The aim of this phase II study is to test a novel concept in the treatment of patients with myeloproliferative neoplasms (MPN), a disease of the bone marrow. With no current cure available, MPN are a group of chronic leukemias (blood cancers) in which patients produce too many blood cells. These increased blood cell numbers cause problems to the patient such as bleedings or thrombosis and some patients may progress to acute leukemia, a life threatening condition. Most MPN patients have a gene mutation called JAK2-V617F. The disease is maintained by mutant MPN stem cells that reside in the bone marrow in specialized locations called "niches". These niches need connections to the nervous system. New findings show that these connections are destroyed by the presence of the mutated MPN stem cells. Research teams found that some drugs (beta3-sympathicomimetics) can restore these damaged niches and at the same time reduce the MPN disease manifestation in a mouse model of MPN. Such sympathicomimetic drugs are already being used to treat patients with asthma or hyperactive bladder. These drugs have shown to have only few side effects. The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. The hypothesis is that Mirabegron will have a beneficial effect on bone marrow niche cells and will thereby improve the disease manifestation in MPN patients. This study should provide a rapid answer whether targeting the nervous system of the niche cells could be useful for patients with MPN and warrants to be tested in larger and more long-term studies.
Name: Mirabegron
Description: 25 mg daily during the first week followed by 50 mg Mirabegron daily during the remaining treatment period.Type: DrugArm Mirabegron
Description: Primary endpoint of the trial is reduction in the burden of mutated alleles of ≥50% at 24 weeks (Red-50@24). Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.
Measure: Reduction in the burden of mutated alleles of ≥50% at 24 weeks. Time: at 24 weeksDescription: Reduction in the burden of mutated alleles of ≥50% at 12 weeks (Red-50@12) defined in the same way as the primary endpoint, but evaluated at 12 weeks ± 4 weeks after registration.
Measure: Reduction in the burden of mutated alleles of ≥50% Time: at 12 weeksDescription: Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. All other evaluable patients will be considered as failures for this endpoint.
Measure: Reduction in the burden of mutated alleles of ≥25% Time: at 24 weeksDescription: Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.
Measure: Reduction in the burden of mutated alleles of ≥25% Time: at 12 weeksSingle Group Assignment
There is one SNP
Most MPN patients have a gene mutation called JAK2-V617F. --- V617F ---
The study tests the effects of the beta-3-sympathicomimetic drug Mirabegron (Betmiga®) on MPN disease in 39 patients that carry a JAK2-V617F mutation. --- V617F ---
Patients are defined as success for this endpoint, if they show a reduction of the JAK2-V617F allelic burden of 50% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---
Reduction in the burden of mutated alleles of ≥25% at 24 weeks (Red-25@24): Patients are defined as success for the Red-25@24 endpoint, if they show a reduction of the Jak2-V617F allelic burden of 25% or more 24 weeks ± 4 weeks after registration when compared to baseline, and if they did not start a new MPN treatment before. --- V617F ---
Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---
Reduction in the burden of mutated alleles of ≥25% at 12 weeks (Red-25@12) defined in the same way as the Red-25@24 endpoint, but evaluated at 12 weeks ± 4 weeks after registration.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---
Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F ---
Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of JAK2-V617F positive ET, PV or PMF at primary diagnosis or pretreated - JAK2-V617F mutant allele burden > 20% in the peripheral blood at study entry - Patient must give written informed consent before registration - WHO performance status 0-2 - Age ≥ 18 years - Adequate hematological values: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/ L - Adequate hepatic function: bilirubin ≤ 1.5 x ULN, AST/ALT/AP ≤ 2.5 x ULN - Adequate renal function (calculated creatinine clearance > 50 mL/min, according to the formula of Cockcroft-Gault) - Women are not breastfeeding. --- V617F --- --- V617F ---
Three genes are frequently mutated in MPN and are implicated to be the phenotypic driver mutations: more than 95% of PV patients carry a somatic JAK2-V617F mutation, while about half of the remaining PV patients (2-3%) display mutations in JAK2 exon 12. Thus, almost all patients with PV have somatic mutations in the JAK2 gene. --- V617F ---
The mutational profiles of ET and PMF are more diverse: JAK2-V617F is found in 50-60% of the patients, whereas the recently described mutations in calreticulin (CALR) occur in 20-25% of the patients. --- V617F ---
Ruxolitinib, recently approved for PMF with splenomegaly, is effective in reducing spleen size and improving quality of life, but has little effect on the JAK2-V617F mutant allele burden and has so far not been reported to induce remissions. --- V617F ---
Furthermore, in a mouse model of MPN expressing the human JAK2-V617F mutation, this effect was found to be caused by early glial and sympathetic nerve damage and apoptosis of nestin+ MSCs triggered by the mutant HSCs. --- V617F ---
Mice with JAK2-V617F driven MPN treated with a beta-3-sympathicomimetic agonist not only restored nestin+ MSCs numbers, but also showed correction of thrombocytosis, neutrophilia, and bone marrow fibrosis, and efficiently reduced mutant hematopoietic progenitor numbers in bone marrow and peripheral blood. --- V617F ---