Reduced administration of rasburicase for tumor lysis syndrome: A single-institution experience.

In the present study, the dosage and duration of rasburicase administration were retrospectively evaluated for the ability to control the serum uric acid (S-UA) level in 13 patients diagnosed with hematological malignancies and tumor lysis syndrome (TLS), or those at risk of developing TLS, at the University of Fukui Hospital. At the time of diagnosis, seven patients already exhibited laboratory TLS, and three demonstrated clinical TLS. All patients received rasburicase in addition to chemotherapy agents. The median dose was 0.19 mg/kg (range, 0.13-0.25 mg/kg), and the median duration was four days (range, 1-7 days). Six patients sequentially received a xanthine oxidase inhibitor, allopurinol or febuxostat. The primary estimate was the normalization of the S-UA level at the end of rasburicase treatment and on treatment day seven. The average S-UA level prior to treatment was 10.4±4.5 mg/dl (mean ±standard deviation), and 11 out of 13 patients demonstrated a S-UA level >7 mg/dl. The S-UA level at the end of rasburicase administration was 0.5±1.5 mg/dl and the S-UA level at day seven was 1.4±1.5 mg/dl. All the patients achieved normalization of the S-UA level. On day seven subsequent to the initiation of treatment, the patients receiving rasburicase for a maximum of three days exhibited an S-UA level of 1.9±1.8 mg/dl, while the patients receiving rasburicase for longer than three days demonstrated an S-UA level of 1.0±1.3 mg/dl (P=0.20; Mann-Whitney test). The administration of 0.13 mg/kg and 0.22 mg/kg resulted in comparable UA level reductions. The administration of allopurinol or febuxostat following rasburicase administration suppressed the re-increase in S-UA level. Therefore, it was concluded that reduced administration of rasburicase successfully controlled the S-UA level in TLS.

Febuxostat for management of tumor lysis syndrome including its effects on levels of purine metabolites in patients with hematological malignancies - a single institution's, pharmacokinetic and pilot prospective study.

BACKGROUND/AIM: Tumor lysis syndrome (TLS) is a life-threatening oncological emergency, and control of serum uric acid level (S-UA) is most important. In this single-institution, short-term and pilot prospective study, the efficacy of a new xanthine oxidase inhibitor, febuxostat, as an alternative to conventional allopurinol, including its effects on hypoxanthine and xanthine, was evaluated in 10 consecutive patients with hematological malignancies at intermediate risk for TLS. PATIENTS AND METHODS: Febuxostat at 40 mg (n=7) or 60 mg (n=3) daily was administered according to renal function, and induction chemotherapy was started within 24 h. The primary end-point was the reduction of S-UA to ≤ 7.5 mg/dl by day 5. RESULTS: The median S-UA at base-line was 8.0 mg/dl (range=3.2-10.6 mg/dl). The median S-UA on day 5 after chemotherapy was 3.3 mg/dl (range=1.1-5.8 mg/dl) (p<0.0001, by paired t-test), indicating successful control of S-UA during chemotherapy. All patients achieved S-UA ≤ 7.5 mg/dl. A simultaneous decrease in serum creatinine and increase in estimated glomerular filtration rate were seen. Serum hypoxanthine and xanthine levels (as the consequence of inhibition of xanthine oxidase) were elevated along with the decrease in S-UA. Xanthine level was elevated higher compared to hypoxanthine level and reached the level reported to cause xanthine nephropathy, but no advance of renal impairment was observed. Serum febuxostat concentrations at 2 h after administration were 891.8 ± 285.0 ng/ml (mean ± SE) for the 40-mg dose and 770.6 ± 242.7 ng/ml for the 60-mg dose (p=0.80, unpaired t-test), showing no accumulation in patients with renal impairment. No febuxostat-related adverse reactions were noted. No patients experienced progressive TLS. CONCLUSION: Febuxostat is promising for the management of TLS of an intermediate-risk patient and further observation and reevaluation regarding xanthine nephropathy should be performed.

The response to induction therapy is crucial for the treatment outcomes of elderly patients with acute myeloid leukemia: single-institution experience.

