Long-term follow-up of essential thrombocythemia patients treated with anagrelide: subgroup analysis according to JAK2/CALR/MPL mutational status.

BACKGROUND: Anagrelide represents a treatment option for essential thrombocythemia, although its place in therapy remains controversial. AIM: To assess the impact of mutational status in response rates and development of adverse events during long-term use of anagrelide. METHODS: We retrospectively evaluated 67 patients with essential thrombocythemia treated with anagrelide during 68 (4-176) months. RESULTS: Mutational frequencies were 46.3%, 28.3%, and 1.5% for JAK2V617F, CALR and MPL mutations. Anagrelide yielded a high rate of hematologic responses, which were complete in 49.25% and partial in 46.25%, without differences among molecular subsets. The rate of thrombosis during treatment was one per 100 patient-years, without excess bleeding. Anemia was the major adverse event, 30.3% at 5-yr follow-up, being more frequent in CALR(+) (P < 0.05). Myelofibrotic transformation developed in 14.9% (12.9%, 21%, and 12.5% in JAK2V617F(+), CALR(+), and triple-negative patients, respectively, P = NS) and those treated >60 months were at higher risk, OR (95% CI) 9.32 (1.1-78.5), P < 0.01, indicating the need for bone marrow monitoring during prolonged treatment. CONCLUSION: Although CALR(+) patients were at higher risk of developing anemia, anagrelide proved effective among all molecular subsets, indicating that mutational status does not seem to represent a major determinant of choice of cytoreductive treatment among essential thrombocythemia therapies.

Test of an electronic program to query clinicians about nonspecific causes reported for pneumonia deaths, New York City, 2012.

We tested an electronic cause-of-death query system at a hospital in New York City to evaluate clinicians' reporting of cause of death. We used the system to query clinicians about all deaths assigned International Classification of Disease code J189 (pneumonia, unspecified) as the underlying cause of death. Of 29 death certificates that generated queries, 28 were updated with additional information, which led to revisions in the underlying cause of 27 deaths. The electronic system for querying reported cause of death was feasible and enabled quicker than usual responses; however, follow-up with clinicians to ensure timely, accurate, and complete responses was labor-intensive. Educating clinicians and enforcing reporting standards would reduce the time and effort required to ensure accurate and timely cause-of-death reporting.

Screening for MPL mutations in essential thrombocythemia and primary myelofibrosis: normal Mpl expression and absence of constitutive STAT3 and STAT5 activation in MPLW515L-positive platelets.

OBJECTIVES: To evaluate the frequency of MPL W515L, W515K and S505N mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) and to determine whether MPLW515L leads to impaired Mpl expression, constitutive STAT3 and STAT5 activation and enhanced response to thrombopoietin (TPO). METHODS: Mutation detection was performed by allele-specific PCR and sequencing. Platelet Mpl expression was evaluated by flow cytometry, immunoblotting and real-time RT-PCR. Activation of STAT3 and STAT5 before and after stimulation with increasing concentrations of TPO was studied by immunoblotting. Plasma TPO was measured by ELISA. RESULTS: MPLW515L was detected in 1 of 100 patients with ET and 1 of 11 with PMF. Platelets from the PMF patient showed 100% mutant allele, which was <50% in platelets from the ET patient, who also showed the mutation in granulocytes, monocytes and B cells. Mpl surface and total protein expression were normal, and TPO levels were mildly increased in the MPLW515L-positive ET patient, while MPL transcripts did not differ from controls in both MPLW515L-positive patients. Constitutive STAT3 and STAT5 phosphorylation was absent and dose response to TPO-induced phosphorylation was not enhanced. CONCLUSIONS: The low frequency of MPL mutations in this cohort is in agreement with previous studies. The finding of normal Mpl levels in MPLW515L-positive platelets indicates this mutation does not lead to dysregulated Mpl expression, as frequently shown for myeloproliferative neoplasms. The lack of spontaneous STAT3 and STAT5 activation and the normal response to TPO is unexpected as MPLW515L leads to constitutive receptor activation and hypersensitivity to TPO in experimental models.