Table 2.
Recounting evolving endpoints in MPNs and looking forward.
| Therapeutic paradigm | Representative studies | Mechanism of action | Clinical endpoints | Molecular endpoints | Interpretation |
|---|---|---|---|---|---|
| Hydroxyurea in PV/ET | PVSG-08; CYTO-PV [84] | Non-specific cytoreduction of proliferating hematopoietic cells | Hematocrit control ( < 45%); platelet normalization; reduction in thrombosis | Not routinely assessed | Clinical benefit defined by hematological control without assessment of underlying clonal disease burden |
| Interferon in PV/ET | Quintás-Cardama et al [85].; MPN-RC 112; PROUD-PV/CONTINUATION-PV [81] | Immunomodulatory suppression of malignant hematopoietic clones | Complete hematological response; normalization of counts | Reduction in driver mutation allele burden (JAK2, CALR); partial and complete molecular responses | Introduction of molecular response as a measurable indicator of disease modification |
| JAK inhibition in MF | COMFORT-I; COMFORT-II [86] | Inhibition of JAK–STAT signaling and downstream inflammatory cytokine production | ≥35% spleen volume reduction; ≥50% symptom improvement; overall survival (secondary) | Not routinely assessed | Clinical benefit reflects modulation of disease phenotype without direct targeting of the malignant clone |
| CALR-directed immunotherapy in MF (proposed) | Vaccines, Antibody-antagonists, bispecific engagers, CAR-T | Selective targeting of mutant CALR neoepitope on malignant hematopoietic cells | Spleen volume reduction; symptom improvement; hematological response | Reduction in CALR variant allele frequency; molecular response; depletion of mutant hematopoietic progenitors; improvement in bone marrow fibrosis | Maintains phenotypic measurement for comparison with JAK inhibitors while additional molecular end points align with potentially disease modifying drug mechanism |
CALR calreticulin, ET essential thrombocythemia, JAK Janus kinase, JAK2 Janus kinase 2, MF myelofibrosis, PV polycythemia vera.
PVSG-08, CYTO-PV, MPN-RC 112, PROUD-PV, CONTINUATION-PV, COMFORT-I, and COMFORT-II are established clinical trial names, not general abbreviations, and are not expanded here.