Endoplasmic Reticulum Stress and Resistance to Treatments in Ph-negative Myeloproliferative Neoplasms

Completed

• Conditions: Polycythemia Vera; Essential Thrombocythemia
• Interventions: Biological: RNA sample of total leukocytes before start of treatment

• Registration Number: NCT02823184
• Lead Sponsor: University Hospital, Bordeaux

Brief Summary

The aim of this study is to evaluate the endoplasmic reticulum stress markers as predictive for response to hydroxyurea in polycythemia vera (PV) and essential thrombocythemia (ET).

Detailed Description

The recent discovery of calreticulin mutations in myeloproliferative neoplasms point to the unexpected role of the endoplasmic reticulum biology in the pathophysiology in these diseases. Otherwise, the association of endoplasmic reticulum stress with solid cancers, in particular in resistance to chemotherapy, is well documented, contrary to hematological malignancies. The study aims to evaluate endoplasmic reticulum stress markers as predictors for the response to hydroxyurea in polycythemia vera and essential thrombocythemia patients. The main objective is to correlate endoplasmic reticulum stress (defined as splicing of XBP1 above 30%) to the rate of complete response after 6 months according to the 2009 ELN criteria. This is an observational retrospective study.

Study Timeline

• Study First Submitted: 2016-06-24
• Study First Submitted QC: 2016-07-05
• Study First Posted: 2016-07-06
• Study Start: 2017-04-27
• Primary Completion: 2019-04-27
• Study Completion: 2019-04-27
• Status Verified: 2020-06
• Last Update Submitted: 2020-06-18
• Last Update Posted: 2020-06-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 148

Inclusion Criteria

• ET or PV patients diagnosed before acceleration phase and treated by hydroxyurea with a follow up period of at least 6 months following treatment start.

• Diagnosis criteria of PV :

  • WHO criteria of PV with :

    • Acquired JAK2V617F mutation > 5%
    • Absence of evident cause of secondary polycythemia

• Diagnosis criteria of ET :

  • Platelet count > 450 G/L
  • Absence of PV or Chronic Myeloid Leukemia
  • Bone marrow biopsy preferred but not necessary in absence of reactional causes (CRP and ferritin levels normal) and/or presence of acquired JAK2V617F, CALR exon 9 or MPL exon 10

• Availability of RNA sample of total leukocytes before start of treatment.

Exclusion Criteria

In absence of clonality marker, presence of secondary cause of :

• Thrombocytosis :

  • Inflammatory syndrom (CRP or SV increased)
  • Iron deficiency (decreased ferritin level or increased soluble transferrin receptor level)

• Polycythemia :

  • Increased or normal level of EPO in context of :

    • Hypoxia, respiratory insufficiency
    • Sleep apnea syndrome
    • Hyperaffin hemoglobin

• Absence of treatment by hydroxyurea

• Treatment by anagrelide, P32, pipobroman, interferon without subsequent hydroxyurea treatment.

• Concommitant treatment by other cancer chemotherapy (in a context of solid cancer for example).

• Diagnostic during transformation to acute leukemia

• Treatment by hydroxyurea during less than 6 months

• Bad observance of the cytotoxic treatment

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Patients	RNA sample of total leukocytes before start of treatment	ET or PV patients diagnosed before acceleration phase and treated by hydroxyurea with a follow up period of at least 6 months following treatment start, with a RNA sample of total leukocytes before start of treatment available

Primary Outcome Measures

Name	Time	Method
To correlate endoplasmic reticulum stress (defined as splicing of XBP1 above 30%) to the rate of complete response after 6 months according to the 2009 ELN criteria	After 6 months of treatment

Trial Locations

Locations (7)

Chu Angers; 🇫🇷 Angers, France

Ch de La Cöte Basque; 🇫🇷 Bayonne, France

Ch de Dax; 🇫🇷 DAX, France

Crlcc Bergonie; 🇫🇷 Bordeaux, France

Chu de Brest; 🇫🇷 Brest, France

Ch de Libourne; 🇫🇷 Libourne, France

Chu de Bordeaux; 🇫🇷 Bordeaux, France