3 receptor (CSF3R) T618I mutation was frequently identified in patients with CNL and is defined as a molecular marker of the disease. Ruxolitinib, a JAK2 inhibitor, provided a promising therapeutic effect in a phase II study. In particular, ruxolitinib was more efficient for patients with CSF3R mutation. Allogeneic stem cell transplantation (Allo-SCT) may be a curative treatment for CNL. On the other hand, further studies are needed to define the optimal method of transplantation, source of donor, conditioning therapy, and timing of transplantation. Chronic eosinophilic leukemia (CEL) is a clonal disorder that is characterized by increasing eosinophils. In the World Health Organization Classification 5th edition, diagnostic criteria for CEL are renewed. Because the new criteria will be more specific for CEL than criteria in the older edition, "not otherwise specified (NOS) " is removed from the name of the disease. Anti-CD52 antibody, alemtuzumab, or anti-IL-5 antibody, mepolizumab, are promising drugs to control symptoms that are associated with hypereosinophilic syndrome. Allo-SCT is anticipated as a curative treatment for CEL, but the evidence of Allo-SCT for CEL is still limited. Further study is required to define the treatment strategy.
Subject(s)
Hypereosinophilic Syndrome , Leukemia, Myeloid , Leukemia, Neutrophilic, Chronic , Humans , Leukemia, Neutrophilic, Chronic/genetics , Leukemia, Neutrophilic, Chronic/therapy , Leukemia, Neutrophilic, Chronic/complications , Mutation , Hypereosinophilic Syndrome/diagnosis , Hypereosinophilic Syndrome/therapy , Hypereosinophilic Syndrome/complications , Leukemia, Myeloid/complicationsABSTRACT
Hypokalemia is common in allogeneic hematopoietic stem cell transplantation (allo-HCT) patients and is associated with non-relapse mortality (NRM). Therefore, it is extremely important to replace potassium adequately. We evaluated the safety and efficacy of potassium replacement therapy by retrospectively analyzing the incidence and severity of hypokalemia in 75 patients who received allo-HCT at our institution. 75% of patients developed hypokalemia during the allo-HSCT, and 44% of patients had grade 3-4 levels of hypokalemia. NRM was significantly higher in patients with grade 3-4 hypokalemia than in patients without severe hypokalemia (one-year NRM: 30% vs 7%, p=0.008). Although 75% of the patients required potassium replacement that exceeded the range of potassium chloride solutions package inserts in Japan, we did not experience any adverse events associated with hyperkalemia. Our current observations suggested that the Japanese package insert for potassium solution injection should be revised for potassium needs.
Subject(s)
Hematopoietic Stem Cell Transplantation , Hypokalemia , Humans , Retrospective Studies , Potassium , Hypokalemia/etiology , Transplantation, Homologous/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effectsABSTRACT
BACKGROUND: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is increasingly applied to the diagnosis of bone marrow failure such as myeloproliferative neoplasm, aplastic anemia, and myelodysplastic syndrome, as well as malignant lymphoma and multiple myeloma. However, few studies have shown a normal FDG uptake pattern. This study aimed to establish a standard of bone marrow FDG uptake by a reproducible quantitative method with fewer steps using deep learning-based organ segmentation. METHODS: Bone marrow PET images were obtained using segmented whole-spine and pelvic bone marrow cavity CT as mask images using a commercially available imaging workstation that implemented an automatic organ segmentation algorithm based on deep learning. The correlation between clinical indicators and quantitative PET parameters, including histogram features, was evaluated. RESULTS: A total of 98 healthy adults were analyzed. The volume of bone marrow PET extracted in men was significantly higher than that in women (p < 0.0001). Univariate and multivariate regression analyses showed that mean of standardized uptake value corrected by lean body mass (SULmean) and entropy in both men and women were inversely correlated with age (all p < 0.0001), and SULmax in women were also inversely correlated with age (p = 0.011). CONCLUSION: A normal FDG uptake pattern was demonstrated by simplified FDG PET/CT bone marrow quantification.
