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Validation of flow cytometric phospho-STAT5 as a diagnostic tool for juvenile myelomonocytic leukemia.

ABSTRACT: To diagnose juvenile myelomonocytic leukemia (JMML) is sometimes challenging, because around 10% of patients lack molecular abnormalities affecting Ras-MAPK (mitogen-activated protein kinase) pathway and other diseases such as cytomegalovirus infection can mimic clinical signs of JMML. In order to validate a phospho-specific flow cytometry assay assessing phospho-signal transducer and activator of transcription factor 5 (p-STAT5) as a new diagnostic tool for JMML, we examined 22 samples from children with JMML and 47 controls. CD33+/CD34+ cells from 22 patients with JMML showed hyperphosphorylation of STAT5 induced by sub-saturating doses of granulocyte-macrophage colony-stimulating factor (GM-CSF). Using a training set of samples (11 JMML and 23 controls), we identified a threshold for p-STAT5-positive after stimulation with 0.1?ng/ml GM-CSF (17.17%) that discriminates JMML from controls. This threshold was validated in an independent series (11 JMML, 24 controls and 7 cases with diseases other than JMML) where we demonstrated that patients with JMML could be distinguished from other subjects with a sensitivity of 91% (confidence interval (CI) 59-100%) and a specificity of 87% (CI 70-96%). Positive and negative predictive values were 71% (CI 42-92%) and 96% (CI 82-100%), respectively. In conclusion, flow cytometric p-STAT5 profiling is a reliable diagnostic tool for identifying patients with JMML and can contribute to consistency of current diagnostic criteria.

SUBMITTER: Hasegawa D

PROVIDER: S-EPMC3880439 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Validation of flow cytometric phospho-STAT5 as a diagnostic tool for juvenile myelomonocytic leukemia.

Hasegawa D D Bugarin C C Giordan M M Bresolin S S Longoni D D Micalizzi C C Ramenghi U U Bertaina A A Basso G G Locatelli F F Biondi A A Te Kronnie G G Gaipa G G

Blood cancer journal 20131115

To diagnose juvenile myelomonocytic leukemia (JMML) is sometimes challenging, because around 10% of patients lack molecular abnormalities affecting Ras-MAPK (mitogen-activated protein kinase) pathway and other diseases such as cytomegalovirus infection can mimic clinical signs of JMML. In order to validate a phospho-specific flow cytometry assay assessing phospho-signal transducer and activator of transcription factor 5 (p-STAT5) as a new diagnostic tool for JMML, we examined 22 samples from chi ...[more]

PMID: 24241400

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Project description:Background: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm diagnosed in young children, characterized by somatic or germline mutations that lead to hyperactive RAS signaling. The only curative option is hematopoietic stem cell transplantation (HSCT). Recent data showing that aberrant DNA methylation plays a significant role in pathogenesis and correlates with clinical risk suggest a possible benefit of hypomethylating agents (HMA) in JMML treatment. Aim: The aim is to report the results of HMA-based therapy with 5-azacytidine (AZA) in three JMML patients treated in a single center, non-participating in EWOG-MDS study. Methods: The diagnosis and treatment response were evaluated according to international consensus criteria. AZA 75 mg/m2 intravenous (i.v.) was administered once daily on days 1-7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. Targeted next generation sequencing (NGS) were performed after the 3rd AZA cycle and before SCT to evaluate the molecular alterations and genetic response. Results: Three patients diagnosed with JMML were treated with AZA (off-label indication) in Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania between 2017 and 2019. There were two females and one male with median age 11 months, range 2-16 months. The cytogenetic analysis showed normal karyotype in all patients. Molecular analysis confirmed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. The clinical evaluation showed important splenomegaly and hepatomegaly in all 3 pts. One patient received AZA for early relapse after haploidentical HSCT and the other two patients received upfront AZA, as bridging therapy before HSCT. After HMA therapy, 2/3 patients achieved clinical partial response (cPR), 1/3 had clinical stable disease (cSD) and all had genetic stable disease (gSD) after 3 cycles and were able to receive the planned HSTC. One patient achieved clinical and genetic complete response before HSCT. During 22 cycles of AZA there were only four adverse events but only one determined dose reduction and treatment delay. Conclusion: Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.

Dataset Information

Validation of flow cytometric phospho-STAT5 as a diagnostic tool for juvenile myelomonocytic leukemia.

Publications

Validation of flow cytometric phospho-STAT5 as a diagnostic tool for juvenile myelomonocytic leukemia.

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