Among patients with calreticulin (CALR)-mutated myelofibrosis, real-world data reveal insights into those with splenomegaly and/or symptoms requiring therapy with Janus kinase 2 (JAK2) inhibitors.
The findings suggest that while Jakafi (ruxolitinib) shows some initial benefits, CALR-mutated patients may require more targeted and innovative therapeutic approaches for better long-term outcomes, according to study findings published in Annals of Hematology.
“Overall, despite the initial benefits of [Jakafi], CALR-mutated patients may require more innovative therapeutic interventions to achieve optimal outcomes. This further emphasizes the necessity of exploring alternative or adjunctive therapies tailored specifically for CALR-mutated individuals,” lead study author Dr. Francesca Palandri and colleagues wrote in the study.
Palandri is currently an adjunct professor primarily based in the Department of Experimental, Diagnostic and Specialty Medicine at the Università di Bologna, Bologna, Italy. She is also a junior researcher at Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology, Bologna, Italy.
Glossary:
Splenomegaly: enlargement of the spleen.
Spleen responses: changes in spleen size or function following treatment, used to assess therapy effectiveness.
Hematological toxicity: adverse effects on the blood system, such as anemia or leukopenia, often from JAK2 inhibitors.
Anemia: a condition with low red blood cells or hemoglobin, causing fatigue and weakness, common in myelofibrosis.
High-risk biological features: markers indicating worse prognosis in myelofibrosis, like high blast counts or specific mutations.
HMR mutations: genetic mutations linked to aggressive myelofibrosis and poor outcomes.
Erythropoiesis-stimulating agents: drugs that stimulate red blood cell production, often used to treat anemia.
Patients with CALR mutations began Jakafi with more severe disease, including higher peripheral blast counts, lower hemoglobin levels and worse marrow fibrosis, and after a longer median time from diagnosis (2.6 versus 0.7 years) compared to patients with JAK2 mutations. At six months, spleen responses were numerically lower in CALR-mutated patients, who also had lower rates of symptom responses (56.1% versus 66.7%, respectively). However, CALR-mutated patients experienced lower rates of high white blood cell counts.
Furthermore, in patients with delayed Jakafi initiation, anemia and reduced starting doses correlated with poorer survival. Managing anemia through interventions like danazol, erythropoiesis-stimulating agents, iron chelation and optimized Jakafi dosing may improve outcomes, according to study authors. The study also highlights the potential benefits of alternative JAK2 inhibitors with lower hematological toxicity.
Early identification of high-risk features, such as anemia, can guide timely treatment decisions. However, the study’s retrospective nature and limited molecular data hinder definitive conclusions.
To assess the efficacy and safety of Jakafi in patients with CALR mutations, a sub-analysis of the RUX-MF study included 135 patients CALR-mutated disease and 786 patients with JAK2-mutated disease, treated with Jakafi.
After approval from the institutional review board, the RUX-MF retrospective study analyzed 1,055 patients with myelofibrosis who received Jakafi outside clinical trials at 25 hematology centers. All patients were in the chronic phase at the start of treatment. Two analyses were conducted: one with 921 patients with JAK2V167F or CALR mutations and another with transplant-eligible patients under age 70. Data included demographics, comorbidities, medications, lab results and side effects.
CALR mutations occur in about 20% of patients with primary and post-essential thrombocythemia myelofibrosis, as per the study. Regardless of driver mutations, patients with splenomegaly and symptoms are typically treated with JAK2 inhibitors, most often Jakafi. New therapies targeting the CALR mutant clone are now in clinical investigation.
Reference:
“Impact of calreticulin mutations on treatment and survival outcomes in myelofibrosis during Jakafi therapy,” by Dr. Francesca Palandri, et al., Annals of Hematology.
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