Subject(s)
Bone Marrow , Fluorodeoxyglucose F18 , Adult , Bone Marrow/diagnostic imaging , Bone Marrow/pathology , Female , Humans , Male , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography/methods , Radiopharmaceuticals , Retrospective StudiesABSTRACT
After the discovery of driver mutations for myeloproliferative neoplasms (MPN), treatment approach for the disease has achieved tremendous progress. Ruxolitinib, a JAK inhibitor, is now widely used for both patients with myelofibrosis and polycythemia vera in several countries, including Japan. Fedratinib, another JAK inhibitor, has been recently approved in the United States. One of the biggest limitations of treatment with JAK inhibitors is the relatively small proportion of patients who achieve a complete molecular response. Furthermore, most of the patients with myelofibrosis had to discontinue the treatment due to drug-related adverse events or disease progression. Therefore, MPN treatment is still at an early and challenging stage, thereby highlighting the urgent need for establishment of a new and more effective therapeutic strategy. One of the promising candidates for MPN treatment is the use of interferons. Modern forms of interferons demonstrate not only a good hematological response but also a deep molecular response, eradicating abnormal MPN clones harboring driver mutations. A number of new agents targeting molecules outside of the JAK-STAT pathway, PI3kinase, NF-kB, or Bcl-2 family of anti-apoptotic proteins are also being considered and tested in clinical studies as single-agent therapies or in combination with JAK inhibitors.
Subject(s)
Janus Kinase Inhibitors , Myeloproliferative Disorders , Polycythemia Vera , Primary Myelofibrosis , Humans , Janus Kinase 2 , Japan , Protein Kinase InhibitorsABSTRACT
Post-transplant lymphoproliferative disorder (PTLD) usually develops with systemic symptoms, such as fever, generalized lymphadenopathy, and elevation in the lactate dehydrogenase level. Here, we present the case of a 65-year-old female patient with PTLD localized to the colon; the patient only had mild diarrhea without systemic symptoms. She had myelodysplastic syndrome and was treated with cord blood transplantation (CBT). She had a past medical history of sigmoid colon cancer treated with colonosectomy and adjuvant chemotherapy. After CBT, she achieved complete remission and was discharged after 60 days. Further, 79 days after CBT, she presented with abdominal pain. Computed tomography scan revealed adhesive ileus. The abdominal pain was resolved in 1 day with conservative treatment, however, mild diarrhea persisted. Therefore, we performed colonoscopy and found multiple ulcerative lesions in the upper colon. A pathological examination revealed PTLD. Furthermore, elevation of EBV-DNA in the blood was also confirmed. There was no detectable lesion on positron emission tomography-computed tomography (PET-CT) outside the colon; thus, we diagnosed PTLD localized into the colon that was successfully treated with rituximab. Our present experience suggests that it might be important to perform endoscopy and monitoring of EBV-DNA for early detection of PTLD, especially localized in the gastrointestinal tract.
Subject(s)
Cord Blood Stem Cell Transplantation , Epstein-Barr Virus Infections , Lymphoproliferative Disorders , Aged , Colon , Cord Blood Stem Cell Transplantation/adverse effects , Diarrhea/etiology , Diarrhea/therapy , Early Detection of Cancer , Epstein-Barr Virus Infections/complications , Female , Humans , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/therapy , Positron Emission Tomography Computed TomographyABSTRACT
Monoclonal B-cell lymphocytosis (MBL) is an early or precursor asymptomatic proliferation of chronic lymphocytic lymphoma (CLL)-like B-cells. Lymphoplasmacytic lymphoma (LPL), often clinically associated with Waldenström macroglobulinemia, is a B-cell neoplasm characterized by frequent MYD88 L265P mutation. Here, we report a rare composite MBL and LPL in a patient with IgM light chain (AL) amyloidosis. A 74-year-old male with a known IgM monoclonal protein developed proteinuria. No lymphocytosis was detected. Renal biopsy showed deposition of AL λ amyloid in the glomeruli and vessels. Subsequent bone marrow biopsy revealed nodular atypical CLL-like small B-cell proliferation and scattered peripheral LPL. Immunohistochemistry and/or flow cytometry revealed that the atypical CLL-like population expressed CD19, CD20, CD5, weak CD23, LEF-1 and diminished surface Igκ. The LPL was positive for CD19, CD20 and surface Igλ. Using laser-capture microdissection and allele-specific polymerase chain reaction, we confirmed that MYD88 L265P was detectable in the LPL but not in the atypical CLL-like population. Thus, we demonstrated that these two populations were clonally independent, and made the diagnosis of composite MBL and LPL. An integrated clinical, pathological, immunophenotypic and genetic assessment is essential in such complicated cases, and especially 'clone-specific' MYD88 genotyping may facilitate the differential diagnoses of low-grade B-cell lymphomas.
