Mechanism of Action of Interferon in the Treatment of Myeloproliferative Neoplasms
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 80
- 试验地点
- 2
- 主要终点
- Clonal architecture of hematopoietic progenitors of patients
研究概览
简要总结
Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are myeloid malignancies resulting from the transformation of a multipotent hematopoietic stem cell (HSC) caused by mutations activating the JAK2/STAT pathway. The most prevalent mutation is JAK2V617F. Type 1 and Type 2 calreticulin (CALR) and thrombopoietin receptor (MPL) mutations are also observed in ET and PMF. Additional non-MPN mutations affecting different pathways are also found, particularly in PMF, and are involved in disease initiation and/or in phenotypic changes and /or disease progression and/or response to therapy.
There is an obvious and urgent need for an efficient therapy for MPN. In particular, PMF remain without curative treatment, except allogeneic HSC transplantation and JAK inhibitors have limited effects on the disease outcome. Among novel therapeutic approaches, Peg-IFNα2a (IFN) is the most efficient harboring both high rates of hematological responses in JAK2V617F and CALRmut MPN patients and some molecular responses mainly in JAK2V617F patients including deep molecular response (DMR). Nevertheless, several studies, including our own, have demonstrated that the IFN molecular response in CALRmut patients is heterogeneous and overall much lower than in JAK2V617F patients. Moreover, some JAK2V617F MPN patients do not respond to IFN, and DMR is only observed in around 20% of JAK2V617F patients. Finally, long-term treatments are needed (2-5 years) to obtain a DMR, jeopardizing its success due to possible long-term toxicity.
The underlying reasons for failure, drug resistance, heterogeneous molecular response in CALRmut patients and the long delays for DMR in JAK2V617F patients remain unclear, largely because the mechanisms by which IFNα targets MPN malignant clones remain elusive.
Significant improvement of IFN efficacy cannot be achieved without basic and clinical research. Hence our two lines of research are to
- Understand how IFNα specifically targets neoplastic HSCs
- Predicting and improving patient response during IFNα therapy
详细描述
Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) include: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are myeloid malignancies resulting from the transformation of a multipotent hematopoietic stem cell (HSC) caused by mutations activating the JAK2/STAT pathway. The most prevalent mutation is JAK2V617F. Type 1 and Type 2 calreticulin (CALR) and thrombopoietin receptor (MPL) mutations are also observed in ET and PMF. Additional non-MPN mutations affecting different pathways are also found, particularly in PMF, and are involved in disease initiation and/or in phenotypic changes and /or disease progression and/or response to therapy.
There is an obvious and urgent need for an efficient therapy for MPN. In particular, PMF remain without curative treatment, except allogeneic HSC transplantation and JAK inhibitors have limited effects on the disease outcome. Among novel therapeutic approaches, Peg-IFNα2a (IFN) is the most efficient harboring both high rates of hematological responses in JAK2V617F and CALRmut MPN patients and some molecular responses mainly in JAK2V617F patients including deep molecular response (DMR). Nevertheless, several studies, including our own, have demonstrated that the IFN molecular response in CALRmut patients is heterogeneous and overall much lower than in JAK2V617F patients. Moreover, some JAK2V617F MPN patients do not respond to IFN, and DMR is only observed in around 20% of JAK2V617F patients. Finally, long-term treatments are needed (2-5 years) to obtain a DMR, jeopardizing its success due to possible long-term toxicity.
The underlying reasons for failure, drug resistance, heterogeneous molecular response in CALRmut patients and the long delays for DMR in JAK2V617F patients remain unclear, largely because the mechanisms by which IFNα targets MPN malignant clones remain elusive.
Significant improvement of IFN efficacy cannot be achieved without basic and clinical research. Hence our two lines of research are to
- Understand how IFNα specifically targets neoplastic HSCs
- Predicting and improving patient response during IFNα therapy
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult male or female 18 years of age or older
- •Diagnosis of MPN has been previously established by the referring physician and that physician will have decided to treat with pegylated IFN. Patients will be treated or untreated at the time of inclusion and may be newly diagnosed patients.
- •These patients will be affiliated with or benefit from a social security plan
- •For all these patients an additional 20-40 mL will be collected except for some PV patients who are treated conventionally by phlebotomy. In this case, we will collect blood bags from these patients. The volumes vary between 300 and 450 mL of blood depending on the weight and size of the patients.
- •We will also include in this protocol any patient whose MPN, either PV, TE or MF, will have progressed to acute leukemia (AL) during treatment. These will be patients with AP of MPN (MPN can also progress to acute myeloid leukemia (AML) by acute transformation (AT) of MPN).
- •Patient with signed informed consent
排除标准
- •The non-inclusion criterion concerns the anemia that some MF patients may suffer from. Therefore, patients with anemia (Hb<10g) or transfusion dependency (≥ 1 packed red blood cell per month) at the time of the referral monitoring visit are not included in the research.
- •Persons under court protection, guardianship or curatorship
结局指标
主要结局
Clonal architecture of hematopoietic progenitors of patients
时间窗: During 5 years from day 0 of IFN treatment, 3 to 4 times per year
Blood samples are processed to separate mature cells (granulocytes) from progenitors (CD34+ marker). Progenitors are isolated and separated by FACS according to their more or less mature CD34+/CD38±/CD90± phenotype and then cultured for 14 days at the single-cell level. The cells resulting from their differentiation in culture are lysed and their DNA is isolated and stored for PCR or NGS analysis in order to define their mutational profile. Once the genotyping of these cells is established, the DNA is destroyed and nothing remains of the initial biological sample.
Single cell RNA sequencing coupled to genotyping
时间窗: at day 0 of IFN treatment and at two other time point (between 3 and 24 months of treatment)
Blood samples are processed to separate mature cells (granulocytes) from progenitors (CD34+ marker). Progenitors are isolated and subjected to scRNA-seq using long-read techniques (PromethION). The trajectories of hematopoietic differentiation and RNA sequencing will be analyzed in each cell
Culture of progenitors in vitro
时间窗: during 5 years from day 0
Blood samples are processed to separate mature cells (granulocytes) from progenitors (CD34+ marker). Progenitors (CD34+) are then cultured in serum free medium with cytokines or in semisolid medium in the presence of IFN alone or in association.
次要结局
未报告次要终点