Currently approved therapies for myelofibrosis (MF), such as ruxolitinib (RUX; a JAK inhibitor), are effective in treating symptoms associated with intermediate- or high-risk disease. Nonetheless, disease progression inexorably continues while on therapy, as JAK inhibitors do not modify the underlying mechanisms of MF disease progression. Overexpression of the murine double minute 2 (MDM2) gene in CD34+ cells reduces the activity of the p53 tumor suppressor protein, which allows malignant CD34+ cells to replicate uncontrollably. Navtemadlin (KRT-232) selectively inhibits MDM2, restores the unimpeded state of p53 function, and modulates apoptosis of malignant cells. Therefore, navtemadlin may be a potential candidate to address the need for a disease-modifying therapy in patients with MF.
The goal of this open-label phase 2 study (NCT03662126) was to examine the relationship between biomarkers of MF and clinical outcomes in patients with relapsed/refractory MF (n = 113) who were treated with navtemadlin. Peripheral blood samples were collected at baseline and after 12 and 24 weeks of navtemadlin therapy to assess driver and high-molecular-risk (HMR) mutations and variant allele frequency (VAF) by next-generation sequencing (NGS). Among the 111 evaluable patients for mutations, NGS detected ≥1 driver mutations (n = 108: JAK2, 73%, CALR, 19%, and MPL, 12%), as well as mutations in ≥1 HMR (n = 75), and ≥2 HMR (n = 28) genes. In patients evaluable for VAFs (n = 65), driver allele reduction of ≥20% was observed in 22 (34%) patients, while 19 (29%) patients showed VAF reduction below the limit of detection for both driver and HMR genes. Reduction in driver allele VAF at any time on study significantly correlated with spleen volume response (SVR), which was more likely to be observed with patients who had ≥20% decrease in driver VAFs compared with those with <20% (32% vs 5%, respectively; P = .0072).
Frequencies of circulating CD34+ cells, serum cytokine TNFα levels, and bone marrow biopsies were collected at baseline and week 24 of navtemadlin treatment. Patients with refractory MF treated with navtemadlin demonstrated spleen responses that were correlated with reductions in decreased circulating CD34+ cells, improved bone marrow fibrosis scores, and reduction in serum TNFα. Reductions in circulating CD34+ cells in peripheral blood correlated significantly with best observed SVR. Navtemadlin also reduced serum TNFα with a median best decrease from baseline of 41%, which was also correlated with improved symptom burden as assessed by best observed SVR and total symptom score responses.
Bone marrow fibrosis was assessed by review of bone marrow biopsy samples from 45 evaluable patients at baseline and after 24 weeks of navtemadlin treatment. At baseline, fibrosis scores by grading were ≥1 in 93% of evaluable patients (n = 41) with 70% and 9% of patients having fibrosis scores of 2 (n = 31) and 3 (n = 4), respectively. After navtemadlin treatment, 12 (27%) patients showed improved fibrosis grade by ≥1 score and 23 (51%) patients exhibited stable scores. Among responders, fibrosis scores were improved or stable in 67% of patients with SVR ≥35% and 100% of patients with total symptom score improvement of ≥50%. Fibrosis scores were also associated with improvements in mutation burden with 12 patients exhibiting VAF reductions of ≥20%, while bone marrow assessments showed improvements or stability in fibrosis score in 25% (n = 3) and 57% (n = 8) of patients, respectively.
Taken together, these findings reveal a strong correlation between the reduction in markers of mutation burden and frequencies of CD34+ cells with improved bone marrow fibrosis by formal grading and spleen responses post-navtemadlin therapy. The potential disease-modifying effect of this new agent represents a promising clinical management alternative for patients with MF who are resistant or intolerant to JAK inhibitors.
Source: Vachhani P, Lange A, Delgado RG, et al. Potential disease-modifying activity of navtemadlin (KRT-232), a first-in-class MDM2 inhibitor, correlates with clinical benefits in relapsed/refractory myelofibrosis (MF). American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 3581.