Hemophagocytic lymphohistiocytosis (HLH) is a rare and life threatening disorder characterized by excessive immune activation with resulting tissue injury [1]. Ibrutinib is an irreversible inhibito...

The phase 1 portion of SENTRY/XPORT-MF-034 (NCT04562389) evaluated the exportin 1 inhibitor selinexor (40 mg/60 mg once weekly) plus ruxolitinib in JAK inhibitor–naïve patients with myelofibrosis (n = 24). Primary end points were maximum tolerated selinexor dose, recommended clinical trial dose, and safety. No dose-limiting toxicities were reported. Common adverse events were nausea, fatigue, anemia, thrombocytopenia, constipation, vomiting, and headache. Nausea was transient, mainly grade 1, and managed by prophylactic antiemetics. Four deaths occurred, all unrelated to study treatment. Selinexor 60 mg in combination with ruxolitinib was identified as the recommended phase 3 dose based on safety, efficacy, and exposure–response analyses. Overall safety profiles and grades of clinically significant adverse events were similar and generally manageable regardless of selinexor dose. A greater proportion of patients achieved spleen volume reduction of ≥35% (SVR35) and total symptom score reduction of ≥50% (TSS50) at week 24 in the selinexor 60-mg group (79% and 58%) than the 40-mg group (38% and 25%). Among evaluable patients who received suboptimal ruxolitinib ≤5 mg twice daily in the selinexor 60-mg group, SVR35 was observed in 100% (6/6) and TSS50 in 75% (3/4) of patients. The trial was registered at ClinicalTrials.gov as NCT04562389.

Mutations in calreticulin (CALR) represent the second most common oncogenic driver of myeloproliferative neoplasms. CALR mutations result in the introduction of a neomorphic C-terminal tail that is absent from the normal proteome, which has positioned it as a compelling target for immunotherapeutic intervention. Early studies have demonstrated mutant CALR can elicit T-cell responses, laying the foundation for efforts to exploit this vulnerability through vaccines, antibody-based strategies, and T-cell–based therapies. Here, we summarize the current understanding of normal and mutant CALR biology, discuss progress in developing CALR-directed immunotherapies, and highlight the challenges and opportunities for translating these approaches into the clinic.

Chronic myeloid leukemia in the chronic phase (CML-CP) has undergone therapeutic transformation with the advent of BCR::ABL1 tyrosine kinase inhibitors (TKIs), improving 10-year survival rates from 20% to ∼90%. These outcomes place increasing importance on maintaining quality of life (QoL), which can be compromised by adverse events (AEs) that may lead to decreased adherence or sub-therapeutic doses. Currently, there is no standardized definition of treatment intolerance, and treatment switches are based on individual physician practices. A 13-member expert panel used a validated methodology (RAND/UCLA modified Delphi panel) to develop consensus on a definition of treatment intolerance in CML-CP. Panelists reviewed literature and provided 480 ratings on 96 unique patient scenarios that varied by TKI generation, line, and length of time on TKI treatment, frequency of AE interference on daily life, and TKI management strategies. Ratings were discussed at a meeting. After discussion, panelists agreed on 99% of scenarios. The group defined TKI treatment intolerance as patients whose AEs often interfered with daily activities, leading to TKI modifications. Panelists developed a tool to assess patient intolerance and recommendations for managing TKI therapy in the context of intolerance. Recognizing that treatment intolerance is influenced by laboratory findings, reported symptoms, and how patients experience their treatment, experts agreed on a patient-centered definition of TKI treatment intolerance in CML-CP. This definition represents a step forward in standardizing care for patients with CML-CP by presenting a balanced framework for managing TKI therapy, which will support shared decision-making.