Clin Lymphoma Myeloma Leuk: MPN-238 single-cell RNA analysis in patients with myelofibrosis showed pelabresib-induced megakaryocyte progenitor and normalization of CD4+ T cells in peripheral blood

Abnormal differentiation of the megakaryocyte lineage and overproduction of pro-inflammatory cytokines lead to myelofibrosis, anaemia, symptoms, extramedullary hematopoiesis, and often hepatosplenomegaly
.
Bromodomain and extraterminal domain (BET) proteins play an important role
in the regulation of neoplastic myeloproliferation and pro-inflammatory cytokine production.
Pelabresib (CPI-0610), an ongoing oral small molecule BET inhibitor, is being investigated
by a team of researchers in the treatment of myelofibrosis.

The investigators explored from three groups of ongoing MANIFEST Phase 2 studies (NCT02158858), Group 1: pelabresib monotherapy; Group 2: In patients with poor response to ruxolitinib, pelabresib is an "add-on" to rusolitinib; Group 3: use of piperacesi in combination with rusolitinib
in young patients with JAKi.

They performed single-cell RNA sequencing
on mature PB cells.
Baseline and treatment samples were obtained from a randomized pool of 20 patients, and analysis of CD34+ HSPC showed an increased number of megakaryocytes, neutrophils, and erythroid progenitors in patients with myelofibrosis compared to HD, and a significant decrease in
bone marrow and B cell lineage progenitor cells.
Pelabresib as monotherapy in combination with ruxolitinib significantly reduces megakaryocytes, neutrophils, and erythroid progenitor cells
compared with baseline.
Analysis of CD34-cells in patients with myelofibrosis compared to HD found a significantly lower proportion of CD4+ T cells and an increase
in the number of erythroid cells at baseline.

They found that pelabresib as monotherapy and in combination with ruxolitinib increased the proportion of CD4+ T cells and, importantly, reduced megakaryocyte lineage cells
in both primary treatment and ruxolitinib relapsed/refractory patients.
In patients with baseline myelofibrosis, greater spleen volume
was observed in patients with a low number of CD4+ T cells and an increased number of megakaryocytes and bone marrow CSF3R+ cells.

Overall, single-cell analysis of a subset of myelofibrosis patients in the MANIFEST study showed that pelabresib alone or in combination with ruxolitinib improved myeloid lymphatic imbalance
.
This potential disease-modifying effect requires further study
.

Original source:

Zavidij O, Haradhvala NJ, Meyer R, et al.
MPN-238 Single-Cell RNA Profiling of Myelofibrosis Patients Reveals Pelabresib-Induced Decrease of Megakaryocytic Progenitors and Normalization of CD4+ T Cells in Peripheral Blood.
Clin Lymphoma Myeloma Leuk.
2022; 22 Suppl 2:S331-S332.
doi:10.
1016/S2152-2650(22)01448-3