BACKGROUND/AIM: The prognosis of acute myeloid leukemia (AML) in elderly patients remains poor due to their poor general condition and the intrinsic chemotherapy-resistant nature of their leukemia cells. The present retrospective study evaluated the clinical background as well as the response to treatment, of an unselected group of elderly patients with AML who were admitted to our Institution over a period of six years. PATIENTS AND METHODS: Patients aged 65 years or older with AML admitted to our Institution between January 2005 and May 2011 were evaluated retrospectively. RESULTS: Forty-six patients were admitted to our Institution, among whom 41 received remission induction chemotherapy. Twenty-four patients received intensive chemotherapy, while 13 received low-dose cytarabine-based chemotherapy. Other modalities were used in four patients. Complete remission was obtained in 20 patients (48.8%). The complete remission rate (50.0%) tended to be higher in patients receiving intensive chemotherapy than in those receiving low-dose cytarabine-based regimens (30.7%; p=0.25). The median survival time for the whole patient group was 12 months and the 2-year overall survival was 18%. The median survival times for patients with complete remission and for non-responding patients were 14 months and 7 months, respectively. The 2-year overall survival in patients with complete remission was 32%, while that of non-responding patients was 6% (p=0.0025, log-rank test). CONCLUSION: The present study suggests the necessity of achieving complete remission for obtaining better survival for elderly patients with AML.

Controlling serum uric acid using febuxostat in cancer patients at risk of tumor lysis syndrome.

Tumor lysis syndrome (TLS) is a life-threatening oncological emergency, in which control of serum uric acid (S-UA) levels is important. S-UA-lowering efficacy of a new xanthine oxidase inhibitor, febuxostat, was retrospectively evaluated in seven patients with hematological malignancies who were at an intermediate risk of developing TLS. A 10-mg dose of febuxostat was initiated and chemotherapy was started within 24 h of administering the first dose of febuxostat. Febuxostat was continued until at least day 7 of chemotherapy treatment. The UA-lowering treatment was considered effective if febuxostat reduced S-UA levels to ≤7.5 mg/dl by day 5. The mean S-UA level at base line was 6.4±2.6 mg/dl and, on day 5, the mean S-UA level was 4.7±1.8 mg/dl. All the patients achieved S-UA levels ≤7.5 mg/dl. Serum creatinine levels decreased from 0.93±0.25 to 0.85±0.25 mg/dl. The estimated glomerular filtration rate values increased from 69.7±24.5 to 76.9±26.2 ml/min. No adverse reactions were noted during the study period and no patients experienced progressive TLS. Successful control of S-UA and improved renal function were obtained in response to febuxostat treatment in cancer patients at a risk of TLS.

Variation of urate transport in the nephrons in subtypes of hyperuricemia.

BACKGROUND: Hyperuricemia cases (HU) can be classified into four subgroups by combining the two main causes of hyperuricemia, i.e. urate underexcretion and overproduction. These subgroups are as follows: underexcretion-type cases (UE); overproduction-type cases (OP); combined-type cases, and normal-type cases. Since urinary urate excretion (Uua) and urate clearance differ significantly between UE and OP, urate transport in the nephrons and the intratubular urate contents might also differ. Such differences might help clarify the pathophysiology of urate underexcretion in subgroups of hyperuricemia, and thus reveal its underlying mechanisms. METHODS: Urate transport coefficients in each subtype of HU were determined employing the previously reported benzbromarone-loading urate clearance tests. The subtype cases of HU were plotted on a graph of urate transport coefficients versus Uua as coordinates. The characteristic features in the distribution of subtype cases on graphs were analyzed in relation to Uua. RESULTS: The mean (±standard error) tubular secretion rate (TSR) in the UE (48.7 ± 1.7 ml/min) was significantly lower and the postsecretory urate reabsorption rate (R2) in the UE (0.904 ± 0.004) was significantly higher than those in the normal controls (78.0 ± 2.1 ml/min and 0.877 ± 0.003) or the OP (61.1 ± 3.2 ml/min and 0.861 ± 0.009). Decrements of TSR and increments of R2 in the UE were largest in the subtypes of the HU, in terms of case numbers and the deviation rate of the group. Conversely, decrements of TSR and increments of R2 were smallest in the OP. A significant correlation was identified between TSR and Uua (r = 0.345, p < 0.0001), and a significant negative correlation was also found between R2 and Uua (r = -0.393, p < 0.0001). CONCLUSION: IN THE UE, HYPERURICEMIA IS INDUCED MAINLY BY URATE UNDEREXCRETION, WHICH RESULTS FROM THE COMBINATION OF TWO MAIN CAUSES IN URATE TRANSPORTERS OF THE NEPHRON: significantly lower TSR and significantly higher R2. Neither of these was observed in OP. Differences in urate transporters in subtypes of the HU might be important not only for understanding the pathophysiology and mechanisms of urate underexcretion and hyperuricemia, but also for providing a strategic therapy for hyperuricemia.

