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Defining disease modification with novel targeted agents in MF

Jun 24, 2022
Learning objective: After reading this article, learners will be able to cite a new clinical development in myelofibrosis.

Current targeted therapy options approved for the treatment of myelofibrosis (MF) by the U.S. Food and Drug Administration (FDA), namely the JAK1/2 inhibitor ruxolitinib, and the JAK2 inhibitor fedratinib, have demonstrated improvements in disease-related symptoms; however, relapse/refractoriness remains a hurdle. These factors encourage the better definition of clinical trial endpoints that incorporate disease modification in MF, rather than just symptom relief; nevertheless, there is no accepted assessment or consensus in defining disease modification in MF.

In a recent review article published by Naveen Pemmaraju et al.1 in Cancer, disease modification and associated response criteria in MF were defined. We summarize key points below.

Importance of JAK/STAT signalling

It is well understood that disruption of JAK/STAT signalling is a key driver of myeloproliferative neoplasms (MPN) pathology. When observing symptoms, initial activation of JAK/STAT signalling can increase myeloproliferation of megakaryocytes which aggregate in the bone marrow. This results in the infiltration of neutrophils, producing cytokine release and a pro-inflammatory microenvironment in the bone marrow. On the other hand, this promotes bone marrow fibrosis (BMF) and causes hematopoietic progenitor cells to migrate to extra medullary sites, thus driving splenomegaly. Despite the influence on disease course in the frontline setting, approved JAK inhibitors fail to disrupt disease progression, with clonal expansion and BMF remaining unaffected. As a result, trials investigating these compounds focus on total symptom score (TSS) and spleen volume reduction (SVR) ≥35/50% to infer efficacy.

Clearly, further options that may compliment these regimens and target other pathological mechanisms at an earlier stage are needed.

Allogeneic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative option for MF; however, a standardized view of clinical endpoints that enables patients to be identified as eligible for transplant remains unclear. To this end, measurable residual disease (MRD) is used for other hematologic malignancies, and molecular remission provides evidence of halting disease progression.

Clinical trials for novel targeted agents

The MPN Hub recently provided an overview of novel targeted agents for MF. This review provided a summary of clinical trials currently underway targeting different mechanisms that support MF progression. Such studies have started to add endpoints of BMF reduction, cytokine modulation, and mutational status, all of which provide evidence of disease modifying potential. Despite this, precise definition of these endpoints varies across clinical trials and the exact association with standard endpoints, such as overall survival (OS) and progression-free survival (PFS), need clarification.

New clinical trial endpoints

Disease modification is objectively difficult to measure; nevertheless, the authors of the review article1 proposed a definition of modification of MF stating “Disease modification in MF is defined as therapy that exerts a clinically meaningful impact on survival outcomes and/or restoration of normal haematopoiesis in conjunction with improvement in bone marrow fibrosis through a substantial and durable reduction in the clonal burden of disease.” Key modifiers are summarized in Figure 1, alongside a definition of disease modification suggested by the authors.1

Figure 1. Key disease modifier outcomes suggested for measuring in MF*

allo-HSCT, allogeneic hematopoietic stem cell transplantation; BM, bone marrow; BMF, bone marrow fibrosis; EFS, event-free survival; LFS, leukemia-free survival; MF, myelofibrosis; OS, overall survival; PFS, progression-free survival.
*Adapted from Pemmaraju et al.1


When considering new disease modifying endpoints in MF, the authors1 highlighted the following key points: Firstly, JAKi therapy will continue to remain a valid option despite its lack of impact on disease progression, and combinations of JAK inhibitors with novel agents is a likely treatment strategy to be investigated in clinical trials; Secondly, novel targeted agents have demonstrated evidence for disease modification, however a more unified approach to defining endpoints is needed across trials. Identifying such changes early in treatment may help to accelerate approval for promising agents.

  1. Pemmaraju N, Verstovsek S, Mesa R, et al. Defining disease modification in myelofibrosis in the era of targeted therapy. Cancer. 2022;128(13):2420-2432. DOI: 1002/cncr.34205