Subject(s)
Amyloidosis/complications , B-Lymphocytes/pathology , Lymphocytosis/complications , Precancerous Conditions/complications , Waldenstrom Macroglobulinemia/complications , Aged , Amyloidosis/pathology , Clone Cells/pathology , Humans , Lymphocytosis/pathology , Male , Myeloid Differentiation Factor 88/genetics , Precancerous Conditions/pathology , Waldenstrom Macroglobulinemia/genetics , Waldenstrom Macroglobulinemia/pathologyABSTRACT
Hydroxycarbamide is a widely used cytoreductive agent for treating polycythemia vera and essential thrombocythemia. Although hydroxycarbamide is usually well tolerated by most patients for long periods, some patients experience mucosal or cutaneous adverse events. Furthermore, a series of case report have indicated an association of hydroxycarbamide use with the development of non-melanoma skin cancer, especially in western countries. Here, we present the case of an elderly Japanese polycythemia vera patient who developed squamous cell carcinoma of the skin on the scalp after 10 years of exposure to hydroxyurea.
Subject(s)
Carcinoma, Squamous Cell , Polycythemia Vera , Thrombocythemia, Essential , Aged , Carcinoma, Squamous Cell/chemically induced , Humans , Hydroxyurea/adverse effects , Polycythemia Vera/drug therapy , Scalp , Thrombocythemia, Essential/drug therapyABSTRACT
Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with immunological abnormalities, such as hypergammaglobulinemia, autoimmune cytopenia, and the presence of various autoantibodies. Few reports on AITL have also described the development of myelofibrosis resulting from the invasion of lymphoma cells that produced various cytokines, including TGF-ß. Interestingly, recent studies demonstrated that autoimmunity can directly cause autoimmune myelofibrosis (AIMF). Usually, bone marrow fibrosis associated with AIMF is rapidly improved by treatment. Here, we describe our experience with a case of AITL complicated with the presence of numerous autoimmune abnormalities, including positive Coombs, anti-nuclear antibody, anti-ds-DNA antibody, anti-phospholipid antibody, and cold agglutinin tests. The patient presented with severe bone marrow fibrosis (MF-3) at the initial diagnosis. After two courses of the CHASE therapy, myelofibrosis rapidly disappeared, and the autoimmune abnormalities were ameliorated. These findings suggest that the bone marrow fibrosis observed in this case was partly attributable to an AIMF-like mechanism.
Subject(s)
Immunoblastic Lymphadenopathy , Lymphoma, T-Cell , Primary Myelofibrosis , Autoantibodies , Fibrosis , HumansABSTRACT
The 8p11 myeloproliferative syndrome (EMS) is a relatively rare hematological malignancy defined by the presence of chromosomal abnormalities associated with fibroblast growth factor-1 gene, located in the 8p11-12.1 chromosomal locus. To date, only around a hundred cases have been reported in the literature. Patients with EMS present with various forms of myeloid/lymphoid malignancies, such as myeloproliferative neoplasms, acute myeloid leukemia, and T- or B-linage lymphoblastic lymphoma, which are frequently associated with eosinophilia. Prognosis of EMS is poor and a standard treatment strategy has not yet been established. In contrast to myeloid/lymphoid neoplasms associated with PDGFR-A or PDGFR-B rearrangement, the tyrosine kinase inhibitor (TKI) imatinib is not an effective therapeutic option for EMS patients. Other types of TKI, i.e., PKC412, sorafenib, ponatinib, dasatinib, and dovitinib, show growth-inhibitory effects against the cells harboring several types of FGFR-1 fusion genes in in vitro studies; however, the usefulness of either drug has not been confirmed by clinical trials. Therefore, at present, allo-hematopoietic stem cell transplantation is the only curative methods for EMS. Very recently, a phase-2 study with pemigatinib, an inhibitor for FGFR1, showed clinical benefits for EMS patients, including major cytogenetic response, suggesting a new therapeutic option for EMS.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 8/genetics , Hematologic Neoplasms/genetics , Myeloproliferative Disorders/genetics , Clinical Trials, Phase II as Topic , Hematopoietic Stem Cell Transplantation , Humans , Protein Kinase Inhibitors/therapeutic use , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitorsABSTRACT
OBJECTIVE: The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. METHODS: The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels. RESULTS: Thirty-two patients with chronic-phase CML (CML-CP) were enrolled and 30 received 100 mg dasatinib once daily. At 24 months of follow-up, 21 (72%) and 24 (83%) patients achieved an MMR by 12 and 24 months, respectively; the rates of a deep molecular response (DMR) by 12 and 24 months were 48 and 59%, respectively. A shorter halving time of BCR-ABL1 transcripts (≤10.6 days) accurately predicted both an MMR and a DMR. The incidence of pleural effusion was 50%. Our study reconfirmed the efficacy and safety of dasatinib treatment in Japanese patients with newly diagnosed CML-CP. In addition, the usefulness of the halving time of BCR-ABL1 transcripts was validated. CONCLUSION: These data emphasize the significance of an early treatment response in achieving a DMR during dasatinib therapy.