A high serum uric acid level is associated with poor prognosis in patients with acute myeloid leukemia.

Uric acid in serum (S-UA) is produced by the breakdown of the cellular nucleic acids of leukemia cells, and may be a marker of disease aggressiveness. S-UA levels were examined for association with clinical outcomes in patients with acute myeloid leukemia (AML). Fifty-six patients with AML admitted to our Institution were evaluated retrospectively. The median S-UA level at diagnosis was 5.0 mg/dl (range 2-13.8 mg/dl). The S-UA levels did not correlate with peripheral lactate dehydrogenase, peripheral white blood cell counts, or peripheral blast counts, and were not proportional to bone marrow blast counts or marrow cellularity. The S-UA levels in the patients who achieved complete remission were slightly lower than those in those who did not. S-UA levels less than, or equal to the median (5.0 mg/dl) were significantly associated with better prognoses, compared with S-UA levels greater than 5.0 mg/dl. Thus, the S-UA level may predict the prognosis of AML, and is a versatile and cost-effective test for such a purpose.

Detectable Wilms' tumor-1 transcription at treatment completion is associated with poor prognosis of acute myeloid leukemia: a single institution's experience.

BACKGROUND/AIM: The present retrospective study was conducted to measure Wilms' tumor-1 (WT1) mRNA levels in the peripheral blood of patients with acute myeloid leukemia (AML) in order to examine any association with the clinical outcomes. PATIENTS AND METHODS: A total of 58 AML patients were evaluated retrospectively in our institution. WT1 transcripts were determined by real-time reverse transcriptase-polymerase chain reaction in peripheral blood samples. RESULTS: WT1 levels at diagnosis did not vary according to response of induction treatments, and the levels were comparable between the patients with durable remission and the patients with relapse of disease. WT1 levels at the completion of the treatment were higher in the group with relapse of disease than in the group with sustained remission. Detectable WT1 transcripts after the completion of chemotherapy courses were associated with poor prognoses. CONCLUSION: WT1 mRNA levels at treatment completion may predict for prognosis of AML.

Early relapse is associated with high serum soluble interleukin-2 receptor after the sixth cycle of R-CHOP chemotherapy in patients with advanced diffuse large B-cell lymphoma.

The clinical significance of serum soluble interleukin-2 receptor (sIL2R) levels was retrospectively assessed in patients with advanced diffuse large B-cell lymphoma (DLBCL). Twenty-one patients, who were newly-diagnosed with advanced DLBCL (stage III and IV) between 2006 and 2009, were evaluated. The median follow-up period was 37 months. All patients received 6-8 cycles of chemotherapy with rituximab in combination with doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP)-like regimens and attained complete remission. Although all patients reached complete remission, six patients experienced disease relapse within 1 year after treatment completion. The overall survival was significantly poorer in patients with relapse than in patients with durable remission. The sIL2R levels after the sixth cycle of treatment were significantly higher in the relapse group than in the non-relapse group. Thus, the present study suggests sIL2R levels to be a valuable predictor for the prognosis of patients with advanced DLBCL.

Wilms' tumor-1 transcript in peripheral blood helps diagnose acute myeloid leukemia and myelodysplastic syndrome in patients with pancytopenia.

BACKGROUND/AIM: Pancytopenia is caused by acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia (AA), or by non-hematological diseases. Because Wilms' tumor-1 (WT1) is overexpressed in patients with AML and MDS, its expression level may be helpful for diagnosing these hematological malignancies. PATIENTS AND METHODS: We retrospectively investigated the WT1 transcripts in peripheral blood (PB) from 47 patients with decreased blood cell counts. RESULTS: The final diagnoses included AML, MDS, AA, drug poisoning, and non-hematological diseases. PB WT1 mRNA was overexpressed in AML and MDS, whereas the patients with other diseases mostly tested negatively for the transcript. The patients with MDS with higher marrow blast counts had higher PB WT1 mRNA levels. The sensitivity of the PB WT1 transcript in detecting AML and MDS was 78%, and the specificity was 90%. CONCLUSION: The WT1 mRNA level in PB may help diagnose AML and MDS in patients with pancytopenia.