Subject(s)
Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myeloid, Chronic-Phase/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Humans , Japan , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myeloid, Chronic-Phase/genetics , Male , Middle Aged , Prognosis , Prospective StudiesABSTRACT
The JAK2V617F mutation is the commonest major genetic mutation of myeloproliferative neoplasms (MPNs) and has been defined in the WHO diagnostic criteria for MPNs. However, there is still no approved in vitro diagnostic test kit available in Japan. We evaluated a JAK2V617F allele quantification kit (test method) in a prospective, multicenter clinical performance study involving patients with MPNs who were diagnosed with polycythemia vera, essential thrombocythemia, and primary myelofibrosis; healthy volunteers were also included in the analysis. Good correlation was observed between the allele burden determined using the test method vs. that determined using next-generation sequencing (NGS) in the patient group (r=0.998, y=1.071x-0.069; n=156). Furthermore, all allele burdens in the healthy group (n=54) were below the lower limit of the measurement range of the test method (0.042%). Our results confirmed that the test method could quantitatively measure the JAK2V617F allele burden in patients with MPN. Thus, the novel JAK2V617F allele quantification kit can be considered useful for the diagnosis of MPNs.
Subject(s)
Genetic Testing/instrumentation , Janus Kinase 2/genetics , Myeloproliferative Disorders/genetics , Polycythemia Vera/genetics , Case-Control Studies , Humans , Japan , Mutation , Prospective StudiesABSTRACT
Herein, we present an elderly onset case of aHUS successfully treated with eculizumab. An 80-year-old woman with severe anemia, thrombocytopenia, and acute renal dysfunction was admitted to our hospital. A laboratory test revealed steep elevation in the LDH level, and the peripheral blood smear showed erythrocyte fragmentations. Accordingly, we diagnosed thrombotic microangiopathy, and treatment with plasma exchange was immediately initiated. In addition, she required hemodialysis because of rapid impairment of the renal function. After excluding Shiga toxin-producing Escherichia coli infection and malignancy and confirming her ADMTS13 activity above 10%, we diagnosed aHUS, according to the Japanese diagnostic criteria for aHUS. Next, we initiated treatment with eculizumab. Her hematological findings improved 23 days after the starting of eculizumab. In addition, her renal function gradually recovered, and hemodialysis was discontinued. The genetic test for several complement regulatory genes tested negative. The onset of aHUS is reported in children or young adults and is rarely reported in elderly. However, our case suggests the importance of precisely diagnosing aHUS and initiating early administration of eculizumab for improving the outcome even in elderly patients.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Atypical Hemolytic Uremic Syndrome/drug therapy , Aged, 80 and over , Atypical Hemolytic Uremic Syndrome/pathology , Atypical Hemolytic Uremic Syndrome/therapy , Female , Humans , Plasma Exchange , Treatment OutcomeABSTRACT
Since the discovery of the activating mutation of JAK2, known as JAK2V617F, our understanding of mutation profiles, and the biological significance of this mutation in Philadelphia-negative (Ph-) MPNs has drastically changed over the last decade. Mutations of the thrombopoietin receptor MPL and chaperone protein calreticulin gene also induce aberrant activation of JAK and downstream molecules, including STAT proteins, and contribute to the development of MPNs. Mutations of the genes JAK2, MPL, and calreticulin are referred to as "driver mutations" for MPNs. Recent advances in genetic tests using next-generation sequencing have revealed that in addition to driver mutations, approximately half of Ph-MPN patients have at least one more mutation. These genes serve as components of spliceosomal machinery, DNA methylation modifiers, and regulators of histone function. Mutations of these genes are known as "non-driver mutations" and are thought to be involved in modifying the disease phenotype and progression of Ph-MPNs. In addition to its biological significance, the mutation profile also provides numerous pieces of important information for the clinical aspects of Ph-MPNs. In this study, the role of molecular profiling of Ph-MPNs for diagnosis, risk evaluation, and treatment decisions was discussed.
Subject(s)
Mutation , Myeloproliferative Disorders/genetics , Humans , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/therapy , Risk Factors , Treatment OutcomeABSTRACT
Although myelofibrosis is mainly associated with myeloproliferative neoplasms (MPN), especially primary myelofibrosis (PMF), a variety of hematological malignancies, including acute myeloid leukemia, multiple myeloma and malignant lymphoma, also cause myelofibrosis with markedly varying degrees of severity. Thus, it is extremely important to accurately diagnose the underlying diseases that cause fibrosis in bone marrow. Analyses of JAK2, MPL and calreticulin gene mutations are useful for distinguishing MPN from other diseases, since 90% of MPN patients have a mutation in one of these genes. However, 10% of PMF patients do not have mutations in any of these genes, and these patients have a disease known as triple negative PMF. It is sometimes difficult to accurately distinguish triple negative PMF from secondary myelofibrosis caused by other diseases. Herein, we present a case of diffuse large B cell lymphoma (DLBCL) with bone marrow involvement, mimicking triple negative primary myelofibrosis. 18F-FDG-PET was useful for correctly diagnosing DLBCL.
Subject(s)
Bone Marrow/pathology , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Primary Myelofibrosis/diagnostic imaging , Aged , Diagnosis, Differential , Fluorodeoxyglucose F18 , Humans , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Mutation/genetics , Positron Emission Tomography Computed Tomography , Primary Myelofibrosis/geneticsABSTRACT
RESPONSE is an open-label phase 3 study evaluating the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib versus best available therapy for efficacy/safety in hydroxyurea-resistant or intolerant patients with polycythemia vera. This preplanned analysis occurred when all patients completed the Week 80 visit or discontinued. Objectives included evaluating the durability of the primary response (Week 32 phlebotomy-independent hematocrit control plus ≥35% spleen volume reduction), its components, and that of complete hematologic remission; and long-term safety. Median exposure was 111 weeks; 91/110 (82.7%) patients randomized to ruxolitinib remained on treatment. No patients continued best available therapy (98/112 [87.5%] crossed over to ruxolitinib, most at/soon after Week 32). At Week 32, primary response was achieved by 22.7% vs. 0.9% of patients randomized to ruxolitinib and best available therapy, respectively (hematocrit control, 60.0% vs. 18.8%; spleen response, 40.0% vs. 0.9%). The probability of maintaining primary and hematocrit responses for ≥80 weeks was 92% and 89%, respectively; 43/44 spleen responses were maintained until Week 80. Complete hematologic remission at Week 32 was achieved in 23.6% of ruxolitinib-randomized patients; the probability of maintaining complete hematologic remission for ≥80 weeks was 69%. Among ruxolitinib crossover patients, 79.2% were not phlebotomized, and 18.8% achieved a ≥35% reduction from baseline in spleen volume after 32 weeks of treatment. New or worsening hematologic laboratory abnormalities in ruxolitinib-treated patients were primarily grade 1/2 decreases in hemoglobin, lymphocytes, and platelets. The thromboembolic event rate per 100 patient-years was 1.8 with randomized ruxolitinib treatment vs. 8.2 with best available therapy. These data support ruxolitinib as an effective long-term treatment option for hydroxyurea-resistant or intolerant patients with polycythemia vera. This trial was registered at clinicaltrials.gov identifier: 01243944.
Subject(s)
Polycythemia Vera/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Adult , Aged , Alleles , Combined Modality Therapy , Female , Follow-Up Studies , Gene Frequency , Hematocrit , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/genetics , Male , Middle Aged , Molecular Targeted Therapy , Mutation , Nitriles , Polycythemia Vera/diagnosis , Polycythemia Vera/genetics , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyrimidines , Treatment OutcomeABSTRACT
BACKGROUND: Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. METHODS: An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. RESULTS: Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. CONCLUSION: Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. TRIAL REGISTRY: http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.